Oral epitheliotropic lymphoma: An uncommon presentation of a common disease

A 9-year-old female spayed Welsh Corgi was presented to the Hope Oncology Service for evaluation and discussion of treatment options for suspected lymphoma. An enlarged mandibular lymph node was noted by the owner approximately 10 days prior to presentation. Fine needle aspiration was performed by her primary care veterinarian and submitted to a clinical pathologist for interpretation. Cytology showed an expanded population of large lymphocytes (40% of lymphocyte population) which was concerning for an emerging, high-grade lymphoma. PARR was performed and showed clonality supportive of lymphoma. Labwork (CBC, chemistry panel, urine analysis), 2-view chest radiographs, and 1-view abdominal radiographs were performed prior to referral. Labwork and imaging were unremarkable.

At consultation, physical examination was performed and revealed a moderately to severely enlarged (~3 cm) right mandibular lymph node. All other peripheral lymph nodes palpated normally. The gingiva and lip folds were uniformly, mildly hyperemic. On the R lower lip fold a focal, mildly erythematous area was noted. The skin over the snout was also subtly erythematous. All prior diagnostics were reviewed with the client and the diagnosis of lymphoma was discussed given supportive cytology and PARR testing.

Oral cavity of this 9-year-old female spayed Corgi

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Lymphoma is considered one of the most common cancers seen in the dog, comprising approximately 7-24% of all canine malignancies.1 This cancer arises from lymphocytes in lymphoid tissues like the lymph nodes, spleen, and bone marrow, but can arise from almost any tissue in the body. Breeds reported having a higher incidence include Boxers, Bullmastiffs, Basset hounds, St. Bernards, Scottish terriers, Airedales, and Bulldogs.1

Classification of lymphoma in dogs is based on anatomic location (e.g. multicentric, gastrointestinal, mediastinal, cutaneous), histologic criteria (large cell/high grade v. small cell/low grade), and immunophenotype (B cell, T cell, null cell/non-B, non-T). Approximately 85% of dogs with lymphoma develop the multicentric, high-grade form which is characterized by generalized peripheral lymphadenopathy.1 Enlarged peripheral lymph nodes are generally painless and discrete. Infiltration of liver and spleen leading to enlargement of these organs is also common. Most dogs with multicentric lymphoma present without systemic signs of illness, however, a large array of systemic signs such as anorexia, weight loss, vomiting, diarrhea, polyuria/polydipsia, and fever may occur. For dogs suspected of having multicentric, high-grade lymphoma, a diagnostic evaluation includes a physical examination, complete blood count (CBC), serum biochemical profile, urine analysis, aspirates of an enlarged peripheral lymph node, and, in some cases, imaging (radiographs of the thorax, ultrasound of the abdomen). With this information, stage of the disease is determined:

Stage I-involvement of a single lymph node or lymphoid tissue in a single organ
Stage II-involvement of many lymph nodes in one regional area
Stage III-generalized lymph node involvement
Stage IV-Liver and spleen involvement (+/- stage III)
Stage V-Bone marrow, mediastinal, GI tract, and/or other organ system involvement.

 

A diagnosis of lymphoma is often easily made on the evaluation of fine needle aspirates of affected lymph nodes. Samples of the lymph nodes generally reveal a homogenous population of large lymphocytes (>2 times the size of a RBC or larger than a neutrophil). Immunophenotyping through immunocytochemistry (ICC), immunohistochemistry (IHC), flow cytometry, or PCR for antigen receptor rearrangement (PARR) further categorizes lymphomas as B cell, T cell and null cell (non-B, non-T cell) lymphoma. This testing is done on cytology (ICC, flow cytometry) or biopsy (IHC, PARR) specimens and provides prognostic information (B cell lymphomas are associated with a better prognosis than T cell lymphomas), allows for customization of the chemotherapy protocol, and can help confirm lymphoma if cytology or biopsy is inconclusive. Multiagent chemotherapy (CHOP-based protocols) is the treatment of choice for multicentric large cell (intermediate to high grade) lymphoma in dogs. The acronym “CHOP” denotes the four drugs thought to have the greatest activity against lymphomas: Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and Prednisone. CHOP-based chemotherapy induces remission in 80-95% of dogs with overall median survival times of ~ 1 yr. Approximately 20-25% of treated dogs will be alive 2 years after initiation of these protocols.1

Enlargement of a single lymph node (stage I disease), as was found in this case, is a very atypical presentation for high-grade multicentric lymphoma. This, along with subtle but uniformly bright pink gingiva (rather than just around the free gingival margin as is seen with conventional gingivitis) raised suspicion for cutaneous epitheliotropic T cell lymphoma.

Cutaneous epitheliotropic T cell lymphoma (CETL) is characterized by infiltration of neoplastic T lymphocytes with specific tropism for the epidermis and adnexal structures. 2 The skin and/or mucous membranes/mucocutaneous junctions can be affected and typically lesions are generalized or multifocal. Skin lesions manifest as erythema, alopecia, scaling, crusting, ulceration/erosion, papules, plaques, nodules, or focal hypopigmentation. Oral involvement may also occur and this can appear as erythematous plaque-like lesions or nodules associated with the gum or lips. Extracutaneous/ extramucosal involvement can also occur, most often in the lymph nodes, spleen, liver and bone marrow.1 Definitive diagnosis requires biopsy of representative skin or oral lesions, though fine needle aspiration or direct imprint smear of an eroded/ulcerated lesion may be strongly supportive.2

Pictured below are dogs with localized oral lymphoma or oral involvement of diffuse epitheliotropic lymphoma:

10-year-old female spayed mixed breed dog

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Note dark pink/red, slightly proliferative maxillary gingiva, and focal dark pink/red lesion at lower lip margin.

11-year-old male castrated Cockapoo:

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Note diffusely erythematous gingiva, lip, muzzle, and chin

As this is typically a multicentric disease, epitheliotropic lymphoma is generally treated with chemotherapy. Combination protocols have not been shown to offer a survival advantage over single agent protocols.1 Currently, the most promising agent used in the treatment of epithliotropic lymphoma is lomustine (CCNU) in conjunction with oral corticosteroids. In a retrospective study of 36 dogs with epitheliotropic lymphoma including 31 (86%) with cutaneous disease and 5 (14%) with oral disease, response rate to CCNU was 78% (17% complete, 61% partial) and overall remission duration of 106 days.3 In a second retrospective study evaluating 46 dogs, response rate was 83% (33% complete response, 50% partial response) and median duration of response was 94 days. There was no difference in response between dogs with or without oral involvement.4

In rare cases, CETL may be solitary or localized (e.g. solitary skin lesion or oral involvement only). In these cases, local therapies such as radiation therapy or surgery can be considered as the primary treatment strategy. Lymphocytes, whether normal or malignant, are known to be exquisitely radiosensitive.5 A study evaluating 14 dogs with localized oral lymphoma with or without mandibular lymph node involvement was published in 2011. In this study all dogs were treated with radiation therapy (various protocols: six dogs received 8 Gy x 3, five dogs received 8 Gy x 4, one dog received 6 Gy x 5, two dogs received 3.2 Gy x 15). Average (mean) survival was 1129 days [range 711-1546 days] with median survival of 770 days. The overall response to radiation therapy was 67% (five complete responses and three partial responses). A survival advantage was seen in dogs with no evidence of lymph node metastasis (mean survival 1726 and median survival not reached for those without lymph node involvement v. median survival 305 days for those with lymph node involvement) and those that achieved a complete response to radiation therapy. 5 dogs received chemotherapy before or after radiation therapy, in each case for different reasons. Statistical analysis was not performed to determine affect on outcome.6

For this patient, abdominal ultrasound was performed and excluded the presence of intraabdominal disease. Oral biopsies and lymph node extirpation were then performed to confirm oral lymphoma and reduce disease burden. Representative samples of lip and gingiva were taken, both of which revealed an infiltrate of large round cells with frequent epitheliotropism, moderate anisokaryosis, and high mitotic activity, confirming a diagnosis of epitheliotropic lymphoma. The removed lymph node revealed a similar population of large round cells, moderate anisokaryosis and high mitotic activity consistent with lymphoma.

Radiation therapy was recently administered to the entire oral cavity and remaining mandibular lymph nodes. Daily treatments were given Monday through Friday over 1 week (4Gy x 5). At the time of her fourth dose of radiation therapy, the dog began to develop radiation side effects in the form of progressive gingival inflammation/irritation and lip margin crusting. A tapering course of prednisone was begun to manage these side effects. CCNU chemotherapy was recommended and will likely be pursued in this patient once radiation side effects peak and subside given lymph node involvement and its negative impact on prognosis.

Submitted by:

Kristin Kicenuik DVM, DACVIM (Oncology)

References:

1. Vail DM and Young KM. Hematopoietic Tumors. In: Withrow and MacEwen’s Small Animal Clinical Oncology, 5th edn., St. Louis, Saunders Elsevier, 2007: 608–637

2. Fontaine J, Bovens, C, Bettenay S. Canine cutaneous epitheliotropic T cell lymphoma: a review. Veterinary and comparative oncology 2009; 7: 1-14

3. Williams LE, Rassnick KM, Power HT, Lana SE, Morrison-Collister KE, Hansen K and Johnson JL. CCNU in the treatment of canine epitheliotropic lymphoma. Journal of Veterinary Internal Medicine 2006; 20: 136–143. 

4. Risbon RE, de Lorimier LP, Skorupski K, Burgess KE, Bergman PJ, Carreras J, Hahn K, LeBlanc A, Turek M, Impellizeri J, Iii RF, Wojcieszyn JW, Drobatz K and Clifford CA. Response of canine cutaneous epitheliotropic lymphoma to lomustine (CCNU): a retrospective study of 46 cases (1999–2004). Journal of Veterinary Internal Medicine 2006; 20: 1389–1397.

5. de Lorimier LP. Updates on the management of canine epitheliotropic cutaneous T-cell lymphoma. Veterinary Clinic of North America: Small Animal Practice 2006; 36: 213 – 228.

6. Berlato D, Schrempp D, Van Den Steen N, and Murphy S. Radiotherapy in the management of localized mucocutaneous oral lymphoma in dogs: 14 cases. Journal of Veterinary and Comparative Oncology 2011; 10: 16-23.

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