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Pathobiology, College of Veterinary Medicine, Texas A & M University, ... and 6Department of Pathology, College of Medicine, University of Florida, Gainesville,.
Veterinary Clinical Pathology ISSN 0275-6382

CASE REPORT

B-cell lymphoma with Mott cell differentiation in two young adult dogs Nicole I. Stacy1, Mary B. Nabity2, Nicole Hackendahl3, Melanie Buote2, Jennifer Ward4, Pamela E. Ginn4, William Vernau5, William L. Clapp6, John W. Harvey1 1

Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA; 2Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A & M University, College Station, TX, USA; 3Western Veterinary Specialist Centre, Edmonton, AB, Canada; 4Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA; 5School of Veterinary Medicine, University of California-Davis, Davis, CA, USA; and 6Department of Pathology, College of Medicine, University of Florida, Gainesville, FL, USA

Key Words B-cell, canine, intestinal, lymphoma, Mott cells, Russell bodies Correspondence Dr. John W. Harvey, Department of Physiological Sciences, PO Box 100144, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USA E-mail: [email protected] DOI:10.1111/j.1939-165X.2008.00101.x

Abstract: Two young adult dogs with gastrointestinal signs were each found to have an intra-abdominal mass based on physical examination and diagnostic imaging. On exploratory laparotomy, small intestinal masses and mesenteric lymphadenopathy were found in both dogs; a liver mass was also found in dog 1. Cytologic and histologic examination of intestinal and liver masses and mesenteric lymph nodes revealed 2 distinct lymphoid cell populations: lymphoblasts and atypical Mott cells. With Romanowsky stains, the atypical Mott cells contained many discrete, clear to pale blue cytoplasmic inclusions consistent with Russell bodies that were positive by immunohistochemistry for IgM and CD79a in both dogs and for IgG in dog 2. The Mott cells and occasional lymphoblasts stained strongly positive with periodic acid-Schiff. Using flow cytometric immunophenotyping in dog 1, 60% of peripheral blood mononuclear cells and 85% of cells in an affected lymph node were positive for CD21, CD79a, IgM, and MCH II, indicative of B-cells. With electron microscopy, disorganized and dilated endoplasmic reticulum was seen in Mott cells in tumors from both dogs. Antigen receptor gene rearrangement analysis of lymph node and intestinal masses indicated a clonal B-cell population. Based on cell morphology, tissue involvement, and evidence for clonal B-cell proliferation, we diagnosed neoplasms involving Mott cells. To the authors’ knowledge, this is the second report of Mott cell tumors or, more appropriately, B-cell lymphoma with Mott cell differentiation, in dogs. More complete characterization of this neoplasm requires further investigation of additional cases. This lymphoproliferative disease should be considered as a differential diagnosis for canine gastrointestinal tumors.

Case Presentations Dog 1 A 2-year-old, male castrated Dachshund was presented to the Veterinary Medical Center at the University of Florida with a 1-week history of lethargy, anorexia, polyuria, polydipsia, and dark soft stools. On physical examination the dog had a mild fever (102.81F), and normal pulse and respiration rates. A 10  4 cm mass was palpated in the cranial ventral abdomen. Results of a CBC (ADVIA 120, Siemens Healthcare Diagnostics, Deerfield, IL, USA) included a HCT of 51%

(reference interval 40.0–57.0%) with moderate microcytosis (MCV 56 fL, reference interval 65–75 fL), mild hypochromia (MCHC 33 g/dL, reference interval 34–37 g/dL; cell hemoglobin concentration mean 32 g/dL, reference interval 33–37 g/dL), and moderate anisocytosis (red cell distribution width 19%, reference interval 11–14%); mild leukocytosis (WBC 22.9  103/mL, reference interval 5.0–14.5  103/mL); mild monocytosis (3.1  103/mL, reference interval 0.2–1.1  103/mL); and moderate lymphocytosis (8.5  103/mL, reference interval 0.70–3.4  103/mL). Mild hyperfibrinogenemia (500 mg/dL, reference interval 200–300 mg/dL) was detected by the heat

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precipitation method. Blood film evaluation confirmed the moderate anisocytosis (with microcytes) and slight hypochromasia. A few intermediate to large lymphocytes with scant deeply basophilic cytoplasm that contained small, discrete pale basophilic inclusions (Russell bodies) of variable sizes were observed (Figure 1). Significant biochemical abnormalities (Hitachi 912, Roche Diagnostics Corp., Indianapolis, IN, USA) included marked hypercalcemia (15.0 mg/dL, reference interval 9.9–11.9 mg/dL) with an increased ionized calcium concentration (1.85 mmol/L, reference interval 1.25–1.45 mmol/L), and mild hypoproteinemia (5.0 g/dL, reference interval 5.8–7.8 g/dL) with mild hypoalbuminemia (2.6 g/dL, reference interval 2.8–3.8 g/dL) and mild hypoglobulinemia (2.4 g/dL, reference interval 2.6–4.3 g/dL). Serum protein electrophoresis results confirmed the hypoalbuminemia and revealed a mild decrease in b2-globulins concentration (0.48 g/dL, reference interval 0.59–0.96 g/dL). A monoclonal globulin spike was not observed. Abnormalities were not detected in a urinalysis. The specific gravity was 1.014. On examination of thoracic radiographs, marked sternal lymphadenopathy and a focal 2  3 cm diaphragmatic protrusion ventrally and slightly to the right of midline were observed. Abdominal ultrasonography showed a severely thickened, segmental, 8-cmlong portion of small intestine with complete loss of normal wall layering and wall thickness 4 1 cm. Severe mesenteric lymphadenopathy (3–5 cm in diameter), a possible hepatic mass, and a small volume of peritoneal fluid were also noted. Fine needle aspirates were obtained from the small intestinal mass, a mesenteric lymph node, and the liver mass for cytologic examination. Exploratory laparotomy was performed and an 8  2  2 cm, irregularly marginated, necrotic mass was removed from the caudal border of the liver. A 6cm portion of severely thickened distal duodenum and one of the markedly enlarged mesenteric lymph nodes

were also removed. The samples were imprinted for cytologic examination and placed in buffered formalin for histopathologic evaluation. A diagnosis of lymphoma was made. The Madison–Wisconsin chemotherapy protocol was instituted.1 On day 14, ionized calcium concentration decreased to within the reference interval and the patient improved clinically. During week 10 of chemotherapy, the dog became anorexic and started vomiting. Because of the likelihood that the patient had come out of remission, the owners elected euthanasia approximately 3 months after the original presentation, and declined a necropsy.

Dog 2 A 2-year-old, male castrated Jack Russell Terrier was presented to the Texas Veterinary Medical Center, Texas A&M University, with a 1-month history of mild anorexia, lethargy, pica, vomiting foamy yellow material, and 1 episode of diarrhea. The dog had been treated symptomatically for 1 week by the referring veterinarian without clinical improvement. Physical examination and abdominal radiographic findings included a 4–5-cm midabdominal soft tissue mass and moderate abdominal discomfort. Vital signs were within normal limits. Results of a CBC (CELL-DYN 3700, Abbott Laboratories, Abbott Park, IL, USA) and chemistry panel (Vitros 250, Ortho-Clinical Diagnostics Inc., Rochester, NY, USA) included moderate thrombocytopenia (90  103/mL, reference interval 200–500  103/mL), mild hypoproteinemia (5.3 g/dL, reference interval 6.0–8.0 g/dL), and mild hypoalbuminemia (2.5 g/dL, reference interval 2.4–3.6 g/dL). The lymphocyte count (1.9  103/mL) was within the reference interval (1.0–4.8  103/mL), but rare atypical lymphocytes with Russell bodies were seen in a peripheral blood film (Figure 1).

Figure 1. Lymphocytes containing Russell bodies in the peripheral blood of dog 1 (left) and dog 2 (right). Wright–Giemsa,  100 objective.

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Surgery was performed for a presumed foreign body obstruction. Intraoperatively, approximately 20 variably sized pale ovoid intramural masses were noted throughout the duodenum, jejunum, and ileum. Several of the masses partially obstructed the intestinal lumen. All mesenteric lymph nodes were enlarged, with the largest measuring 5 cm in diameter. Biopsies of a lymph node and one of the intestinal masses were imprinted for cytologic examination and placed in buffered formalin for histopathologic evaluation. The owner elected euthanasia intraoperatively after a cytologic diagnosis of lymphoma was made, based on the poor prognosis associated with extensive involvement of the gastrointestinal (GI) tract. The owner declined a necropsy.

Morphologic and molecular characterization of the lymphomas Fine-needle aspirates of the small intestinal mass, a mesenteric lymph node, and the liver mass from dog 1 (taken before surgery); tissue imprint preparations of the small intestinal mass, an ileocecal lymph node, and the liver mass from dog 1 (taken during surgery); and tissue imprint preparations of a mesenteric lymph node and the intestinal mass from dog 2 (taken during surgery) were examined after staining with WrightGiemsa and Diff–Quik, respectively. The tissue aspirates and imprints were all similar in their cytologic appearance. The preparations were highly cellular and mildly hemodiluted. A pale basophilic, proteinaceous background contained numerous lysed cells, cytoplasmic fragments, and many pale basophilic, round to oval globules of variable sizes consistent with extracellular Russell bodies. The predominant cell population was composed of intermediate to large lymphocytes ranging from 12 to 28 mm in diameter (Figure 2). The lymphocytes had relatively scant moderately basophilic cytoplasm that occasionally contained a few small, discrete, clear, or pale blue inclusions. Nuclei were round and eccentric, with smooth chromatin and 1 to multiple, round or oval, eccentric, distinct nucleoli. Occasional mitotic figures were noted. Numerous Mott cells were noted in various proportions (up to 50% of nucleated cells) throughout the impression smear preparations. They varied from 20 to 35 mm in diameter; anisokaryosis and anisocytosis were mild. The Mott cells had eccentric nuclei and contained numerous variably sized clear or pale blue Russell bodies. Low numbers of small mature-appearing lymphocytes, mildly reactive macrophages, and nondegenerate neutrophils were also noted. A cytologic interpretation of lymphoma with a

Figure 2. Tissue imprints from 2 dogs with lymphoma. A predominant population of neoplastic intermediate to large lymphocytes is admixed with numerous Mott cells having mild anisokaryosis and anisocytosis. (A) Gastrointestinal mass from dog 1. Wright–Giemsa,  100 objective. (B) Mesenteric lymph node from dog 2. Diff–Quik,  100 objective.

high proportion of mildly atypical Mott cells was made. Given the large number of Mott cells, a B-cell lymphoma was suspected. Other differential diagnoses included B-cell-rich T-cell lymphoma or plasmacytoma with Mott cell differentiation. Histopathologic evaluation of the small intestinal masses and lymph nodes (dogs 1 and 2), and liver mass (dog 1) were processed routinely and stained with H&E. Sections consisted of highly cellular, nonencapsulated infiltrates of neoplastic lymphocytes that had effaced normal tissue architecture (Figure 3). Neoplastic cells were of 2 distinct populations: 50–60% of cells were intermediate to large sized lymphocytes with scant lightly eosinophilic cytoplasm, indistinct cell borders, and coarsely granular hyperchromatic nuclei approximately 7–15 mm in diameter. Many of these cells had 1 or more small but prominent nucleoli. Mitotic figures ranged from 6 to 16 per  40 objective field and appeared to be primarily within this cell population. Approximately 40–50% of cells were large,

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Immunohistochemical staining of paraffinembedded tissue sections was routinely performed on samples from each of the 2 dogs. In dog 1, both cell populations strongly expressed CD79a (murine monoclonal, 1:400 dilution; Biocare, Concord, CA, USA) and did not express CD3 (rabbit polyclonal, 1:700 dilution; Dako Cytomation, Carpinteria, CA, USA). Strong cytoplasmic positivity for IgM was consistently present in the Mott cells and was scattered among the remaining neoplastic lymphocytes (Figure 4). No cells were positive for IgG or IgA expression. In dog 2, both cell populations strongly expressed CD79a (mouse monoclonal, 1:300 dilution; Dako) and did not express CD3 (rabbit polyclonal, 1:300 dilution, Dako). Strong cytoplasmic staining with IgM and IgG antibodies was noted in Mott cells and in occasional neoplastic lymphocytes. The cytoplasmic globules in the Mott cells and occasional lymphoblasts in the tumors from both

Figure 3. Histologic sections of small intestinal masses from dogs 1 (A, B) and 2 (C). (A) A highly cellular, nonencapsulated round cell infiltrate effaces normal tissue architecture in the mass. H&E,  20 objective. (B, C) Neoplastic intermediate to large lymphocytes and Mott cells are seen. H&E,  100 objective.

well-differentiated Mott cells with small dense basophilic nuclei and abundant eosinophilic cytoplasm composed of variably distinct eosinophilic globules (Russell bodies). The proportions of these 2 cell populations varied throughout the sections. The diagnosis was lymphoma in both cases.

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Figure 4. Histologic section of the small intestinal mass from dog 1. (A) IgM expression is seen predominantly in neoplastic Mott cells and to a lesser extent in neoplastic lymphocytes. Immunoperoxidase with 3,3 0 diamino-benzidine,  100 objective. (B) Intracytoplasmic periodic acid–Schiff-positive staining can be seen in Mott cells and infrequently in neoplastic lymphocytes.  100 objective.

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Figure 5. Transmission electron micrographs of the small intestinal mass from dog 1. Uranyl acetate and lead citrate. (Left) A neoplastic lymphocyte (center) contains an intracytoplasmic inclusion similar to the Russell bodies in the Mott cell (left center)  3400. (Center) Neoplastic lymphocytes contain intracytoplasmic inclusions similar to Mott cells (top of image).  3400. (Right) A Mott cell is seen with an eccentric nucleus, marginated heterochromatin, and dilated cisternae of endoplasmic reticulum containing electron-dense material consistent with immunoglobulin (Russell body inclusions).  9700.

dogs were strongly positive with periodic acid-Schiff (PAS), indicating the presence of cytoplasmic carbohydrate and suggesting complete immunoglobulin synthesis, including the glycoprotein component (Figure 4). Positive and negative controls for the described antibodies were routinely performed. Immunophenotyping by flow cytometry was performed on a lymph node aspirate and peripheral blood sample from dog 1 at Kansas State University with a dual-laser FACSCalibur (Becton Dickinson, San Jose, CA, USA) as previously described.2 The lymph node aspirate had a cell viability of 76%. Approximately 85% of the cells were of B-cell lineage (positive for CD21, C79a, IgM, and MHC II). Less than 10% of the cells expressed specific T-cell and myeloid markers. The peripheral blood sample had 98% cell viability. The sample was composed of approximately 24% mononuclear and 75% granulocytic cells. Analysis of the mononuclear cells showed that approximately 60% of the cells were B-cell in origin (positive for CD21, CD79a, IgM, and MHC II). The remaining mononuclear cells were identified as T-cells ( o 10%; positive for CD3, CD4, and CD8) and monocytic cells (o 10%; positive for CD14, and CD172a). Residual percentages reflected nonvital cells. Antigen receptor gene rearrangement analysis was used to assess clonality on genomic DNA extracted from frozen sections of a mesenteric lymph node and the small intestinal mass from dog 1 (performed at the University of California-Davis) and from a lymph node impression smear from dog 2 (performed at Texas A&M University). At both institutions, identical canine-specific PCR-based techniques were performed as previously described.3,4 Single distinct bands (dog 1 at 180 bp, dog 2 at 120 bp) were obtained with the B-cellspecific primer set in all samples, indicating the pres-

ence of B-cell clonality and confirming the diagnosis of B-cell lymphoma. Samples of paraffin-embedded tissue from the intestinal mass from dog 1 and from a mesenteric lymph node from dog 2 were prepared for examination with transmission electron microscopy by routine methods. Two distinct round cell populations were observed (Figure 5). The predominant population was comprised of intermediate to large lymphocytes with high nuclear to cytoplasmic ratios and scant cytoplasm that infrequently contained variable numbers of small, round, electron-dense, proteinaceous inclusions. The lymphocytes had a single round, oval to irregular nucleus that occasionally contained peripheral heterochromatin. Lower numbers of Mott cells were identified throughout the sections. These cells had single round to oval, eccentric nuclei with prominent peripheral heterochromatin and occasionally 1–3 prominent nucleoli. The cytoplasm of the Mott cells was filled with variably dilated, attenuated, and disorganized cisternae of endoplasmic reticulum (ER) containing electron-dense proteinaceous material interpreted as immunoglobulin. In addition, Mott cells frequently had disorganized cisternal ER membranes accompanied by the coalescence of secretory products (Figure 5); however, ribosomes (part of rough ER) were visible only in samples from dog 2 (not shown). The Golgi apparatus was poorly developed in the Mott cells. The ultrastructural diagnosis was lymphoma with Mott cell differentiation.

Discussion In this report we describe 2 dogs with intestinal B-cell lymphoma having Mott cell differentiation. Mott cells are lymphocytes of B-lymphocyte lineage that have

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accumulated large inclusions of nonsecreted immunoglobulins (Russell bodies).5 In inflammatory conditions, Mott cells have typically been considered a plasma cell variant; however, based on the findings in these cases, we hypothesize that Mott cells in neoplastic conditions may develop directly from immature lymphocytes, without an overt plasma cell stage. In dog 1, the lymphocytosis with a few atypical lymphocytes, palpable intra-abdominal mass, and hypercalcemia raised concern for lymphoid malignancy. Monocytosis and hyperfibrinogenemia were consistent with chronic immune stimulation or inflammation. Although the dog was not anemic, the microcytic and mildly hypochromic erythrocytes suggested altered iron metabolism, potentially also caused by inflammation or by blood loss through the GI tract. Hypoproteinemia was attributed to GI loss in both dogs. Additionally, an acute phase reaction may have contributed to the mild hypoalbuminemia. Hypercalcemia was attributed to malignancy, although hyperparathyroidism and granulomatous disease were not ruled out. Altered tubular function secondary to hypercalcemia likely contributed to polyuria, polydipsia, and the relatively low urine specific gravity. Thrombocytopenia in dog 2 remained unexplained, as coagulation tests and bone marrow evaluation were not done. Few cases of GI ‘‘Mott cell tumors’’ have been reported in humans, with the most recent report describing an association with Helicobacter pylori.6 In that case, the authors categorized the Mott cell tumor as an extramedullary plasmacytoma, although it was first erroneously diagnosed as a signet-ring cell carcinoma at biopsy. Mott cell tumors have not been reported in animals, although plasma cell tumors may contain a few well-differentiated Mott cells. However, a 5-year-old Keeshond diagnosed with submandibular and gastric extramedullary plasmacytomas had lymphocytes with exclusively plasmacytoid differentiation that frequently contained Russell bodies, often apparently coalesced into a single, large intracytoplasmic body that created a signet ring appearance. Electron microscopy demonstrated dilated and disorderly rER. Serum globulin concentrations were within the reference interval, and a monoclonal spike was observed on urine protein electrophoresis but not in serum. There was no evidence for paraprotein production in either of the dogs in this report; however, small amounts may not have been detected by the methods used in these cases (such as electrophoresis), which have low sensitivity. Canine GI lymphoma accounts for 5% to 7% of all canine lymphomas.7 It most commonly occurs in the small intestine and less frequently in the stomach and colon, with frequent involvement of mesenteric lymph

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nodes and the liver.8 Although a necropsy was not performed on either of the dogs in this report, observations during exploratory surgery, including extensive involvement of the small intestine, marked mesenteric lymphadenopathy, and liver involvement in dog 1, were supportive of a diagnosis of primary GI lymphoma. Lymphocytic–plasmacytic inflammation may occur in conjunction with GI lymphoma.9 Focal plasma cell-rich areas associated with neoplastic lymphoid infiltrates may be difficult to distinguish from lymphocytic–plasmacytic enteritis histologically.10 Apart from the morphologic challenge in differentiating these disease processes, an association between lymphocytic–plasmacytic enteritis and the development of lymphoma has been proposed in humans and animals.10,11 A recent report describes 2 unusual cases of Russell body gastritis associated with H. pylori infection in humans.12 Although histopathologic findings were identical to those in Mott cell tumors, polyclonal immunoglobulin light chain expression was found in affected tissues. In humans, the majority of GI lymphomas are B cell in origin (although plasmacytoid differentiation is found rarely), and a strong association between the presence of H. pylori and low-grade mucosa-associated lymphoid tissue (MALT) lymphoma has been observed.11 As in humans, it has been assumed that GI lymphoma in dogs also is most often B-cell in origin. In a recent study, however, 75% of canine GI lymphomas were of T-cell origin.7 The most striking morphologic features of the tumors in the dogs in this report were the abundant neoplastic cells with a Mott cell appearance. During the development of non-neoplastic Mott cells, the globular appearance of the cytoplasm is thought to represent the state of a plasma cell when immunoglobulin is produced at a faster rate than it can be secreted. When this happens, immunoglobulin accumulates in the lumen of the rER, forming large vesicles that ultrastructurally appear as electron-dense Russell bodies.5,13,14 Neoplastic Mott cells may lack cellular differentiation or disorganization of cisternal rER; however, ultrastructural findings cannot definitively distinguish between neoplastic and non-neoplastic cells.15 Ultrastructural analysis of both tumors described here revealed disorganized and dilated cisternae of ER; however, ribosomes were visible only in the second case. Presumably, rER also started to develop in dog 1, but ribosomes were no longer visible at the time of analysis. It is possible that progressive maturation of Mott cells results in continuous loss of ribosomes or that ribosomes are lost during the fixation process.

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Although the Mott cells in the tumors of both dogs appeared morphologically distinct from the numerous lymphoblasts, the latter occasionally contained a few small inclusions similar to those in the Mott cells. As determined by cytologic, histologic, and ultrastructural examination, there was little evidence for plasma cell differentiation in either tumor. Plasma cells are typically characterized by abundant rER and a well-developed Golgi apparatus via electron microscopy13; neither of these features was observed here. The lack of morphologic and ultrastructural evidence for plasma cell differentiation precludes classifying the present tumors as plasmacytomas. Furthermore, the observations suggest that some lymphoblasts may have developed into Mott cells without first developing into plasma cells. Consequently, the lymphoblasts may represent a precursor stage of the neoplastic Mott cells. This hypothesis is further reinforced by the identification of a single clonal B-cell proliferation via gene rearrangement analysis. It is evident that the Mott cells were involved in the neoplastic process, given their morphologic features and metastasis to mesenteric lymph nodes in both cases and to liver in dog 1. In addition, occasional mitotic figures involved Mott-like cells in the cytologic preparations from dog 1. Thus, based on numerous findings, a diagnosis of lymphoma with Mott cell differentiation was made in both cases. This neoplasm must be differentiated from tumors that may have similar morphology, such as signet-ring cell carcinoma, globular leukocyte neoplasms, and balloon-cell melanoma. In most cases of lymphoma, the lineage of the lymphocytes cannot be confidently determined based on morphology alone. In fact, in the study of T-cell lymphoma and leukemia in dogs, neoplastic T-cells with plasmacytoid differentiation were described.16 However, if Mott cells are present and clearly part of a neoplastic cell population, a presumptive diagnosis of B-cell lymphoma can reliably be made. Immunochemical staining and molecular diagnostic tests are still necessary for definitive evaluation of cell lineage and clonality. Subsequent to initial writing of this manuscript, a case of a B-cell intestinal lymphoma with Mott cell differentiation was reported in a 1-year-old miniature Dachshund.17 Clinical, morphologic, immunophenotypic, and molecular characteristics in that case were similar to those presented here. The authors of that case also concluded that lymphoblasts developed directly into Mott cells without a plasma cell stage. However, in contrast to our cases, well-developed rER was observed in the Mott cells of the Dachshund by electron microscopy.

B-cell lymphoma with Mott cell differentiation

Further investigation is needed to determine the most appropriate classification of this entity. In humans, various manifestations of these tumors have been referred to as Mott cell tumors, plasmacytoid lymphomas, extramedullary plasmacytomas, MALT lymphomas, and signet-ring cell lymphomas. In these 2 dogs, we think B-cell lymphoma with Mott cell differentiation best describes the neoplastic process based on our results and the extensive and multifocal nature of the disease. It is important to recognize this type of lymphoproliferative disease as a distinct entity and to consider it as a differential diagnosis for GI tumors in dogs.

Acknowledgments The authors would like to thank Dr. Melinda Wilkerson, Kansas State University, for performing flow cytometry and immunophenotyping; MaryAnn Dixon from the Department of Pathology and Infectious Diseases, University of Florida, for immunohistochemistry and immunoglobulin staining of samples from both cases; Linda Wright from the Department of Pathology, University of Florida, for processing samples for ultrastructural analysis; Rosemary Vollmar and Dr. Andy Ambrus for the special stains and immunohistochemistry; Dr. Ross Payne, from the Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University,for the electron microscopy analysis performed at Texas A&M University; and Dr. Heather Wamsley and Dr Brian Stacy for support in image preparation.

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