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Cutaneous mastocytosis (CM) is a rare condition in young dogs characterized by multicentric cutaneous proliferation of neoplastic mast cells. Clinical data from 8 dogs that met inclusion criteria (age of onset less than 1.5 years, greater than 3 lesions) were obtained via a standardized survey. Biopsy samples were classified by the Kiupel/Patnaik grading systems and analyzed for c-KIT mutations. The median age of onset was 6 months (range: 2-17 months). Dogs had 5 to more than 50 lesions characterized as nodules, plaques, and papules. Seven dogs were pruritic. Clinical staging in 2 dogs did not reveal visceral involvement. No dogs had systemic illnesses at diagnosis. Histologically, CM was similar to cutaneous mast cell tumor (cMCT). Two dogs had neoplasms classified as high-grade/grade II while 6 dogs had low-grade/grade II neoplasms. No dogs had mutations in c-KIT exons 8 and 11. Treatment included antihistamines (8/8), corticosteroids (7/8), lokivetmab (3/8), and toceranib (1/8). Six dogs were alive with lesions at the end of the study with a median follow-up time of 898 days, while 2 dogs were euthanized. In dogs with high-grade/grade II neoplasms, one continued to develop lesions at 1922 days post-diagnosis, while the other dog was euthanized at 56 days post-diagnosis. One dog was euthanized 621 days post-diagnosis due to rupture of a neoplasm. CM occurs in young dogs and is histologically indistinguishable from cMCT. Current histologic grading systems did not apply uniformly to the dogs of the study and further studies are needed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Allergic dermatoses are common in people and domestic animals. Resultant lesions are routinely biopsied and submitted for histological examination to confirm a diagnosis or rule out diseases with overlapping or atypical clinical features. Diagnostic pathologists and clinicians are often faced with the difficult task of determining whether an allergic reaction pattern is present on both the microscopic and macroscopic levels and correlating histopathologic findings with clinical and historical data to achieve a precise clinical diagnosis. The bulk of the current veterinary literature on allergic dermatoses focuses on atopic dermatitis in dogs, distantly followed by cats, horses, and other animals. The objectives of this review are to demonstrate the key histopathologic and clinical diagnostic features of the various allergy-mediated reaction patterns, and to provide diagnosticians with a practical guide for clinicopathological correlations. Current concepts in the pathophysiology of immediate hypersensitivity reactions, with a focus on atopic dermatitis, are discussed. Points of potential histopathologic overlap between the "classic" allergic reaction pattern and less common inflammatory, predominately eosinophilic, conditions that may mimic this pattern will be discussed with the goal of highlighting the critical need for collaboration between pathologists and clinicians in furthering patient care., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.O.M. provides consultation services and has received research support from Stallergenes Greer Laboratories, North Carolina, USA.

Background: Dermal arteritis of the nasal philtrum (DANP) has been described in large-breed dogs., Objectives: To characterise clinically distinct, discrete fissures of the dorsolateral nasal alae associated with severe bleeding in German shepherd dogs (GSDs)., Animals: Fourteen privately owned GSDs with linear rostrolateral nasal alar fissures and a histopathological diagnosis of nasal vasculopathy., Materials and Methods: Retrospective analysis of medical records and histological slides., Results: Mean age of onset was 6 years. Before biopsy, episodic arteriolar bleeding was noted in 11 of the 14 (79%) dogs. Slide analysis revealed enlarged nasal arterioles with expanded vascular tunics and luminal stenosis beneath ulcers. Histopathological lesions consistent with mucocutaneous pyoderma and/or facial discoid lupus erythematosus were present in 5 of the 14 (36%) dogs. Enlarged arterioles stained blue with Alcian blue and Masson's trichrome stains, consistent with deposition of mucin and collagen, respectively. Immunohistochemical stains (neutrophil myeloperoxidase, IBA1, CD3) were performed. CD3 was negative for all dogs, whilst neutrophil myeloperoxidase and IBA1 occasionally demonstrated intramural neutrophils (3 of the 14 dogs, 21%) or histiocytes (1 of the 14 dogs, 7%) in altered vessels, respectively. All dogs underwent medical management and/or surgical excision. Treatments included tacrolimus, prednisone, ciclosporin-modified, pentoxifylline, antimicrobials and doxycycline/niacinamide. No dogs were treated with antimicrobials alone. For seven dogs with long-term follow-up, treatment response was complete in five (71%) and partial in two (29%), with six of the seven (86%) receiving immunomodulatory treatments to maintain remission., Conclusion and Clinical Relevance: Nasal alar arteriopathy of GSDs shares histopathological changes with DANP. It has characteristic clinical and histopathological features and appears amenable to immunomodulation., (© 2023 ESVD and ACVD.)

Darier disease is caused by heterozygous loss of function variants in the ATP2A2 gene encoding the endoplasmic/sarcoplasmic reticulum Ca 2+ pump ATP2A2. Defective intracellular calcium signaling in the epidermis results in a loss of desmosomal adhesion and the development of characteristic skin lesions. In this study, we investigated a Shih Tzu that developed erythematous papules on the ventrum and, over time, the dorsal neck and a nodule in the right ear canal with secondary ear infection. Histopathologic examination demonstrated discrete foci of acantholysis affecting suprabasal layers of the epidermis. Whole genome sequencing of the affected dog identified a heterozygous missense variant, p.N809H, affecting an evolutionarily conserved amino acid residue of the ATP2A2 protein. The highly characteristic clinical and histopathologic findings together with a plausible variant in the only known functional candidate gene establish the diagnosis of canine Darier disease in the studied dog and highlight the potential of genetic analyses as complementary diagnostic approach in veterinary medicine., (© 2023 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Canine cutaneous epitheliotropic T-cell lymphoma is a neoplasm with heterogeneous clinical and histopathological presentations. Survival times and responses to therapy are variable, and indicators to predict outcomes are lacking. Clinical and histopathological parameters from 176 archival cases from the University of Pennsylvania and University of Bern (2012-2018) were investigated for associations with clinical outcomes. Histopathological evaluation used digitized whole slide images and QuPath software. Cases included 107 female and 69 male dogs from 48 breeds, with a mean age of 10.4 years. Most common clinical signs were erythema ( n = 131), crusting ( n = 108), and scaling ( n = 102). Affected sites were haired skin ( n = 159), lip ( n = 74), nasal planum ( n = 49), and paw pads ( n = 48). The median survival time (MST) was 95 days (1-850). Dogs had 4.26-fold and 2.82-fold longer MST when treated with chemotherapy and prednisone, respectively, than when receiving supportive care. Haired skin involvement (hazard ratio [HR]: 2.039, 95% confidence interval [CI]: 1.180-3.523), erosions/ulcers (HR: 1.871, 95% CI: 1.373-2.548), nodules (HR: 1.496, 95% CI: 1.056-2.118), and crusting (HR: 1.454, 95% CI: 1.061-1.994) were clinical parameters predicting poor outcomes, whereas complete posttherapeutic clinical remission (HR: 0.469, 95% CI: 0.324-0.680) and a stable disease (HR: 0.323, 95% CI: 0.229-0.456) were associated with longer survival. Histopathological features associated with the increased risk of death were extensive infiltration of the panniculus (HR: 2.865, 95% CI: 1.565-4.809), mitotic count ≥7/high-power field (HR: 3.027, 95% CI: 2.065-4.439), cell diameter ≥10.0 µm (HR: 2.078, 95% CI: 1.281-3.372), and nuclear diameter ≥8.3 µm (HR: 3.787, 95% CI: 1.647-8.707).

Epidermolysis bullosa (EB) is a group of blistering disorders that includes several subtypes, classified according to their level of cleavage. Typical clinical signs are blisters and erosions resulting from minimal trauma. The disease has been described in many mammalian species and pathogenic variants in at least 18 different genes have been identified. In the present study, we investigated a Cardigan Welsh Corgi with congenital clinical signs consistent with epidermolysis bullosa. The puppy had blisters and erosions on the paw pads, and the oral mucosa. Histologic examination demonstrated the typical clefting between the dermis and epidermis and confirmed the clinical suspicion. We obtained whole genome sequencing data from the affected puppy and searched for variants in candidate genes known to cause EB. This revealed a heterozygous missense variant, KRT5:p.(E476K), affecting the highly conserved KLLEGE motif of keratin 5. The mutant allele in the affected puppy arose owing to a de novo mutation event as it was absent from both unaffected parents. Knowledge of the functional impact of KRT5 variants in other species together with the demonstration of the de novo mutation event establishes KRT5:p.(E476K) as causative variant for the observed EBS., (© 2022 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

The stratum corneum (SC), the outermost layer of the epidermis, serves a crucial role in maintaining body hydration and protection from environmental insults. When the stratum corneum is injured or when the genetic blueprints are flawed, the body is at risk of dehydration, secondary infections and allergen sensitization. Advancements in veterinary dermatology have revealed a wide gamut of disease from relatively benign to lethal that specifically arise from flawed structural proteins, enzymes or lipids needed to create the corneocytes and lipid bilayers of the SC. Some conditions closely mimic their human counterparts while others are unique to the dog. This review will focus on forms of ichthyosis in the dog., (© 2021 ESVD and ACVD.)

Palisading granulomatous dermatitis and panniculitis is recognized in various cutaneous inflammatory lesions secondary to presumed collagen damage. Cutaneous nodules with a palisading arrangement of histiocytes surrounding foci of collagen degeneration have been clinically termed palisading granuloma in dogs. Study aims were to characterize the cellular infiltrate of canine palisading granuloma and document salient clinical features. Inclusion criteria were met for 36 dogs and encompassed nodular dermal and subcutaneous histiocyte-predominant cellular infiltrates targeting and enveloping collagen fibers/necrotic foci with palisading configurations. Infectious causes were ruled out via standard histochemical stains and/or clinical data. Medical records were reviewed for signalment, clinical features, treatment, outcome, and comorbidities. Immunohistochemistry (IBA1, CD204, E-cadherin) and Masson's trichrome stain were used to assess histiocytic populations and dermal collagen, respectively. The histiocytes had moderate or strong immunolabeling for IBA1 and CD204 in 36/36 dogs (100%) and mild positive immunolabeling for E-cadherin in 3/36 dogs (8%). Alteration of collagen was graded as moderate or strong in 32/36 dogs (89%) and mild in 3/36 dogs (8%). Large breeds predominated with 30/36 dogs (83%) being ≥23 kg. Focal nodules were identified in 31/36 dogs (86%). The head/face were involved in 19/36 dogs (53%) and the extremities in 18/36 dogs (50%). Lesions from the 5/36 dogs (14%) with multiple nodules contained prominent eosinophilic infiltrates. Following excision, there was no evidence of recurrence. In conclusion, palisading granulomas are a distinct, non-neoplastic, histiocyte-predominant inflammatory condition in dogs associated with altered dermal collagen and favorable prognosis.

Background: It has long been speculated that sterile granulomatous dermatitis and lymphadenitis (SGDL) occurs in adult dogs. However, only three published case reports exist., Hypothesis/objectives: To describe clinical presentation, identify breed predispositions, and assess treatment and outcomes of adult dogs with the histopathological diagnosis of SGDL., Animals: Included are 90 dogs with biopsies submitted to a veterinary teaching hospital with a histopathological diagnosis consistent with SGDL, from 2004 to 2018, of which 35 had medical records available for review., Methods: Data were analysed retrospectively from histopathology submission forms, medical records, surveys and telephone calls. Scoring systems were created to aid statistical analysis of outcomes., Results: Havanese dog (P < 0.0001), Australian shepherd dog (P < 0.0001), Irish setter (P < 0.0001), Dachshund (P = 0.0002), bichon frise (P = 0.0003) and Maltese dog (P = 0.004) were significantly over-represented breeds. The median age at onset was 1,292 days (3.54 years). Dogs up to five years of age were significantly over-represented (P < 0.01). Of 35 dogs with medical records available for review, the median treatment duration was 60 days and the median time to remission 28 days. Remission status was not established for five dogs but the remaining 30 dogs reached remission. Nineteen dogs remained in complete remission. Recrudescence occurred in 11 dogs (median follow-up 60 days)., Conclusions and Clinical Importance: This study shows a close parallel in clinical appearance, histopathological results and clinical behaviour, of both adult and juvenile onset SGDL; therefore, SGDL should be considered as a differential diagnosis for dogs of all ages., (© 2019 the European Society of Veterinary Dermatology and the American College of Veterinary Dermatology.)

A single male Rottweiler dog with severe footpad hyperkeratosis starting at an age of eight weeks was investigated. The hyperkeratosis was initially restricted to the footpads. The footpad lesions caused severe discomfort to the dog and had to be trimmed under anesthesia every 8-10 weeks. Histologically, the epidermis showed papillated villous projections of dense keratin in the stratum corneum. Starting at eight months of age, the patient additionally developed signs consistent with atopic dermatitis and recurrent bacterial skin and ear infections. Crusted hyperkeratotic plaques developed at sites of infection. We sequenced the genome of the affected dog and compared the data to 655 control genomes. A search for variants in 32 candidate genes associated with human palmoplantar keratoderma (PPK) revealed a single private protein-changing variant in the affected dog. This was located in the DSG1 gene encoding desmoglein 1. Heterozygous monoallelic DSG1 variants have been reported in human patients with striate palmoplantar keratoderma I (SPPK1), while biallelic DSG1 loss of function variants in humans lead to a more pronounced condition termed severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome. The identified canine variant, DSG1 :c.2541&#95;2545delGGGCT, leads to a frameshift and truncates about 20% of the coding sequence. The affected dog was homozygous for the mutant allele. The comparative data on desmoglein 1 function in humans suggest that the identified DSG1 variant may have caused the footpad hyperkeratosis and predisposition for allergies and skin infections in the affected dog.

Cutaneous lupus erythematosus (CLE) in humans encompasses multiple subtypes that exhibit a wide array of skin lesions and, in some cases, are associated with the development of systemic lupus erythematosus (SLE). We investigated dogs with exfoliative cutaneous lupus erythematosus (ECLE), a dog-specific form of chronic CLE that is inherited as a monogenic autosomal recessive trait. A genome-wide association study (GWAS) with 14 cases and 29 controls confirmed a previously published result that the causative variant maps to chromosome 18. Autozygosity mapping refined the ECLE locus to a 493 kb critical interval. Filtering of whole genome sequence data from two cases against 654 controls revealed a single private protein-changing variant in this critical interval, UNC93B1 :c.1438C>A or p.Pro480Thr. The homozygous mutant genotype was exclusively observed in 23 ECLE affected German Shorthaired Pointers and an ECLE affected Vizsla, but absent from 845 controls. UNC93B1 is a transmembrane protein located in the endoplasmic reticulum and endolysosomes, which is required for correct trafficking of several Toll-like receptors (TLRs). The p.Pro480Thr variant is predicted to affect the C-terminal tail of the UNC93B1 that has recently been shown to restrict TLR7 mediated autoimmunity via an interaction with syndecan binding protein (SDCBP). The functional knowledge on UNC93B1 strongly suggests that p.Pro480Thr is causing ECLE in dogs. These dogs therefore represent an interesting spontaneous model for human lupus erythematosus. Our results warrant further investigations of whether genetic variants affecting the C-terminus of UNC93B1 might be involved in specific subsets of CLE or SLE cases in humans and other species., Competing Interests: The authors declare no conflict of interest.

Background: Canine acute eosinophilic dermatitis with oedema (CAEDE) and sterile neutrophilic dermatosis have overlapping clinical and histopathological features., Hypothesis/objectives: The objective of this study was to identify features that differentiate these entities., Animals: Forty dogs., Methods and Materials: Retrospective case series. Forty cases with diagnoses of either CAEDE and/or sterile neutrophilic dermatosis were included based on histopathological review. Medical records (29 of 40 dogs) were reviewed for clinical findings and historical data. Commercially available immunohistochemical stains for granulocytes and a Luna stain were performed (40 of 40 dogs) to assess the granulocytic infiltrate., Results: Nineteen cases had been previously diagnosed as CAEDE, seven cases had been designated as sterile neutrophilic dermatosis and 14 cases had overlapping features. Based on review and receiver operating characteristic (ROC) curve analysis, 30 cases with >12% eosinophils, enumerated by Luna staining, were diagnosed as eosinophilic dermatitis and oedema. Ten cases were diagnosed as sterile neutrophilic dermatosis. Dogs with CAEDE frequently had gastrointestinal signs (24 of 30;80%) and pruritus (11 of 30;33%). In dogs with sterile neutrophilic dermatosis, five of 10 (50%) had diagnoses of or histories compatible with immune-mediated polyarthropathy., Conclusions and Clinical Importance: In this case series, CAEDE was encountered more frequently than neutrophilic dermatosis and could be distinguished by the eosinophilic infiltrate, aided by a Luna stain. Concurrent arthralgia was more frequently identified with neutrophilic dermatosis. It remains unclear whether CAEDE and sterile neutrophilic dermatosis are separate disease entities or varied manifestations of the same disease., (© 2019 ESVD and ACVD.)

Background: Ischaemic dermatopathy encompasses a poorly understood subset of canine diseases that share similar clinical and histological features. Very little information is currently available regarding population characteristics, progression and outcome., Hypothesis/objectives: This study aimed to describe the clinical features and therapeutic outcomes of ischaemia dermatopathy, excluding familial dermatomyositis, using cases diagnosed by histopathological analysis., Animals: One hundred and seventy-seven cases submitted for histopathological analysis between 2005 and 2016 met inclusion criteria, of which 93 had complete medical records available., Methods and Materials: Both records and pointed surveys were used to retrieve information. Scoring systems were created to subjectively evaluate clinical outcomes and likelihood of a vaccine association., Results: Of 177 cases, toy and miniature poodles, Chihuahuas, Maltese, Yorkshire terriers and Jack Russell terriers were significantly over-represented (P < 0.001). Of the 93 cases for which historical data were obtained, median age at skin biopsy was five years (0.42-13 years) and median body weight was 7.3 kg (range 1.32-50.3 kg). The condition in 45 dogs (48.3%) was found likely to be associated with vaccination. Younger ages (P = 0.011) and higher body weights (P = 0.003) were positively correlated with greater likelihood of vaccination. Body weight <10 kg (P = 0.0045) and older ages (P = 0.0048) were significantly associated with worse outcomes., Conclusions and Clinical Importance: This study provides support for breed predispositions and identifies potential prognostic factors. Importantly, over half of the cases were considered unlikely to be vaccine-associated, demonstrating the need to investigate other underlying causes of this condition., (© 2019 ESVD and ACVD.)

Canine acute eosinophilic dermatitis with edema is an uncommon syndromic disorder in dogs with a unique clinical presentation. Most but not all dogs have a history of gastrointestinal upset preceding or concomitant with skin lesion onset. Affected dogs present with macular to generalized erythema that is most evident on the glabrous skin of the abdomen. Although the etiology is not known, an adverse drug reaction or a systemic type I hypersensitivity reaction may play a role. Some cases can be difficult to distinguish from canine sterile neutrophilic dermatosis due to overlapping clinical criteria and eosinophil degranulation in tissue section., (Copyright © 2018 Elsevier Inc. All rights reserved.)

OBJECTIVE To describe the clinical and histologic features of acute erythroderma in dogs with gastrointestinal disease. DESIGN Retrospective case series. ANIMALS 18 dogs with erythroderma and gastrointestinal disease. PROCEDURES Medical records and biopsy specimens were reviewed. Information collected from medical records included signalment, clinical signs, physical examination and diagnostic test results, treatment, and outcome. The Naranjo algorithm was used to estimate the probability of an adverse drug reaction for each dog. RESULTS All dogs had an acute onset of erythematous macules or generalized erythroderma. Histologic features of skin biopsy specimens had 3 patterns representing a progressive spectrum of inflammation. Most dogs had vomiting (n = 17) and hematochezia (10). Signs of gastrointestinal disease became evident before, after, or concurrent with the onset of skin lesions in 10, 3, and 5 dogs, respectively. Inflammatory bowel disease, pancreatitis, and adverse food reaction were diagnosed in 5, 3, and 3 dogs, respectively. The cause of the gastrointestinal signs was not identified for 8 dogs. Eight dogs had a Naranjo score consistent with a possible adverse drug reaction. Treatment of skin lesions included drug withdrawal (n = 15), antihistamines (16), and corticosteroids (14). Signs of gastrointestinal disease and skin lesions resolved at a mean of 4.6 days and 20.8 days, respectively, after onset. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated acute erythroderma may be associated with > 1 gastrointestinal disease or an adverse drug reaction in some dogs. Recognition of the clinical and histologic features of this syndrome is essential for accurate diagnosis.

Background: Plectin, a large linker protein found in many tissues, acts to connect components of the cytoskeleton to each other. In the epidermis, plectin binds keratin intermediate filaments to hemidesmosomes. A deficiency of plectin in the skin leads to blister formation in the basal layer and the disease epidermolysis bullosa simplex (EBS)., Hypothesis/objectives: To describe a novel blistering disease that arose spontaneously in a litter of puppies., Animals: Two female and one male 20-day-old Eurasier puppies, from a litter of six, were presented for evaluation of failure to thrive and then euthanized due to poor prognosis. The puppies had ulcers on the lips, tongue, nasal planum, paw pads and abdomen., Results: Immunolabelling on frozen skin for basement membrane proteins revealed patchy and weak to absent staining for plectin as compared with strong linear staining in normal dogs. Ultrastructurally, hemidesmosomes were irregularly shaped and had loss of distinction between inner and outer plaques. Pedigree analysis supported an autosomal recessive mode of inheritance. A premature stop codon was discovered in exon 27 of PLEC that resulted in the production of a severely truncated protein., Conclusion: The study describes the first documented spontaneous EBS associated with a PLEC variant in domestic animals., (© 2016 ESVD and ACVD.)

Autosomal recessive congenital ichthyosis in the American bulldog is characterized by generalized scaling and erythema with adherent scale on the glabrous skin. We had previously linked this disorder to NIPAL4, which encodes the protein ichthyin. Sequencing of NIPAL4 revealed a homozygous single base deletion (CanFam3.1 canine reference genome sequence NC&#95;06586.3 g.52737379del), the 157th base (cytosine) in exon 6 of NIPAL4 as the most likely causative variant in affected dogs. This frameshift deletion results in a premature stop codon producing a truncated and defective NIPAL4 (ichthyin) protein of 248 amino acids instead of the wild-type length of 404. Obligate carriers were confirmed to be heterozygous for this variant, and 150 clinically non-affected dogs of other breeds were homozygous for the wild-type gene. Among 800 American bulldogs tested, 34% of clinically healthy dogs were discovered to be heterozygous for the defective allele. More importantly, the development of this canine model of autosomal recessive congenital ichthyosis will provide insight into the development of new treatments across species., Competing Interests: The authors have declared that no competing interests exist.

Background: Although zinc responsive dermatosis is typically a disorder of Arctic breed dogs, this study identifies similar cutaneous lesions on the face and pressure points of Boston terrier dogs., Hypothesis/objectives: To document the clinical and histological features of localized parakeratotic hyperkeratosis of Boston terrier dogs, to determine if the lesions respond to zinc supplementation and to determine whether tissue zinc levels were decreased in affected versus unaffected dogs., Material and Methods: Sixteen Boston terrier dogs with similar gross and histological findings were identified retrospectively from two institutions. Follow-up information for nine dogs from one institution was obtained from referring veterinarians using a questionnaire. Tissue zinc levels were measured from formalin-fixed paraffin-embedded skin biopsy samples of affected and unaffected dogs using inductively coupled plasma mass spectrometry., Results: Mild to severe parakeratotic hyperkeratosis with follicular involvement was present in all 16 cases. Of the nine dogs for which follow-up information was available, five dogs received oral zinc supplementation and four dogs had documented clinical improvement or resolution of dermatological lesions. The median skin zinc levels were not significantly different between affected and unaffected dogs., Conclusions and Clinical Importance: To the best of the authors' knowledge this is the first report of localized parakeratotic hyperkeratosis in Boston terrier dogs, some of which improved with oral zinc supplementation. Prospective studies in Boston terrier dogs are warranted to document potential zinc deficiency (serum and/or tissue levels, pre- and post-treatment) and to objectively assess response to zinc supplementation and other therapies., (© 2016 ESVD and ACVD.)

Background: Noninflammatory alopecia is a frequent problem in dogs. Estrogen-induced alopecia is well described in dogs, with estrogen producing testicular tumors and canine female hyperestrogenism., Objectives: To increase awareness that extensive alopecia in dogs can be caused by exposure to estradiol gel used by owners to treat their postmenopausal symptoms., Animals: Skin biopsies from five dogs with extensive alopecia were examined., Methods: Owners were asked for a thorough case history, including possible exposure to an estradiol gel. Complete blood work and serum chemistry panel analysis were performed to investigate possible underlying causes. Formalin-fixed skin biopsy samples were obtained from lesional skin and histopathology was performed., Results: All owners confirmed the use of a transdermal estradiol gel and close contact with the affected dogs before development of alopecia. Histopathologic examination showed a similar picture in all five dogs. Most hair follicles were predominantly either in kenogen or telogen and hair follicle infundibula showed mild to moderate dilation. Hair regrowth was present in all five dogs after the exposure to the estradiol gel was stopped or minimized. Blood work and serum chemistry panel were within normal limits in all cases. One dog had elevated estradiol concentrations, whereas in another dog estradiol concentrations were within normal limits., Conclusion and Clinical Importance: Alopecia can occur after contact with a transdermal gel used as treatment for postmenopausal symptoms in women. Estradiol gel used by female owners therefore represents a possible cause for noninflammatory alopecia in dogs. Estradiol concentrations are not necessarily elevated in affected dogs., (© 2015 ESVD and ACVD.)

Objective: To describe clinical and histopathologic features of furunculosis in dogs following water immersion or exposure to grooming products., Design: Retrospective case series., Animals: 22 dogs with skin lesions consistent with furunculosis and a history of water immersion or grooming prior to onset. Procedures-Information collected from the medical records of affected dogs included signalment, clinical signs, bathing or grooming procedure, diagnostic tests, treatment, and outcome., Results: German Shepherd Dogs (4/22 [18%]) and Labrador Retrievers (4/22 [18%]) were most commonly affected. Skin lesions, particularly hemorrhagic pustules and crusts, were dorsally located in all dogs and occurred a median of 2 days (range, 1 to 7 days) following water immersion or exposure to grooming products. Twenty (91%) dogs were bathed at home or at a commercial grooming facility prior to lesion onset; 1 dog developed skin lesions following hydrotherapy on an underwater treadmill, and 1 dog developed peri-incisional skin lesions after surgery. Lethargy, signs of neck or back pain, and fever were common clinical signs. Pseudomonas aeruginosa was the most common bacterial isolate from dogs with bacteriologic culture performed on skin samples (10/14). The main histologic feature was acute follicular rupture in the superficial dermis with suppurative inflammation and dermal hemorrhage. Systemic antimicrobial treatment, particularly oral administration of fluoroquinolones, resulted in excellent clinical response in 16 of 22 (73%) dogs., Conclusions and Clinical Relevance: Acute-onset furunculosis with characteristic clinical and histopathologic features in dogs following water immersion or exposure to grooming products was described. Knowledge of the historical and clinical features of this syndrome is essential for accurate diagnosis and appropriate treatment of affected dogs.

Background: Seborrhoeic keratoses (SKs) are common benign epidermal neoplasms in humans and are rarely diagnosed in the dog. These circumscribed, raised, variably pigmented plaques arise in middle aged to older humans, with a focal or multicentric distribution; although common, the underlying cause of these lesions is not known. Although less common in the dog, the lesions are similar and have features that overlap with papillomavirus-associated pigmented viral plaques., Hypothesis/objectives: Seborrhoeic keratoses in the dog are negative for canine papillomavirus., Animals: Eleven cases of SK from a 12 year period were reviewed., Methods: This was a retrospective study of the histopathological findings and case histories. Complete clinical records following collection of the skin biopsy were available in five of 11 cases. Immunohistochemistry was performed for all cases; PCR analysis was carried out for papillomavirus in six cases., Results: Histologically, SKs had an exophytic to mildly endophytic epidermal proliferation, creating a papillomatous to acanthotic, hyperkeratotic, frequently pigmented plaque. There was an absence of hypergranulosis or viral cytopathic effect; PCRs for canine papillomavirus within the formalin-fixed paraffin-embedded skin biopsies were negative. No breed, sex or site predilection was recognized. The mean age at biopsy of the lesions was 8.8 years (range 5-14 years)., Conclusions and Clinical Importance: Histopathological features and negative papillomavirus status distinguish SK as an important differential diagnosis for pigmented viral plaques in dogs., (© 2013 The Authors. Veterinary Dermatology © 2013 ESVD and ACVD.)

A familial form of lupus, termed exfoliative cutaneous lupus erythematosus (ECLE) has been recognized for decades in German shorthaired pointer dogs (GSP). Previous studies were suggestive of autosomal recessive inheritance. The disease presents as a severe dermatitis with age of onset between 16 and 40 weeks, and mirrors cutaneous lupus erythematosus (CLE) in humans. Lameness and, in advanced cases, renal disease may be present. Most affected dogs are euthanized before reaching the age of 4 years. The diagnosis is made by clinical observations and microscopic examination of skin biopsies. In humans, many different forms of CLE exist and various genes and chromosomal locations have been implicated. The large number of potential candidate loci combined with often weak association prevented in depth screening of the dog population thus far. During the course of our studies, we developed a colony of dogs with ECLE as a model for human CLE and the genetic analysis of these dogs confirmed the autosomal recessive mode of inheritance of CLE in GSPs. Using canine patient material, we performed a genome-wide association study (GWAS) to identify the genomic region harboring the gene involved in the development of the disease in GSPs. We identified a SNP allele on canine chromosome 18 that segregated with the disease in the 267 dogs tested. The data generated should allow identification of the mutant gene responsible for this form of cutaneous lupus erythematosus in dogs and assist in the understanding of the development of similar disease in humans.

Cowpox virus (CPXV) infections are a sporadic cause of localized or disseminated skin disease in domestic animals and humans in Europe. Rodents are considered the primary reservoir host for CPXV. Cats can become infected by close contact with rodents and are the most important source of human infections. Recently, public awareness has also been drawn to CPXV infections by an outbreak of rat to human infections in central Europe. In dogs, CPXV infections are rare. Here we report a case of a 5-month-old Rottweiler with a focal nodule on the muzzle. The lesion was fully excised, and recovery was uneventful. The preliminary diagnosis of a CPXV infection was established by the characteristic inclusion bodies on histopathological examination. The diagnosis was confirmed by electron microscopy and polymerase chain reaction (PCR). Sequencing of the PCR product led to a 231 bp sequence of the orthopoxvirus HA gene that was identical to a CPXV strain previously isolated from a cat. This is the third documented case of a canine CPXV infection., (© 2010 The Authors. Journal compilation © 2010 ESVD and ACVD.)

Six German shorthaired pointer dogs (two females, four males) with exfoliative cutaneous lupus erythematosus (ECLE) were studied in a controlled setting until disease progression necessitated euthanasia. During investigations into the heredity of disease, five dogs received immunomodulatory drugs to alleviate clinical signs (lameness, erythema, scaling, erosions/ulcers). One dog served as a control and received only baths and oral fatty acids. Four dogs received ciclosporin (5-10 mg/kg once daily) for 4.5 months to 2 years. Ciclosporin decreased erythema and arthralgia, but did not halt worsening of lesions. Three dogs received hydroxychloroquine (5-10 mg/kg once daily) for 8 weeks, 7 months, and 9 months, respectively, with no side effects. Hydroxychloroquine appeared to slow clinical progression in two dogs on extended treatment and normalized globulin levels in all three dogs while receiving the drug. Four dogs, including the control dog, were euthanized between 1 and 4.5 years of age. Two remaining male dogs received a tumour necrosis factor (TNF)-α antagonist, adalimumab, at 0.5 mg/kg every 2 weeks for 8 weeks then weekly for 8 weeks. Serum TNF-α levels were not significantly altered nor were quantifiable changes seen in skin lesions or lameness. Subsequently, the dogs were maintained on hydroxychloroquine for another year. This is the first study to evaluate the use of a TNF-α inhibitor for canine lupus and the first to address the safety of long-term administration of hydroxychloroquine, albeit in a small number of dogs. The study documents the progression of ECLE and generally poor response to therapy., (© 2010 The Authors. Journal compilation © 2010 ESVD and ACVD.)

A scaling disorder specific to Golden Retriever dogs has been recognized by both dermatologists and pathologists, but to date has not been well characterized. At the University of Pennsylvania's Laboratory of Toxicology and Pathology, 46 cases of ichthyosis were diagnosed histologically in Golden Retriever dogs from January 2004 to January 2007. A total of 22 dogs had skin lesions documented at younger than 1 year of age; 3 dogs between 1 and 2 years of age; 13 dogs developed lesions at older than 2 years; and the time of onset was unknown for 8 dogs. A total of 25 dogs were female, and 21 were male. All dogs had strikingly similar histopathologic changes that consisted of mild to moderate laminar orthokeratotic hyperkeratosis with an absence of epidermal hyperplasia and dermal inflammation. Ultrastructural analysis using a ruthenium tetroxide fixation method was performed on punch biopsy samples from 5 dogs and compared with 2 control dogs (1 clinically and histologically normal sibling of an affected dog and 1 Cairn Terrier). All affected dogs had retained and convoluted membranes with crystalline structures in the stratum corneum. Scattered keratinocytes in the granular cell layer had prominent, clear, membrane-bound, cytoplasmic vacuoles. Pedigree analysis of 14 dogs was compatible with autosomal recessive inheritance, but incomplete dominance could not be ruled out. This unique hyperkeratotic/scaling disorder in Golden Retrievers has distinctive clinical, histologic, and ultrastructural features, which are consistent with a primary cornification defect.

Lethal acrodermatitis (LAD) is a genetic disease affecting bull terrier dogs. The phenotype is similar to that for acrodermatitis enteropathica in humans, but is currently without treatment. The purpose of the research presented here is to determine the biochemical defects associated with LAD using proteomic methodologies. Two affected (male and female) and one unaffected (male) bull terrier pups were euthanized at 14 weeks of age, their livers dissected and prepared for two-dimensional gel electrophoresis (2DE) and densitometry. Approximately 200 protein spots were observed. The density of the spots within each gel was normalized to the total spot volume of the gel; only those soluble liver protein spots that were consistently different in both of the livers of the affected pups compared to the unaffected pup were excised manually and submitted for MALDI mass spectrometry. Thirteen proteins were identified as differentially expressed in the affected, compared to the unaffected, pups. The proteins were involved in numerous cellular physiological functions, including chaperones, calcium binding, and energy metabolism, as well as being associated with the inflammatory response. Of note were haptoglobin, glutamine synthetase, prohibitin and keratin 10 which exhibited at least a fourfold level of differential expression. These data represent the first proteomic analysis of this mutation. The differentially expressed proteins that were identified may be key in understanding the etiology of LAD, and may lead to diagnostic tools for its identification within the bull terrier population.

Thirty-two cases of canine cutaneous histiocytosis were retrospectively evaluated. Median age at onset was 4 years. Lesions included nodules and plaques affecting the head/face, trunk and limbs, and erythema, swelling and depigmentation of the nasal planum/nares. Systemic involvement was not ruled out in all cases. All dogs had complete resolution of dermatological lesions after initial treatment (median 45 days). Initial treatment included prednisone +/- antibiotics (12 of 32 dogs), prednisone and tetracycline/niacinamide (four of 32), prednisone and azathioprine (three of 32), tetracycline/niacinamide +/- vitamin E/essential fatty acids (six of 32), antibiotics +/- antihistamines (three of 32), cyclosporine and ketoconazole (one of 32), topical therapy (two of 32), and no treatment (one of 32). Seventeen dogs received maintenance therapy which consisted of tetracycline/niacinamide +/- vitamin E/essential fatty acids (12 of 17), cyclosporine/ketoconazole (two to three times a week) (two of 17), azathioprine daily (one of 17), prednisone/azathioprine (two times a week) (one of 17), and prednisone daily (one of 17). Median follow up was 25 months. Nine dogs had a recurrence of cutaneous histiocytosis (median days to recurrence 130 days), with seven of nine having more than one recurrence. At study completion, six dogs were deceased (no lesions at the time of death) and 26 of 32 were alive with no lesions. Ten of 26 dogs were on maintenance treatment (eight tetracycline/niacinamide, one azathioprine, one vitamin E). Previous dermatological disease and season had no detectable influence on recurrence. Recurrence was significantly more likely in dogs with nasal planum/nares lesions than dogs without these lesions. Tetracycline/niacinamide was an effective treatment option for dogs in this study population.

Background: Histiocytic sarcoma is an aggressive neoplasm of dendritic cells that carries a grave prognosis. The efficacy of chemotherapy against this disease is unknown. The purpose of this study was to determine the efficacy of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in dogs with incompletely resected or metastatic histiocytic sarcoma, to describe the clinical characteristics of these dogs, and to identify factors affecting prognosis., Hypothesis: Our hypothesis is that CCNU has activity against canine histiocytic sarcoma and can improve survival in dogs with advanced disease., Animals: Included in analysis are dogs diagnosed with histiocytic sarcoma who had gross measurable or residual microscopic disease and who received CCNU., Methods: A multi-institutional, retrospective, single-arm cohort study was conducted. Available biopsy samples were tested with an antibody against CD18 when possible to confirm the diagnosis of histiocytic sarcoma., Results: Fifty-nine dogs were treated at 8 institutions. Twenty-three tumor specimens were confirmed to be CD18 positive. Treatment with CCNU at 60 to 90 mg/m2 resulted in an overall response rate of 46% in the 56 dogs with gross measurable disease. All 3 dogs with minimal residual disease experienced tumor relapse but lived 433 days or more after starting CCNU. The median survival of all 59 dogs was 106 days. Thrombocytopenia (< 100,000 platelets/microL) and hypoalbuminemia were found to be negatively associated with prognosis and were predictive of < 1 month survival., Conclusions and Clinical Importance: Results suggest that CCNU is active against canine histiocytic sarcoma and may be useful in the treatment of dogs without negative prognostic factors.

The medical records and histopathological sections of 29 dogs diagnosed with a unique eosinophilic dermatitis resembling Wells' syndrome were reviewed in an attempt to elucidate the pathogenesis of this syndrome. The medical records were reviewed for information on dermatological lesion appearance, systemic signs in other organ systems, clinical analyte abnormalities, and drug therapy. Histological sections of dogs with moderate to severe eosinophilic dermatitis without folliculitis and furunculosis were reviewed and evaluated for the presence of collagen flame figures. Three categories of patients were found. Category 1 consisted of 17 dogs treated for vomiting and/or diarrhoea (often haematochezia or haematemesis) prior (mean: 4.6 days) to the onset of skin lesions. Fourteen category 1 dogs had erythematous lesions (macules, papules or plaques) that were most pronounced on the abdomen. Sixteen of the 17 dogs received multiple classes of drugs, and 59% were hypoalbuminemic. Category 2 consisted of five dogs that had skin lesions and gastrointestinal signs at presentation and four of these dogs were hypoalbuminemic. Category 3 included seven dogs without enteric illness. A positive drug score was found in six category 1 dogs and one each from categories 2 and 3. Eighteen cases had eosinophilic dermatitis without flame figures, seven cases had early flame figures and four had well-developed flame figures. These changes did not correlate with the categories of clinical presentation. More than 50% of the dogs developed eosinophilic dermatitis following treatment for severe gastrointestinal disease. The authors propose that this represents a unique syndrome that may have causal drug association.

Canine X-linked severe combined immunodeficiency (XSCID) is due to mutations in the common gamma chain (gammac) gene and is identical clinically and immunologically to human XSCID, making it a true homologue of the human disease. Bone marrow-transplanted (BMT) XSCID dogs not only engraft donor T cells and reconstitute normal T-cell function but, in contrast to the majority of transplanted human XSCID patients, also engraft donor B cells and reconstitute normal humoral immune function. Shortly after our initial report of successful BMT of XSCID dogs, it soon became evident that transplanted XSCID dogs developed late-onset severe chronic cutaneous infections containing a newly described canine papillomavirus. This is analogous to the late-onset cutaneous papillomavirus infection recently described for human XSCID patients following BMT. Of 24 transplanted XSCID dogs followed for at least 1 year post-BMT, 71% developed chronic canine papillomavirus infection. Six of the transplanted dogs that developed cutaneous papillomas were maintained for >3 1/2 years post-BMT for use as breeders. Four of these six dogs (67%) developed invasive squamous cell carcinoma (SCC), with three of the dogs (75%) eventually developing metastatic SCC, an extremely rare consequence of SCC in the dog. This finding raises the question of whether SCC will develop in transplanted human XSCID patients later in life. Canine XSCID therefore provides an ideal animal model with which to study the role of the gammac-dependent signaling pathway in the response to papillomavirus infections and the progression of these viral infections to metastatic SCC.

Four Large Münsterländer cross-bred dogs affected with black hair follicular dysplasia (BHFD) and one unaffected control littermate were observed, and skin was sampled weekly over the first 19 weeks of life. Affected dogs were born with silvery grey hair, a consequence of melanin clumping in the hair shafts. Hair bulb melanocytes were densely pigmented, and contained abundant stage IV melanosomes but adjacent matrix keratinocytes lacked melanosomes. Melanin clumping was not prominent in epidermal melanocytes in the haired skin but occurred in the foot pads. Follicular changes progressed from bulbar clumping, clumping in the isthmus/infundibulum and finally to dysplastic hair shafts. Alopecia developed progressively in pigmented areas. Silver-grey hair, melanin clumping, accumulation of stage IV melanosomes within melanocytes and insufficient melanin transfer to adjacent keratinocytes are also classic features of human Griscelli syndrome. The underlying cause in Griscelli syndrome is a defect of melanocytic intracellular transport proteins leading to inadequate and disorganized melanosome transfer to keratinocytes with resultant melanin clumping. In view of the correlation in the phenotype, histology and ultrastructure between both disorders, a defect in intracellular melanosome transport is postulated as the pathogenic mechanism in BHFD.

As in many human patients with X-linked hypohidrotic ectodermal dysplasia (XHED), XHED dogs are at an increased risk for pulmonary disorders. Localized immune system defects had been suspected previously in affected dogs because of frequent infections and unexpected deaths due to opportunistic respiratory tract infections. Experiments were designed to examine systemic and localized humoral and cellular responses, development and function of T cells, and thymic morphology. All dogs used in these experiments were clinically healthy at the time of examination and their immune responses were compared to normal littermates. Serum immunoglobulin concentrations differed somewhat between normal dogs and dogs affected with XHED but they were all within normal ranges. The XHED dogs responded appropriately to vaccination with tetanus toxoid suggesting normal systemic B and plasma cell function. Thymic morphology was compared between normal and affected dogs and T cells were assessed for functionality. Numbers and phenotypes of T and B cells in blood and thymus of affected dogs were within normal limits suggesting normal development of T cells. Cytotoxic and phagocytic ability of macrophages and neutrophils was also normal in affected dogs. In contrast, the secretory IgA concentrations found in affected dogs were significantly higher than in normal dogs, while lacrimal secretions were significantly decreased. These results suggest a compensatory mechanism for secretory IgA, so that the total amount equals that in normal dogs. The results presented in this study indicate that the XHED dogs have a relatively intact immune system and suggest that the same is true for humans with the homologous form of XHED.

Ten Chesapeake Bay retriever (CBRS) dogs with hair loss were recruited in collaboration with the American Chesapeake Club. All dogs had nonpruritic, noninflammatory, regionalized hair loss affecting the same areas of the body in male and female dogs. Hormonal investigations showed increased adrenal and sex steroid concentration in seven cases. Histopathology revealed follicular hyperkeratosis and plugging, follicular atrophy, and occasional melanin clumping with malformed hair shafts. This study suggests that hair loss in CBRS is a breed syndrome in which young adult dogs have hair loss characterized by unusual histological features and abnormal steroid production. A familial predisposition seems likely and selective breeding might reduce the occurrence of this condition.

Canine discoid lupus erythematosus (DLE) and mucocutaneous pyoderma (MCP) have overlapping clinical and histopathological changes, often making diagnosis difficult. Histopathological features of 27 nasal planum biopsies were scored to determine whether DLE and MCP were histopathologically distinguishable. Long-term follow-up, enabling assessment of clinical diagnoses, was available on 15 cases; 11/15 cases were immunomodulatory responsive (ImR) and 4/15 were antibiotic responsive (AbR). Clinical diagnosis, determined by response to treatment for 15/27 cases, was not predictable based on scoring of histopathological features. Distinct histopathological patterns were observed: 2/11 ImR cases had a lymphocyte-rich interface dermatitis. All other cases had the same histopathological changes: a band-like diffuse superficial plasmacytic to lymphoplasmacytic dermatitis +/- focal basal cell damage, but different clinical diagnoses (4/4 AbR, 9/11 ImR). German shepherd dogs/crosses were over-represented (44.4% of the cases) and tended to have more multifocal lesions (41.7% vs. 26.7% of all other breeds). Longer duration of disease was associated with a preponderance of plasmacytic infiltrate (P = 0.026).

A 7-year-old spayed female Labrador Retriever was referred because of progressive swelling and bruising of the neck, hemothorax, a possible mediastinal mass, and stridor. At the time of admission, the dog was recumbent, mentally dull, tachycardic, and hypothermic. Fluid therapy with hydroxyethyl starch and a balanced electrolyte solution was administered because of presumed hypovolemic shock secondary to hemorrhage; multiple units of packed RBCs and fresh frozen plasma were also administered. On the basis of the computed tomographic images, extensive subcutaneous, subfascial, and cranial mediastinal hemorrhage; hemothorax; prescapular lymphadenopathy; and a contrast-enhancing mass in the left cranioventral aspect of the neck were diagnosed. Exploratory surgery of the neck was performed. All subcutaneous structures were encased in a large blood clot. During dissection of the clot, pulsatile bleeding was observed just caudal to and to the left of the larynx; ligation of the left common carotid artery resulted in immediate cessation of the pulsatile bleeding. Further surgical exploration revealed a 2.5 x 2.5-cm mass adhered to the left common carotid artery at the level of the branching to the left cranial thyroid artery. The mass was removed; the histologic diagnosis was thyroid carcinoma. Three weeks after surgery, treatment with a combination of radiation and chemotherapy (doxorubicin and carboplatin) was begun. Thirteen months after surgery, the dog continued to be free from clinical signs of disease.

An eight-year-old, spayed female Labrador retriever was presented for evaluation of left thoracic limb lameness. Radiographs of the left elbow revealed mineralization of the soft tissues surrounding the joint, with no evidence of periarticular bony lysis. Biopsy of the synovial tissues of the left radiohumeral joint yielded a diagnosis of osteosarcoma (OSA). The dog was treated with palliative radiotherapy, piroxicam, and carboplatin chemotherapy, which resulted in excellent pain control for approximately eight months. Amputation of the affected limb was then performed. Six months later, the dog developed multiple subcutaneous OSA metastases, and the dog was euthanized 15 months after diagnosis due to refractory vomiting. This report documents the first known case of primary OSA of the synovium in any species.

Forty-one dogs with mast cell tumors (MCTs) were treated with oral prednisone and injectable vinblastine (VBL), both in the adjuvant setting (23 dogs) and in dogs with gross disease (18 dogs). Adverse effects were noted in 20% (8/41) of the patients, usually after the 1st dose of VBL. Adverse effects were considered mild in 6, and severe, necessitating treatment discontinuation, in 2 (5%). Overall response rate in the evaluable dogs with gross disease was 47% (7/15), consisting of 5 complete responses and 2 partial responses. Median response duration was 154 days (24 to >645 days). As adjuvant therapy to incomplete surgical resection, prednisone and VBL conferred a 57% 1- and 2-year disease-free rate. Median survival time (MST) for the entire patient population was not reached with a median follow-up of 573 days; however, the MST for dogs with grade III MCT was 331 days, with 45% of dogs alive at 1 and 2 years. This is an apparent improvement over historical survival data employing surgery alone. Upon univariate analysis, significant prognostic factors (P < .05) for survival included presence of a locally recurrent tumor, presence of gross disease, argyrophilic nucleolar organizer region frequency, lymph node status, histologic grade, previous chemotherapy, and ulceration of the tumor. Similar criteria were significant when analyzed for time to treatment failure. Response to therapy was also predictive of survival in the gross disease group. Upon multivariate analysis, histologic grade (P = .012) and presence of a locally recurrent tumor (P < .001) were significant factors for survival.

Gastrinomas in dogs are difficult to diagnose, localise and treat. In humans, somatostatin analogues have improved localisation and treatment of gastrinomas. The somatostatin analogues pentetreotide and octreotide were evaluated for the detection and treatment of gastrinoma in a dog. 111indium-pentetreotide scintigraphy revealed multiple areas of activity in the patient's mid-ventral abdomen which were consistent with masses in the pancreas and liver at laparotomy. Immunohistochemistry, electron microscopy and binding of 125I-[Tyr3]-octreotide in vitro confirmed the lesion as a gastrinoma which expressed somatostatin receptors. Octreotide at doses of 2, 4 and 8 micrograms/kg caused transient decreases in circulating gastrin. Plasma somatostatin peaked at one hour after octreotide and was still detectable at four and six hours after administration of octreotide. Combination therapy with famotidine, omeprazole, sucralfate and increasing doses of octreotide allowed patient survival for 14 months.