Cutaneous lymphoma in a Dachshund

An 11-year-old, 8.6 kg castrated male miniature Dachshund dog was referred for evaluation of acute onset marked pruritus and dermatitis of the face and trunk of 3-month’s duration. The dog had no history of pruritus or skin disease before this episode. He was initially treated with oclacitinib (Apoquel; Zoetis, Kalamazoo, Michigan, USA), 0.61 mg/kg body weight (BW), PO, q24h for 2 wk with no resolution of clinical signs. Cyclosporine (Atopica; Elanco, Greenfield, Indiana, USA), 5.6 mg/kg BW, PO, q24h was then initiated. When the clinical signs did not abate following another 2 wk of therapy, serum allergy testing was performed, and allergen-specific immunotherapy was started.

On presentation, the dog was quiet but responsive with normal temperature and slightly elevated heart (140 beats/min) and respiration (50 breaths/min) rates. No peripheral lymphadenomegaly was noted on palpation. No abnormalities were noted on palpation of the abdomen. Except for mild lenticular sclerosis affecting both eyes, the general physical examination was unremarkable.

Dermatologic examination revealed moderate alopecia with complete depigmentation and mild crusting of the periocular region bilaterally. The nasal planum and surrounding mucocutaneous junctions also had hypopigmentation to complete depigmentation (Figure 1). The normal “cobblestone” architecture of the nasal planum was effaced, leaving a smooth, shiny appearance (Figure 1). The hair coat was generally dull with multifocal areas of marked scaling and occasional crusts (Figure 2). The oral mucosa was markedly erythematous with mild erosions on the buccal surface. The surrounding lip margins were completely depigmented and thickened in appearance (Figure 3). Marked erythema was noted on the prepuce as well as the perianal region. In addition, mild erosions were noted perianally. There was complete depigmentation of the margins of the metacarpal, metarsal, and complete to partial depigmentation of digital footpads (Figure 4).

Figure 1.

Hypo- to complete depigmentation of the nasal planum and mucocutaneous junctions. The nasal planum also lacks a normal architecture.

Figure 2.

Focal area of marked non-adherent scale/crust on the dorsum.

Figure 3.

Lip margins are completely depigmented and thickened. The oral mucosa is markedly erythematous. Note the mild irregular erosions on the buccal mucosa.

Figure 4.

Complete depigmentation of the margins of the metacarpal and partial to complete depigmentation of digital and carpal footpads of the right thoracic limb paw.

Given the history of pruritus, in addition to the distribution and appearance of cutaneous lesions, a differential diagnosis included: allergic dermatitis with secondary bacterial folliculitis and mucocutaneous pyoderma. An ectoparasite infestation such as sarcoptic mange was also a consideration for marked pruritus. Differential diagnoses for loss of pigment of the mucocutaneous junctions included: cutaneous lupus erythematosus and cutaneous lymphoma.

Deep skin scrapings did not reveal the presence of Demodex. A Wood’s lamp examination did not reveal any fluorescence on the hair coat. Superficial acetate tape cytology yielded 3 to 10 pairs of coccoid bacteria per oil immersion field (1000× magnification) with variable degenerate neutrophils, consistent with a bacterial infection. A complete blood (cell) count (CBC) showed mild non-regenerative anemia, whereas a serum biochemistry panel was unremarkable, except for a mild elevation in alkaline phosphatase (110 IU/L; reference range: 14 to 91 IU/L).

For more definitive evidence, 3 affected sites were selected for biopsy; 6-mm punch biopsies were collected from affected skin adjacent to the nasal planum, the mid-dorsal thoracic region, and the inguinal region and fixed in 10% buffered formalin, embedded in paraffin, and reviewed by a Board-certified pathologist.

Hematoxylin and eosin-stained sections examined histologically had similarities in all samples submitted. The epidermis, follicular walls, glandular epithelium, and superficial dermis were all infiltrated by neoplastic lymphocytes. The neoplastic cells had a distinct border with scant amounts of cytoplasm containing a round to indented, hyperchromatic nucleus and no distinguishable nucleoli. There was mild anisocytosis and anisokaryosis with 5 mitotic figures per 10 high power fields (HPF; 400× magnification). Small numbers of small lymphocytes and occasional plasma cells and mast cells were admixed in the dermis. There were multifocal areas of orthokeratotic and parakeratotic hyperkeratosis with multifocal serocellular crusting. A few discrete pyogranulomas were noted in the epidermis, consistent with Pautrier’s microabscesses.

Immunohistochemistry for CD3 revealed moderate cytoplasmic expression throughout most of the neoplastic population. Immunohistochemistry for CD79a failed to stain the neoplastic population. Based on the clinical findings as well as the results of the histopathologic review, a diagnosis of cutaneous lymphoma was made.

Due to the poor prognosis associated with the diagnosis, the owner declined referral to a veterinary oncologist and elected for conservative palliative treatment at home. Additional diagnostic tests such as thoracic radiographs and abdominal ultrasound were also declined. A 4-week course of cefpodoxime proxetil (Simplicef; Zoetis), 5.8 mg/kg BW, PO, q24h was prescribed for the secondary bacterial infection, as well as a trial of prednisolone (Prednis-Tab; LLOYD, Shenendoah, Iowa, USA), 0.87 mg/kg BW, PO, q24h. Unfortunately, after 2 wk, the owner did not note any decrease in the dog’s discomfort level. Given the refractory nature of the dog’s pruritus as well as progression in severity of skin lesions, the owner opted for euthanasia.

Canine cutaneous lymphoma is also known as epitheliotropic lymphoma or cutaneous T-cell lymphoma. Earlier literature may use the borrowed human terminology, mycosis fungoides, to describe this disease. This cutaneous neoplasm is uncommon, has no sex predilections, and typically affects older individuals. Prior reports suggested that boxers and cocker spaniels are predisposed breeds in contrast to a more recent larger-scale retrospective study that did not detect any significant breed predilections (1–3).

In this dog, histopathologic findings were confirmatory of cutaneous lymphoma. Several differential diagnoses were considered based on the presenting complaint and examination findings. The history of marked pruritus did not preclude refractory allergic dermatitis with secondary bacterial folliculitis and mucocutaneous pyoderma; however, it is unusual for allergic dermatitis to manifest for the first time this late in life. Of the 3 most common canine hypersensitivity reactions, cutaneous adverse food reaction would be the most likely to occur in older individuals. Sarcoptic mange infestations can also present more acutely and with intense pruritus. A consideration for hypopigmentation of the nasal planum and mucocutaneous junctions, and oral erosions was cutaneous lupus erythematosus. However, it is unusual for dogs affected with cutaneous lupus erythematosus to exhibit concurrent marked pruritus.

Overall, the signalment, late onset of acute pruritic dermatitis and progressive clinical lesions, including the coexistence of both mucocutaneous and nasal planum depigmentation, multifocal erythroderma with scaling and crusting, marked inflammation of the oral mucosa, and depigmentation of the footpad margins led to cutaneous lymphoma being the top differential diagnosis in this case.

Cutaneous lymphoma by nature can be difficult for the practitioner to recognize, as the dermatologic features on clinical presentation can be quite pleomorphic, often overlapping with more common dermatologic conditions. The clinical heterogeneity of this disease lends itself to be described as a “great pretender.” Lesions can appear as: i) generalized erythroderma with scaling and crusting and pruritus; ii) erythema with depigmentation, erosions, and ulcerations of the mucocutaneous regions; iii) single or multiple plaques or nodules; or iv) proliferative infiltration causing erosions and ulceration of the oral cavity. The footpads may also be hyperkeratotic or depigmented (4,5). One case report describes vesiculobullous lesions, previously not documented in dogs but recognized as a clinical presentation of human cutaneous lymphoma (6). If neoplastic cells are present in peripheral blood, this is termed Sézary syndrome. Three clinical stages are commonly recognized in humans: patch, plaque, and tumor. However, in dogs, classifying lesions into these clinical phases is not useful because of frequent overlap of lesions and lack of prognostic value (1,7). Depending on what lesions are noted at presentation, this condition may easily be mistaken for various dermatologic conditions, such as allergic dermatitis, ectoparasite infestation, immune-mediated disease, cutaneous or mucocutaneous infection, or keratinization disorders.

To avoid delays in achieving a definitive diagnosis, any skin disease that does not respond to appropriate therapy as expected warrants biopsy for histopathology, especially in an older individual. Similarly, if there is a history of late onset of pruritic skin disease with either no prior history of skin disease or a history of allergic skin disease that suddenly changes either in degree of pruritus or distribution or appearance of skin lesions, cutaneous lymphoma should be a differential diagnosis. An association between allergic dermatitis and the development of cutaneous lymphoma has been theorized; however, a proven association has yet to be established (8).

In most cases, histopathology will provide a definitive diagnosis. Monomorphic, atypical neoplastic lymphocytes have marked tropism for the epidermal and mucosal epithelium as well as the adnexal structures. These cells may also be in aggregates in the upper layers of the epidermis, termed Pautrier’s microabscesses (5,9). Occasionally, early lesions are infiltrated with other cell types, creating considerable inflammation. This influx of inflammatory cells can be confounding to pathologists, often sharing features with cutaneous reactive histocytosis, and preventing an accurate diagnosis (9,10). Repeat biopsies may be required with progression of disease for a more accurate assessment. Additional tests such as immunohistochemistry to confirm T-cell origin, polymerase chain reaction for antigen receptor rearrangement (PARR) to detect clonality of the cell population, or flow cytometry may also be useful for confirmation or support of diagnosis.

Cutaneous lymphoma has a very poor prognosis, with survival rates reportedly ranging from several months to 2 y (2,7,9). The survival time of dogs with cutaneous lesions may be shorter than those presenting solely with mucocutaneous lesions (1). Death by disease dissemination is rare. More likely, affected dogs are euthanized because of severe non-resolving or recurrent secondary infection and unmanageable pruritus (2,7,9).

To date, no effective therapies have been identified. In cases that present with solitary nodules, surgical excision can result in long-term remission; however, frequent monitoring for local recurrence is recommended (4). Any secondary infections should be addressed. Regular use of topical antiseptic therapy can prevent recurrence of infections. Palliation of pruritus is usually achieved with corticosteroids. Oclacitinib and cyclosporine A should be avoided, as both are contraindicated for use in patients with neoplasia. Malignant T-cells in humans with cutaneous lymphoma produce IL-31 (11) a pruritogenic cytokine known to cause pruritus in dogs with atopic dermatitis. Although the role of IL-31 production in dogs with neoplasia has not yet been elucidated, many dermatologists are already using lokivetmab (Cytopoint, Zoetis) to manage pruritus associated with cutaneous lymphoma. It was reported that IL-31 was not elevated in dogs with non-pruritic mast cell tumors, multicentric lymphoma, and cutaneous epitheliotropic and non-epitheliotropic lymphoma (12). Further studies are needed to evaluate the role of IL-31 in dogs with pruritic cutaneous neoplasms.

A standard of care protocol has not been established for canine cutaneous lymphoma. Among many treatment options suggested, the most common chemotherapeutic agent recommended is lomustine (CCNU) as a single-agent or as part of combination therapy (2). However, limited reports with small sample sizes have made it difficult to comment on the true efficacy in achieving complete remission using lomustine-based protocols. A more recent report suggested that despite higher complete remission rates than with other therapies, the median survival time is still only about 6 mo (13).

Limited studies have evaluated linoleic acid in the form of safflower oil, oral retinoids, PEGylated L-asparaginase, PEGylated doxorubricin, masitinib, rabacfosidine, dacarbazine, and electron beam therapy (2,4,13). The median survival for dogs treated with isotretinoin and/or etretinate was the longest at 11 mo (14). One case report describes 2 dogs treated with isotretinoin in conjunction with interferon-a, achieving complete remission with no recurrence or metastasis of disease after 10- and 27-mo, respectively (15). However, retinoids and other vitamin A derivatives have been associated with neuropsychiatric signs, such as depression, aggression, and suicide in humans. Consequently, it is very difficult for veterinary practitioners to acquire these medications. Larger scale clinical trials are needed to better evaluate the use of other therapeutic options in the treatment of cutaneous lymphoma. Other therapies such as histone deacetylase (HDAC) inhibitors have been used to inhibit tumor growth in humans with CD8+ epidermotropic T-cell lymphoma have promise but are likely cost-prohibitive in veterinary patients (2).