Cutaneous T-cell epitheliotropic lymphoma

Cutaneous epitheliotropic lymphoma is an uncommon neoplasia of dogs and cats representing < 1% of cutaneous tumors (1). This form is characterized by infiltration of neoplastic T-lymphocytes with a tropism for the epidermis and adnexal structures (2,3). This type of lymphoma encompasses a spectrum of diseases including Mycosis fungoides, Sezary syndrome, and Pagetoid reticulosis (4).

Pathogenesis

Cutaneous epitheliotropic lymphoma is usually of T-lymphocyte origin with an unknown etiology. The disease in dogs resembles the disease in humans and using criteria from the human literature, can be divided into 3 sub-forms: Mycosis fungoides (MF), Pagetoid reticulosis (PR), and Sezary syndrome (SS) (5). Pagetoid reticulosis and Sezary syndrome are rarely documented in the veterinary literature (2,6). Disease in humans versus dogs is immunophenotypically different. Most canine cases express CD3 and CD8 surface markers, whereas in humans CD3 and CD4 surface markers are expressed (4–6). In dogs this is generally a disease of CD8+ cytotoxic T-cells (4). Lymphocyte epitheliotropism is present throughout the canine spectrum of cutaneous T-cell epitheliotropic lymphoma (CTCL). In humans, this epitheliotropism is absent in advanced stages of MF (6). All affected cats with this disease were serologically FeLV negative (4). However, tumor DNA extracted from a cat with CTCL was positive on PCR for FeLV provirus, suggesting a potential link (7).

One study indicated that individuals with a history of atopic dermatitis were 12 times more likely to develop CTCL (8). Chronic activation and proliferation of T-lymphocytes can be caused by environmental allergens and there is suggestion that clonal expansion of these activated lymphocytes could contribute to development of CTCL (5).

Clinical presentation

In dogs, the clinical presentation is highly variable. In fact, this type of neoplasia is often referred to as “the great mimicker” and is often misdiagnosed. Some studies detected no breed predisposition, but others noted that English cocker spaniels and boxers may be predisposed (2). The average age of onset is 9 to 12 y (4,5).

It is well-documented and understood that most dogs with this type of lymphoma are intensely pruritic. However, in 1 retrospective study, only 40% of the dogs were observed to be pruritic (2).

Mycosis fungoides has 4 main clinical presentations: pruritic erythema and scaling, mucocutaneous erythema, infiltration, depigmentation and ulceration, solitary or multiple plaques or nodules, and infiltrative and ulcerative oral mucosal disease (2,4,5) (Figure 1 A). In a study by Fontaine et al (2), diffuse erythema was noted in 86.6% of cases, scaling in 60%, and focal hypopigmentation in 50% of cases. Footpads may also be hyperkeratotic, depigmented, or ulcerated (3,4). Rarely, dogs can have lesions restricted to the lips, nasal planum, nasal philtrum, and anus (4,9) (Figure 1 B). Systemic signs of illness and lymphadenopathy may be present along with cutaneous signs. Mucocutaneous involvement occurs in up to 50% of patients (2).

Figure 1.

Cutaneous T-cell epitheliotropic lymphoma in dogs, affecting the trunk (A) and the face (B).

In cats with CTCL, lesions often start as well-circumscribed, annular regions of alopecia with erythema and scaling (4). Mycosis fungoides has also developed within lesions of alopecia mucinosa in cats (4).

Sezary syndrome is defined as cutaneous lesions with Sezary cells in the skin and the blood. Sezary cells are lymphocytes with hyper-convoluted nuclei with finger-like projections that produce a cerebriform appearance (3,4). Dogs with this syndrome may also have erythroderma, pruritus, and a peripheral lymphadenopathy (4). This advanced stage of disease with lymphadenopathy or circulating malignant cells in the blood is relatively uncommon (6). Lymph node enlargement was only documented in approximately 20% of cases (2).

Pagetoid reticulosis has 2 forms: localized lesions known as the Woringer-Kopp form and generalized lesions known as the Ketron-Goodman form. The first form has a benign clinical course and the latter a progressive clinical course (9). The Ketron-Goodman form has erythematous papules, plaques, erosions, ulcers at mucocutaneous junctions, oral cavity, paws, and abdomen (4).

Bloodwork will be unremarkable in most cases of CTCL unless Sezary syndrome is present (2,4). Metastasis is uncommon, although there are rare reports in the literature of disseminated disease in the bone marrow, lymph nodes, and spleen as well as other organs (10).

Diagnosis

Cytology taken from lesional skin, either impression smears or fine-needle aspirates, may reveal round cells suggestive of a hemolymphopoietic tumor. If these round cells are noted, they may not be atypical and therefore cannot be differentiated from clonal expansion (5).

For a definitive diagnosis, skin biopsies should be performed and submitted for histopathology. Inflammation in samples is characterized by infiltration of neoplastic T-lymphocytes with a tropism for the epidermal or mucosal epithelium as well as adnexal structures, especially the follicular wall (3,6) (Figure 2). Pautriers microabscesses may be noted in specimens. These are intraepithelial neoplastic lymphocytes present diffusely within the epidermis or more focally in discrete aggregates (3). In samples in which these lymphocytes are diffuse within the epidermis they often remain within the lower levels. Infiltration of apocrine sweat glands by neoplastic lymphocytes occurs in up to 70% of cases and is considered diagnostic for CTCL (2,3). The epidermis may be moderately acantholytic, but hyperplasia is not prominent in the disease. Spongiosis is usually mild or absent. There can be an inflammatory infiltrate if ulceration and exudation are present (3). In the Ketron-Goodman form there is invasion of the epidermis and appendages by CD3+ and CD8+ neoplastic lymphocytes (4).

Figure 2.

Cutaneous T-cell epitheliotropic lymphoma in a dog (magnification 200× and 400×, left and right images, respectively). Note the infiltration with neoplastic lymphocytes. Photographs supplied by Dr. Shannon Martinson.

Treatment

Many treatments are described in the literature for CTCL. These include surgery for solitary lesions, lomustine (CCNU), doxorubicin, L-asparaginase, dacarbazine, retinoids, radiotherapy, oclacitinib, and safflower oil (1,4,5,9,11–20).

For singular lesions, surgical removal is a treatment option. Following surgery, some dogs remain disease-free for > 2 y (1). One study documented that approximately 50% of dogs with a single mucocutaneous lesion did not develop any further lesions for a median follow-up of 501 d and 70% of dogs with a single cutaneous lesion for 691 d (1). Staging should occur prior to surgery to document that there has been no metastasis of the neoplasia. If surgical removal is recommended, it may need to be followed by systemic chemotherapy depending on margins obtained (11).

Topical glucocorticoids are used in human medicine for early stages of the disease with generally high response rates. There is a lack of efficacy data in the veterinary literature for this treatment modality, although it is likely that some individuals with singular, early lesions may respond to this therapy (11).

Radiotherapy has been documented as a treatment option for cutaneous lymphoma. It is best applied for local treatment of CTCL. In a retrospective study by Berlato et al (12), 14 dogs with mucocutaneous lymphoma (12 having epitheliotropic lymphoma) received coarse fractionated radiotherapy. In this study, the overall response rate was 67% with dogs having a median survival time of 770 d. One downside with this type of therapy is access to the radiotherapy and the need to refer.

Retinoids are synthetic analogues of vitamin A. They influence the growth and maturation of many cells including keratinocytes. Retinoids are used in management of human CTCL with response rates of ~45% (11). Retinoids have been occasionally studied for treatment of CTCL in the veterinary literature, with a response rate of 42% in 14 dogs in 1 study (13). In another study, a median survival of 11 mo was obtained with the use of retinoids (12). Due to the high cost of treatment, difficulty obtaining the medication, and the time lapse to effect (weeks to months), retinoids are often not used as the sole or first line therapy for CTCL in companion animals.

One of the most common treatments for CTCL is lomustine (CCNU), an alkylating agent used to also treat mast cell tumors, histiocytic sarcomas, and some brain and spinal cord tumors. Lomustine is generally given every 3 to 4 wk as an oral chemotherapeutic medication. In a retrospective study of 36 dogs, 31 with the cutaneous form and 5 with the oral form, a response rate of 78% to lomustine was documented (15). Six dogs had a complete response, and 22 dogs had a partial response. Dogs received a median dose of 70 mg/m² and a median number of 3 treatments. Survival times were not reported. In a literature review by Laprais et al (14), it was noted that CCNU led to remission in ~30% dogs in multiple studies reviewed. The mean duration of remission was 132 d (range: 26 to 258 d) (14). In this review, some patients received lomustine as a sole chemotherapeutic and others received it is combination with other therapies. Side effects of lomustine include increased liver enzymes, gastrointestinal signs, and myelosuppression (11). In the study by Williams et al (15), these were noted in 86, 22, and 29% of patients, respectively.

In a case report of a dog treated with dacarbazine, there was complete remission after 3 cycles of treatment (16). Dacarbazine is often used for treatment of malignant melanoma and Hodgkin’s disease in humans. Based on this limited efficacy data, further studies are likely warranted to continually recommend treatment with this agent.

L-asparaginase is a chemotherapeutic agent used for treatment of other types of lymphoma. L-asparaginase (L-asp) is an enzyme that breaks down asparagine. Asparagine is an amino acid that tumor cells require to maintain their rapid growth. One study documented responses to pegylated L-asp, a form that has more favorable pharmacokinetic and toxicity profiles. Seven dogs with CTCL responded to the therapy, with improved clinical signs and lesional appearance. Unfortunately, responses were often only partial and short (17). In Risbon et al (6) study, 5 dogs received 1 dose of L-asp at the initiation of therapy with CCNU.

Treatment with doxorubicin for various malignant neoplasia has been studied. In 9 dogs with CTCL treated, 3 had complete responses (median remission of 90 d) and 1 had a partial response, with an overall response rate of 44% (18). One side effect of this therapy is a syndrome known as palmar-plantar erythrodysesthesia (hand-foot syndrome). This is a cutaneous reaction to pegylated doxorubicin and can occur in up to 25% patients (18).

One study documented that 6 of 8 dogs treated with higher amounts of safflower oil containing linoleic acid went into remission with MF (19). In this same study, Iwamoto et al also documented a marked elevation of both white blood cells and lymphocytes.

In one report of a 9-year-old dog given oclacitinib, a decrease in pruritus and lesions was noted as well as an improved demeanor. There was also an 80% reduction in neoplastic lymphocytes within skin samples (20). More studies assessing this medication as a treatment option for CTCL are warranted.

In Laprais and Olivry’s (14) literature review, therapy with prednisone did not lead to remission in any of the treated dogs. In 10 dogs treated with masitinib, only 2 achieved complete remission, 1 for 126 d and 1 for 3 y.

In rare cases of pagetoid reticulosis or Sezary syndrome, treatment options are the same as those recommended for MF.

Prognosis

Prognosis for CTCL is difficult to establish and based on many factors including stage of disease, therapeutic choice, and response to therapy. In the literature, the disease generally has a poor prognosis with many references citing a mean survival time of a few months to 2 y (2,4,5). Without treatment, survival times have been noted to be as low as 3 to 5 mo. In a study by Chan et al (1) survival time was not significantly different between treated and untreated dogs. In 2 retrospective studies of dogs with CTCL, an overall response rate to treatment of 78 to 83% was noted (6,15).

Predictors of poor survival were an individual having the cutaneous form (as opposed to the mucocutaneous form) and individuals with multiple lesions (1). Lymph node involvement as a prognostic indicator is controversial; however, in 1 study lymph node involvement was not associated with survival time for either form of cutaneous or mucocutaneous lymphoma (1). In this same study, complete remission with treatment was associated with longer survival (1).

Unfortunately, due to disease progression, euthanasia is often requested by owners due to the severity of pruritus and the skin condition along with affected individuals having a depressed attitude (5).