Assessment of left and right ventricular systolic function in dogs with multicentric lymphoma.

OBJECTIVE: Myocardial dysfunction in cardio-oncology is generally thought to be related to the cardiotoxicity of chemotherapy treatment. However, it is known that some tumors have direct effects on myocardial function. These effects have already been studied in man, but there are no publications of these of the effects in dogs. Novel advanced echocardiographic techniques may allow early detection of myocardial dysfunction when compared to conventional echocardiographic techniques. This study aims to assess myocardial systolic function in dogs with multicentric lymphoma prior to initiation of chemotherapy. ANIMALS: Fifteen dogs with multicentric lymphoma and nineteen healthy dogs. METHODS: Case-control study. Dogs with multicentric lymphoma and healthy control dogs underwent physical examination, electrocardiography, systolic blood pressure measurement, standard and speckle tracking echocardiography to assess biventricular systolic function. RESULTS: There were no differences between groups in terms of ejection fraction, fractional shortening, left ventricular systolic and diastolic diameter, tricuspid annular plane systolic excursion, mitral annular plane systolic excursion and fractional area change of the right ventricle (RV). However, there was a reduction in the values of global circumferential strain (p = 0.0003), RV strain (p = 0.01) and RV tissue motion annular displacement (p < 0.05) in the dogs with lymphoma when compared to the control group. CONCLUSIONS: Speckle tracking techniques appear to demonstrate early systolic dysfunction, primarily affecting the RV, in dogs with lymphoma prior to chemotherapy treatment.

Assessment of Y chromosome copy number alterations in non-neoplastic and neoplastic leukocytes of male dogs.

The loss of the Y chromosome (ChrY), also known as LOY, is a common genetic alteration observed in men. It occurs in non-neoplastic cells as an age-related change as well as in neoplastic cells of various cancer types. While well-documented in humans, LOY has not been extensively studied in non-human mammals. In this study, we developed simple digital PCR-based assays to assess the copy number of ChrY relative to the X chromosome (ChrX) and chromosome 8 (Chr8) to evaluate ChrY numerical alterations in male canine DNA specimens. Using these assays, we analyzed non-neoplastic leukocytes from 162 male dogs without hematopoietic neoplasia to investigate the occurrence of age-related LOY in non-neoplastic leukocytes. Additionally, we examined 101 tumor DNA specimens obtained from male dogs diagnosed with various types of lymphoma and leukemia to determine whether copy number alterations of the ChrY occur in canine hematopoietic cancers. Analysis of the 162 non-neoplastic leukocyte DNA specimens from male dogs of varying ages revealed a consistent ∼1:1 ChrY:ChrX ratio. This suggests that age-related LOY in non-neoplastic leukocytes is rare or absent in dogs. Conversely, a decreased or increased ChrY:ChrX ratio was detected in canine neoplastic leukocytes at varying frequencies across different canine hematopoietic malignancies (P = 0.01, Fisher's exact test). Notably, a higher incidence of LOY was observed in more aggressive cancer types. To determine if this relative LOY to ChrX was caused by changes in ChrY or ChrX, we further analyzed their relative copy numbers using Chr8 as a reference. Loss of ChrX relative to Chr8 was found in 21% (9/41) of B-cell lymphomas and 6% (1/18) of non-T-zone/high-grade T-cell lymphomas. In contrast, a subset (29%, 4/14) of T-cell chronic lymphocytic leukemia showed gain of ChrX relative to Chr8. Notably, no relative LOY to Chr8 was detected indolent hematopoietic cancers such as T-zone lymphoma (0/9) and chronic lymphocytic leukemia of B-cell (0/11) and T-cell origins (0/14). However, relative LOY to Chr8 was present in more aggressive canine hematopoietic cancers, with incidences of 24% (10/41) in B-cell lymphoma, 44% (8/18) in non-T-zone/high-grade T-cell lymphoma, and 75% (6/8) in acute leukemia. This study highlights both similarities and differences in LOY between human and canine non-neoplastic and neoplastic leukocytes. It underscores the need for further research into the role of ChrY in canine health and disease, as well as the significance of LOY across various species.

Subcutaneous panniculitis-like T-cell lymphoma: Morphological, immunophenotypical and clonality assessment in six cats.

BACKGROUND: Primary cutaneous lymphoma represents 0.2%-3% of all feline lymphomas, with nonepitheliotropic lymphomas being the most common. In humans and dogs, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a primary nonepitheliotropic lymphoma with a T-cell phenotype developing in the subcutis and often mimicking inflammation. OBJECTIVE: The aim of this report is to describe pathological, phenotypical and clonal features of SPTCL in cats. ANIMALS: Six cats with SPTCL were included in this study. MATERIALS AND METHODS: Skin biopsies were formalin-fixed, routinely processed and stained. Histological and immunohistochemical investigation for anti-CD18, CD204, CD79a, CD20, CD3, FeLVp27and FeLVgp70 and clonality assessment were performed. RESULTS: Four male and two female domestic shorthair cats, mean age 11.2 years, developed SPTCL in the abdominal (three), inguinal (two) and thoracic (one) regions. Variably pleomorphic neoplastic lymphoid cells were present in the panniculus in percentages, expanding the septa (six of six) and extending into fat lobules in one of six cats. Tumours were associated with elevated numbers of neutrophils (five of six), lesser macrophages (six of six) and variable necrosis (six of six). Neoplastic cells expressed CD3+ (six of six), with clonal T-cell receptor rearrangement detected in five of six cats. CONCLUSIONS AND CLINICAL RELEVANCE: This is the first description of SPTCL in cats. Lesions can be confused with panniculitis, leading to delay in diagnosis and therapy. Awareness of this neoplastic disease is relevant to avoid misdiagnoses and to gain greater knowledge about the disease in cats.

Assessment of hypoxia-targeting therapy for gastrointestinal lymphoma in dogs: Preclinical test using murine models.

The transcription factor hypoxia-inducible factor 1α (HIF-1α) is expressed in several cancers under intratumoral hypoxic stress that arises during pathogenic processes, resulting in malignant progression. We previously reported that hypoxic stimulation enhances the growth potential of canine lymphoma cells by activating the HIF-1α signaling pathway. In contrast, evofosfamide (Evo) releases a DNA-alkylating moiety within hypoxic tumor regions, suggesting that Evo could serve as a hypoxia-targeting drug in canine lymphoma. This study aimed to use Evo to evaluate hypoxia-targeted therapy in dogs with gastrointestinal lymphoma (GIL) and investigate how Evo affects antitumor efficacy and adverse events in three type of murine xenograft models using T-cell GIL cells. In vitro tests, the sensitivity to Evo of three T-cell GIL cell lines under hypoxic culture was significantly higher than that under normoxic culture. Our metabolic analysis suggested that the three murine models might have high reproducibility as clinical cases in canine GIL. Our data showed that Evo showed significantly higher tumor growth potential and fewer adverse events in three type of murine models compared to lomustine; CeeNu (CCNU). Additionally, Evo suppressed the expression of HIF-1α protein in tumor tissues, suggesting that it may preferentially target and inhibit tumor cells in a hypoxic region. The evidence presented here supports the favorable preclinical evaluation that Evo may be effective for GIL in dogs.

Comparative Oncology Assessment of a Novel Inhibitor of Valosin-Containing Protein in Tumor-Bearing Dogs.

Pet dogs with naturally occurring cancers play an important role in studies of cancer biology and drug development. We assessed tolerability, efficacy, and pharmacokinetic/pharmacodynamic relationships with a first-in-class small molecule inhibitor of valosin-containing protein (VCP/p97), CB-5339, administered to 24 tumor-bearing pet dogs. Tumor types assessed included solid malignancies, lymphomas, and multiple myeloma. Through a stepwise dose and schedule escalation schema, we determined the maximum tolerated dose to be 7.5 mg/kg when administered orally on a 4 days on, 3 days off schedule per week for 3 consecutive weeks. Adverse events were minimal and mainly related to the gastrointestinal system. Pharmacokinetic/pharmacodynamic data suggest a relationship between exposure and modulation of targets related to induction of the unfolded protein response, but not to tolerability of the agent. An efficacy signal was detected in 33% (2/6) of dogs with multiple myeloma, consistent with a mechanism of action relating to induction of proteotoxic stress in a tumor type with abundant protein production. Clinical trials of CB-5339 in humans with acute myelogenous leukemia and multiple myeloma are ongoing.

Lymphoma in Psittacine Birds: A Histological and Immunohistochemical Assessment.

In psittacine birds, round cell neoplasms that originate from lymphocytes, plasma cells, histiocytes, or mast cells are sporadic and poorly described. The lack of morphological and immunohistochemical diagnostic criteria or grading schemes make specific diagnoses and prognoses challenging. We assessed cases of psittacine birds diagnosed with round cell neoplasia from 3 North American veterinary diagnostic laboratories to describe the diagnostic features of these tumors. For all cases, demographic data, anatomic distribution, histological features, and immunoreactivity for T (CD3) and B (Pax5 and MUM-1) cell markers were assessed using tissue microarrays and whole slide mounts. Thirty-eight psittacine birds representing 14 species were included. Tumors were mainly infiltrative and multicentric, were composed of homogenous sheets of round to polygonal cells, and commonly presented with a high mitotic count (average 21 mitoses per high-power field). Based on Pax5 immunoreactivity, B-cell lymphoma was most common (19/38 [50%]), and was significantly associated with involvement of the gastrointestinal and urogenital systems. Of the 38 cases, 6 (16%) were consistent with T-cell lymphoma, 3 (8%) with plasma cell tumor, and 3 (8%) were double-reactive for both B- and T-lymphocyte markers. This is the first study to describe morphologic and immunohistochemical features of round cell neoplasia in a large number of psittacine birds, and provides benchmark data for future studies aimed at elucidating the diagnosis and prognosis of these neoplasms. These data also provide useful information about reactivity of commercially available antibodies as lymphocyte markers in tissues of multiple psittacine species.

Assessment of biomarkers influencing treatment success on small intestinal lymphoma in dogs.

This study aimed to determine a reliable therapeutic biomarker for localized small intestinal lymphoma (SIL) in dogs based on clinical and histopathological features. We retrospectively investigated 84 dogs with localized SIL, including 36 dogs receiving surgery and 48 dogs receiving chemotherapy. The dogs receiving surgery were divided into two subgroups: 18 dogs (group 1) with overall survival (OS) <120 days (median OS) and 18 dogs (group 2) with OS ≥120 days. Correspondingly, the dogs receiving chemotherapy were divided into 24 dogs (group 3) with OS <98 days (median OS) and 24 dogs (group 4) with OS ≥98 days. Clinical, haematological, histopathological and immunohistochemical analyses were comparatively evaluated among the four subgroups. There was no significant difference in OS between the surgery and chemotherapy groups. In dogs receiving surgery, the rate of Ki67-positive cells was significantly increased in group 1 compared to group 2 and showed no significant difference between groups 3 and 4. In dogs receiving chemotherapy, the rate of O6-methylguanine-DNA methyltransferase (MGMT) was significantly higher in group 3 than in group 4 and showed no significant difference between groups 1 and 2. Additionally, our data showed that OS in dogs with higher Ki67 expression might be significantly increased by chemotherapy than by surgery, that of those with higher MGMT expression might be significantly increased by surgery than by chemotherapy, and Ki67 and MGMT were independent of each other. Indices of Ki67 and MGMT are suggested therapeutic biomarkers to determine the optimal first-line treatment for localized SIL in dogs.

Preliminary assessment of serum clusterin as a potential biomarker for canine lymphoma.

Clusterin (CLU), also known as apolipoprotein J, is a widely expressed, heterodimeric, glycoprotein, important in tumourigenesis, apoptosis and immunoregulation. In humans, CLU expression has been associated with anaplastic large cell and Hodgkin's lymphoma. In this study, serum CLU levels in dogs with multicentric lymphoma (MLSA) were compared with healthy control dogs, using both western blot and enzyme-linked immunosorbent assay (ELISA). Western blot confirmed the presence of CLU in dog sera at the predicted molecular weight and the relative levels detected correlated with the levels detected by ELISA. CLU level analysis by ELISA found treatment naïve dogs with MLSA had a significantly (P < .001) lower serum CLU level compared with healthy controls. However, there was no significant difference between MLSA dogs prior to treatment and in complete remission. The wide variation in serum CLU levels may limit its potential as a single candidate biomarker for MLSA, although any prognostic predictive value of serum CLU concentrations has yet to be assessed.

Clonality testing as complementary tool in the assessment of different patient groups with canine chronic enteropathy.

Differentiation between canine chronic enteropathy (CCE) and intestinal lymphoma is a diagnostic challenge as histopathology might fail to yield unequivocal results. Detection of clonal rearrangements of the T-cell-receptor gamma (TCRG) chain and IG heavy chain (IGH) V-J genes offer a useful solution. In this retrospective study, histopathology samples of 35 CCE patients and 7 healthy Beagle dogs underwent clonality testing. Patients suffered either from inflammatory bowel disease (IBD), food responsive diarrhea (FRD) or protein loosing enteropathy secondary to IBD (PLE/IBD). Healthy Beagles served as controls (CO). Canine IBD activity index (CIBDAI) and histopathological WSAVA-grading differed significantly (p<0.001) between groups. CIBDAI improved significantly after appropriate therapy (p < 0.0001). Intestinal biopsies of all CO showed polyclonal patterns for B- and T-cell primers. All samples from CCE patients showed polyclonal patterns for the B-cell primers. Targeting TCRG, 4 patients showed a monoclonal or oligoclonal pattern of the lymphocytic infiltrates in the duodenum and/or colon. Clinical improvement was observed in all dogs. Although a small cell lymphoma cannot be excluded in view of the short follow up duration, a false positive result, in the sense of a canonical rearrangement or unspecific amplification due to a antigenic stimulation in a non-neoplastic inflammatory process is possible.

Immunohistochemical assessment of metalloproteinases MMP2 and MMP9 expression in canine various subtypes of lymphomas in relation with proliferative and apoptotic markers.

Matrix metalloproteinases 2 and 9 (MMP2 and MMP9) are proteolytic enzymes involved with extracellular matrix degradation. They play a role in tumor invasion and metastases. Because of their ability to degrade signaling molecules presented in extracellular matrix, MMPs contribute to tumor proliferation and apoptosis. The aim of this study was to evaluate expression of MMP2 (latent and both active and latent forms) and MMP9 (active, latent, active and latent forms) in different subtypes of canine lymphomas and their relationship with proliferative (mitotic index and percentage of Ki67-positive cells) and apoptotic (apoptotic index) markers. Expression of MMPs was assessed immunohistochemically using an immunoreactive score system. Expression of both MMPs was found in all 20 examined lymphomas belonging to six subtypes. Most cases showed a moderate level of all analyzed forms of MMP2 and MMP9. High expression of MMPs was found in single cases. Except for a positive correlation between the active form of MMP9 and the mitotic index for all lymphoma cases, no other correlations between any remaining forms of MMPs and neither proliferative nor apoptotic markers were found, irrespective of whether the analysis encompassed all cases or the most numerous lymphoma subtypes i.e. centroblastic and Burkitt-like. Our results were not able to clearly confirm the influence of MMPs on the proliferation and apoptotic activity of canine lymphoma cells. However, further studies examining MMPs activity by zymography, expression of their inhibitors and other factors involved in activation of cell proliferation and apoptosis inhibition are needed to clarify the role of MMPs, especially the active form of MMP9, in the behavior of canine lymphoma cells.

Assessment of Lymphoid Molecular Clonality in Canine Thymoma.

The aim of this study was to document the molecular clonality of lymphoid cells in canine thymoma using polymerase chain reaction for antigen receptor rearrangement (PARR). Fifteen formalin-fixed and paraffin wax-embedded samples of canine thymoma were analyzed for T- and B-cell receptor clonality. Two of these 15 cases were excluded from the study due to insufficient DNA concentration. Twelve of the 13 remaining samples (92.3%) showed a polyclonal lymphoid component and in one case the lymphoid component was monoclonal (T-cell clonality). PARR could therefore be a useful tool for differentiating canine thymoma from canine mediastinal lymphoma.

Vasovagal tonus index (VVTI) as an indirect assessment of remission status in canine multicentric lymphoma undergoing multi-drug chemotherapy.

Vasovagal tonus index (VVTI) is an indirect measure of heart rate variability and may serve as a marker of disease severity. Higher heart rate variability has predicted lower tumour burden and improved survival in humans with various tumour types. The purpose of this pilot study was to evaluate VVTI as a biomarker of remission status in canine lymphoma. The primary hypothesis was that VVTI would be increased in dogs in remission compared to dogs out of remission. Twenty-seven dogs were prospectively enrolled if they had a diagnosis of intermediate to high-grade lymphoma and underwent multidrug chemotherapy. Serial electrocardiogram data were collected under standard conditions and relationships between VVTI, remission status and other clinical variables were evaluated. VVTI from dogs in remission (partial or complete) did not differ from dogs with fulminant lymphoma (naive or at time of relapse). Dogs in partial remission had higher VVTI than dogs in complete remission (p = 0.021). Higher baseline VVTI was associated with higher subsequent scores (p < 0.001). VVTI also correlated with anxiety level (p = 0.03). Based on this pilot study, VVTI did not hold any obvious promise as a useful clinical biomarker of remission status. Further investigation may better elucidate the clinical and prognostic utility of VVTI in dogs with lymphoma.

Assessment of cardiac troponin I (cTnI) and tissue velocity imaging (TVI) in 14 dogs with malignant lymphoma undergoing chemotherapy treatment with doxorubicin.

Doxorubicin has been shown to be cardiotoxic at high doses but is an efficacious chemotherapeutic agent in the treatment of canine lymphoma. Echocardiographic measurements and serum ultrasensitive cardiac troponin I (cTnI) levels were obtained before and after doxorubicin administration in 14 dogs diagnosed with lymphoma. The aim of this prospective study was to evaluate changes in cTnI concentrations and tissue velocity imaging (TVI) values in dogs with lymphoma undergoing chemotherapy with doxorubicin. A total of 182 cTnI and 1017 TVI measurements were performed. Standard echocardiographic parameters, tissue Doppler indices and cTnI concentrations did not differ at any time point within a 12-week cyclic combination protocol. In conclusion, the use of doxorubicin at standard doses in the treatment of canine lymphoma may not be associated with significant myocardial damage.

Identification of a novel feline large granular lymphoma cell line (S87) as non-MHC-restricted cytotoxic T-cell line and assessment of its genetic instability.

Feline large granular lymphocyte lymphomas are rare but very aggressive tumors with a poor prognosis. In this study, a cell line from an abdominal effusion of a cat with large granular lymphoma was characterized. Immunophenotype staining was positive for CD3 and CD45R, and negative for CD4, CD8, CD56, CD79α, BLA.36 and NK1. A TCR γ gene rearrangement was detectable by PARR. Neither FeLV antigen nor exogenous FeLV provirus could be detected. A chromosomal instability associated with a centrosome hyperamplification could also be determined. The cell line is able to lyse target cells without antigen presentation or interaction with antigen presenting cells. Therefore, these cells were classified as genetically instable non-MHC-restricted cytotoxic T cells with large granular lymphocyte morphology.

Assessment of temporal association of relapse of canine multicentric lymphoma with components of the CHOP protocol: Is cyclophosphamide the weakest link?

Combination chemotherapy, using cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone (CHOP), is the most commonly used treatment for canine lymphoma. Most affected dogs respond during the initial stages of chemotherapy, but many relapse. The aim of this study was to evaluate the relationship between the use of specific chemotherapy drugs and clinical relapse, using the modified Madison-Wisconsin, 25 week chemotherapy protocol. Forty-one of 68 dogs affected with multicentric lymphoma relapsed during the treatment period. Relapse occurred more frequently after the administration of cyclophosphamide (n = 24; P < 0.01), compared with vincristine (n = 9) or doxorubicin (n = 5). Therefore, the therapeutic outcome of traditional CHOP-based chemotherapy might be improved by replacing cyclophosphamide with other cytotoxic drugs.

Concurrent diseases in hyperthyroid cats undergoing assessment prior to radioiodine treatment.

Hyperthyroidism is a common endocrinopathy of geriatric cats, which are also prone to various other diseases. This retrospective study examined the prevalence and type of non-renal concurrent diseases present in cats referred for radioiodine assessment that were believed to have no other comorbidities at the time of referral. Ninety-four cats were included and analysed. Seventeen cases (18%) were identified as having concurrent disorders, with alimentary lymphoma (n = 5) and chronic enteropathy (n = 4) as the two most common comorbid diseases. The eosinophil count, total bilirubin and total calcium were significantly higher in the concurrent disease group, although the differences are unlikely to be clinically useful. The results support the utility of careful and individual assessment for all hyperthyroid cats prior to receiving radioiodine.

[Diagnostic assessment of peritoneal fluid cytology in horses with abdominal neoplasia]. / Diagnostische Aussagekraft der Zytologie von Bauchpunktaten bei abdominalen Tumoren des Pferdes.

OBJECTIVE: To evaluate the diagnostic value of peritoneal fluid (PF) cytology for clinical diagnosis of abdominal neoplasia in horses. MATERIAL AND METHODS: Ten horses with histopathologically confirmed abdominal neoplasia, in which a PF analysis was performed, were included in this retrospective study. PF was analyzed for total protein concentration and a nucleated cell count was performed. Using cytological criteria of malignancy, the PF samples were evaluated regarding their probability of malignancy. RESULTS: Cytologic classification of cells according to criteria of malignancy allowed a positive cytologic diagnosis of neoplasia in 5 out of 10 peritoneal fluid samples. Malignant lymphoma was the most commonly diagnosed neoplasia (3/10) and could be identified by cytology in 2/3 cases. In 1/2 horses with plasma cell myeloma neoplastic cells were similarly found. Malignant melanoma (2/10) was diagnosed using cytology in one case (presence of melanin-containing cells). Cytological diagnosis of malignant neoplasia was established in the only horse with gastric squamous cell carcinoma, but the morphology of the identified tumour cells did not allow a specific diagnosis. Thus, a definitive diagnosis was achieved in 4/5 horses with proven abdominal neoplasia. The horses with adenocarcinoma (1/10) and haemangiosarcoma (1/10) had no evidence of neoplasia based on cytological findings. No relationship between total protein concentration or the nucleated cell count with the histolopathological diagnosis of abdominal neoplasia was found. Abnormal mitotic figures were considered of greater diagnostic value than the overall mitotic rate. CONCLUSION: The implementation of nuclear criteria of malignancy in the cytologic evaluation of PF samples allows the identification of neoplastic cells to an acceptable degree. For this purpose, the knowledge of the highly variable morphological features of mesothelial cells is essential. The absence of malignant cells does not rule out abdominal neoplasia. CLINICAL RELEVANCE: PF cytology should be considered as a valuable, minimally invasive, simple, and rapid diagnostic technique in horses with suspected abdominal neoplasia.

Effect of a nutritional reconditioning program for thin dairy cattle on body weight, carcass quality, and fecal pathogen shedding.

OBJECTIVE: To assess changes in body weight, carcass quality, and fecal pathogen shedding in cull dairy cows fed a high-energy ration for 28 or 56 days prior to slaughter. DESIGN: Randomized clinical trial. ANIMALS: 31 adult Holstein dairy cows. PROCEDURES: Cows were randomly assigned to a control (immediate slaughter) group or a 28-day or 56-day feeding group. Cows in the feeding groups received a high-energy feed and were weighed every 7 days. Carcasses were evaluated by USDA employees. Fecal and blood samples were collected at the start and end of the feeding periods. RESULTS: Body condition score and adjusted preliminary yield grade were significantly increased in both feeding groups, compared with values for the control group; body weight, hot carcass weight, dressing percentage, and ribeye area were significantly increased after 56 days, but not after 28 days, compared with values for the control group. Average daily gain and marbling score were significantly lower after feeding for 28 days versus after 56 days. Prevalence of Escherichia coli O157:H7 shedding in feces decreased from 14% to 5.6%, but this difference was not significant. Cows seropositive for antibodies against bovine leukemia virus that had signs of lymphoma and lame cows had a low average daily gain. Net loss was $71.32/cow and $112.80/cow for the 28-day and 56-day feeding groups, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Feeding market dairy cows improved body condition and carcass quality. Cows seropositive for antibodies against bovine leukemia virus that have signs of lymphoma and lame cows might be poor candidates for reconditioning.

The diagnostic assessment of canine lymphoma: implications for treatment.

Lymphoma in dogs is a heterogeneous cancer with highly variable prognosis. Many types of canine lymphoma have similar counterparts in the World Health Organization classification of human lymphoid tumors. The most common variant of canine lymphoma is diffuse large B-cell lymphoma, which, if treated with multiagent chemotherapy, has a survival time of approximately 12 months. T-cell lymphomas are more heterogeneous and high- and low-grade variants are common, which necessitates classification beyond B- versus T-cell lineage.