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Home , Cancer in dogs, Lymphedema, Mastocytosis, Splenic tumor

Canine MCT: One Size Does Not Fit All Sue Ettinger, DVM, DACVIM Dr. Sue Vet Tarrytown, NY

Biology and etiology Mast cells arise from bone marrow, are located in connective tissues throughout body, and are an important component of . Mast cells play a central role in inflammatory and immediate allergic reactions. Mature mast cells store inflammatory mediators, including , proteases, chemotactic factors, cytokines, and arachidonic acid metabolites. These may induce paraneoplastic syndromes in with MCT

MCT epidemiology & risk factors MCT are the most common cutaneous tumor in dogs, accounting for 16 to 21% of tumors. Risk factors include 1. Age: Higher incidence in older dogs (mean 9 y.o.) but also reported in young dogs 2. Breed: Mixed breeds most common; Boxers, Boston Terriers, Labradors, beagles, schnauzers 3. Gender Not correlated MCT Etiology: The cause is largely unknown and they are rarely associated with chronic or application of skin irritants. There is no clear evidence of viral cause. The role of estrogen and progesterone are poorly defined. Genetic alterations are also not completely understood, but the following have been associated: p53 - tumor suppressor, p21 and p27 - cell cycle regulation, c- KIT – RTK for factor C-Kit is tyrosine kinase (RTK) that binds to stem cell factor (SCF), the ligand. STF- interactions promote development of mast cells from hematopoietic progenitors. RTK are enzymes that transfer phosphate from ATP to cell and the phosphate is on the amino acid tyrosine. These are important in signal transduction and cellular activity, like cell division. Dysregulation in c-kit may promote mast cells’ uncontrolled growth or survival. 30-50% dogs with MCT have c-kit , essentially causing the cells to be stuck in “on” position, leading to continuous c-kit activation and unregulated cell growth. The is internal tandem duplications (ITD) in exons 11 &12 (in the juxtamembrane domain). ITD mutations associated with increased recurrence and death. Mutations have also been identified in exons 8 and 9.

Clinical presentation MCT are most common in dermal and SQ tissues. The sites are: Trunk 50-60%, Limbs 25%, and head & neck least common. They have a varied appearance. They are typically solitary, but 11-22% has multiple lesions. The tumor clinical appearance is associated with histologic differentiation. Well-differentiated MCT are typically single, 1-4 cm diameter, slow growing, rubbery, non-ulcerated, alopecic, and present 6+ months. Undifferentiated MCT are large, rapidly growing, ulcerated and irritated, and the surrounding tissue is edematous and inflamed. Small satellite nodules may be present Disease symptoms can be complicate by signs attributable to release of , heparin and other vasoactive amines. Darier’s sign refers to the wheal & flare in surrounding tissues following manipulation of the MCT and is caused by . GI ulceration causes possibly with , melena, anorexia, and . GI ulceration is due to histamine stimulation of H2 receptors on parietal cells that increased HCl. GI ulceration is noted in 35 to 83% necropsy specimens. Prognostic factors • Histologic grade • Clinical stage • Location • Systemic signs • Recurrence • Tumor size • Mitotic index (MI)

Diagnostics Preliminary Diagnosis is typically made with fine needle aspirate. On cytology, the neoplastic cells are small to medium sized round cells, with abundant, small, uniform cytoplasmic granules that stain purplish-red (metachromatic) To stage or not to stage? (or I’ve done my aspirate, now what) Should you do first OR diagnostics prior to surgery? Diagnostics may include incisional for grade, LN FNA, CBC, chemistry panel, UA,AUS +/- / FNA, Bone marrow cytology, and buffy coat?

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Who clinical stage There is problems with current staging, and the usefulness of WHO is being questioned. Stage III is vague, and combines multiple cutaneous nodules with large infiltrating tumor. There was a presumption that multiple tumors represent systemic metastasis vs. de novo MCT. IN addition, the diagnosis of metastasis based on presence of mast cells in LN FNA, but mast cells are also present in healthy animals. There is also questionable value of buffy coat smears and bone marrow in staging. Histologic classification: 3-Tiered • Grade 1: clearly defined cytoplasmic boundaries with regular, spherical or ovoid nuclei, rare or absent mitosis, abundant large deep staining cytoplasmic granules • Grade 2: closely packed cells with indistinct cytoplasmic boundaries, N:C ratio lowers than anaplastic type, infrequent mitoses, and more granules that anaplastic type • Grade 3: highly cellular, frequent mitoses, undifferentiated cytoplasmic boundaries, nuclei irregular in size and shape, sparse cytoplasmic granules Histologic grade is a prognostic for biologic behavior and clinical outcome, and an accurate predictor for metastatic behavior. Low grade: <10%, Intermediate grade: low to moderate, High grade: 55-96%. Metastasis is typically to local LN, liver and spleen, bone marrow. Mitotic index (MI) Mitotic Index is an indirect measure of cell proliferation based on number of mitotic figures, and is a strong prognostic factor. It can be performed during routine histology and is easier than other proliferation markers that require additional immunohistochemical staining (AgNOR, Ki-67) Romansik 2007, Vet Path, 148 dogs: MI was significantly increased with grade, but there was no association MI and tumor recurrence. MI was associated with metastasis and survival: 1. MI all grades: <5/10 HPF, MST 70 mos.; >5/10 HPF, MST 5 mos. 2. MI associated with metastasis and survival 3. MI all grades: <5/10 HPF, MST 70 mos., >5/10 HPF, MST 5 mos. 4. For grade 2: <5/10 HPF, MST 70 mos., >5/10 HPF, MST 5 mos. 5. For grade 3: <5/10 HPF, MST not reached, >5/10 HPF, MST < 2 mos. Note MI not consistent from study to study & expect that the cutoff will continue to be refined as more studies evaluate mitotic index

Molecular prognostic factors Argyrophilic nucleolar organizing regions (AgNORs) are loops of DNA on nucleoli and sites for rRNA transcription/ AgNORs are related to DNA synthesis and metabolic activities, and the size and number reflect nuclear activity. The quantity has been correlated with indirect measure of cell proliferation Prognostic for : Mammary tumors (Bostock 1992, Bratulic 1996), STS (Ettinger 2004), MCT (Simoes 1994; Kravis 1996; Bostock 1989) Proliferating cell nuclear antigen (PCNA) is a 36 kDa nuclear non-histone protein, essential for DNA synthesis, plays fundamental role in initiation of cell proliferation, preferentially occurs in dividing cells. PCNA is undetectable or present in small amounts in resting cells but maximal during S-phase, so the level correlates directly with cellular proliferation rates & DNA synthesis. PCNA is predictive for MCT recurrence (Simoes 1994). It is an Indirect measure of cell proliferation and associated with prognosis but NOT independent of grade. Ki67 is a nuclear protein expressed in all phases of cell cycle, highest in M phase, but NOT expressed in non-cycling cells (Go), Associated with high MI and grade. It is used to determine proliferation index. Correlations in MCT: surgery outcome in MCT (Abadie 1999). This prognostic factor is independent of grade. KIT is a tyrosine receptor in hematopoietic stem cells and other cell types. Cytoplasm expression is associated with c-KIT mutation and poor clinical outcomes (Webster, Vet Path 2007) Key findings Increased Ki67 and AgNORS both significantly associated with decreased survival. MCT with aberrant KIT localization or ITD c-KIT mutations are associated with increased cell proliferation. Multivariable analysis showed Ki67 were significantly associated with incidence & rate of subsequent tumor occurrence at original tumor site, rate of MCT at distant site

The new 2-tiered grading system Unfortunately there is inter-observer variation among pathologists, and pathologists tend to opt for grade 2 when it is borderline between grade 1 & 2. If more pathologists are calling tumors grade 2, the prognostic value is weakened. Based on the original work by Patnaik, there is ~ 50/50 chance of 5 year survival for grade 2 tumors

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A 2 tiered system had been developed and is based on the number of mitoses (< or > 7), presence of multinucleated cells or bizarre nuclei, and karyomegaly (increased nuclear size). High grade tumors significantly associated with shorter time to metastasis mast cell tumor associated mortality, shorter overall survival time. MST for high-grade MCT < 4 months vs. > 2 years for low-grade MCT This system is still relatively new and should continue to be validated in future studies.

Other diagnostics Buffy coats have been used historically but are unreliable. There can be high number of false positives with inflammatory skin disease, parvovirus, regenerative , traumas, other (McManus 1999) Spleen and liver cytology: According to Finora, 2006, routine FNA of normal liver and spleen on AUS is not useful but then another study concluded cytology was indicated whether AUS is normal or abnormal (Stefanello 2009).

Treatment Surgery: Surgery all that you need? Surgery is the ideal treatment in areas amenable to wide resection. The recommendations for margins have historically 3 cm, but 2 cm lateral margins may be adequate for most (Simpson 2004). For small and lower grade, extensive deep margins are just as crucial: 1 fascial plane deep, 4 mm deep margins. The majority of naïve dermal MCT are intermediate or low grade will be cured with surgery alone, provided site is amenable. Location: In some locations, wide margins often not possible, i.e. distal limb. In my opinion, amputation is probably too aggressive. But further therapy will likely be needed after surgery. Post-operative options include external beam RT, scar revision, and Surgery and margins Histologic assessment of margins may be unreliable. 37.5% recur with clean margins, and 36% have no recurrence with incomplete margins. In Seguin 2001: grade 2 MCT with clean excision, only 5% completely removed grade 2 recur, 5% metastasized, and 11% developed 2nd MCT. Note that microscopic formalin-fixed parameters do not reflect margin size at surgery. Tissue shrinkage of up to 30% for cutaneous tissues occurs. (RT) is recommended when wide surgical excision not feasible. Monotherapy has varying control rates 40 to 45 Gy 1 year control rates of 50, but surgery to achieve clinical stage 0 (microscopic disease) followed by full course RT, (typically 15 treatments over 3 weeks) has high control rates of 85-95% 2-year control rates for grade 1 and 2. Should do prophylactic nodal irradiation (PNI)? It is probably unwarranted in low to intermediate grade MCT.

Chemotherapy: Single-agent • Vincristine McCaw 1997: NOT effective for measurable disease • Vinorelbine: Grant 2008: Overall Response rate (ORR) 8% • Single-Agent Vinblastine o Henry 2007: ORR 12% o Rassnick 2008L Higher dose higher RR (27 vs 12%) o Greater GI toxicities and grade 3 or 4 neutropenias • Single-Agent Lomustine: Rassnick 1999: ORR 42%, Neutropenia was dose limiting toxicity • Single-Agent Hyroxyurea: Rassnick 2010: ORR 28%, overall remission duration 60 d., Neutropenia was dose limiting toxicity Steroids As a single agent in grade 2-3 (McCaw 1994), ORR was 20% (5 of 25). But prior to RT for non-resectable grade 1-3 (Dobson 2004), RR was higher at 75% (18/24). When given prior to surgery (neoadjuvant) for grade 1-3 pre-op (Stanclift, 2008), ORR was 70%. Single agent summary Response rates (CR &PR) are variable • Vincristine 7% • Lomustine 42% • Steroids 20-75% Combination therapies Studies have shown that combination therapies offer improved efficacy 1. Vinblastine and prednisone, Thamm 1999: Pred @ 2 mg/kg/d, tapered and discontinued over 12-26 weeks; VBL @ 2mg/m2 every 1 to 2 weeks. Efficacy (gross disease) ORR 47%. Adverse effects (AE): 8/41 (20%), typically after 1st VBL, 15% mild, 5% severe and treatment discontinued

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2. VBL, CTX and prednisone, Camps-Palau 2007: Pred @ 1 mg/kg/d, tapered and discontinued over 24-32 weeks; VBL @ 2- 2.2 mg/m2 every 3 weeks; CTX @ 200-250 mg/m2 IV or PO every 3 weeks. Efficacy (gross disease, n=11), ORR 64% AE: Well-tolerated, Grade 1 neutropenia & grade 2 GI toxicity 3. Vinblastine, CCNU and prednisone, Rassnick 2010: Pred @ 2 mg/kg/d, tapered and discontinued over 24-28 weeks; CCNU @ 70 mg/m every 4 weeks, wk 1, 5, 9, then q 6 wk; VBL @ 3.5 mg/m2 every 4 weeks, wk 3, 7, 11, then q 6 wk, Prophylactic TMS for 1st treatments, Efficacy (gross disease) ORR 65%, Overall PFS for adjuvant 489 d (16 months), AE: febrile neutropenia, Persistent ALT 9% 4. Leukeran and prednisone Taylor 2009: ORR 38% Median response duration 533 d Tyrosine kinase inhibitors (TKI) are drugs that inhibit RTK, and most block kinase binding to ATP competitive inhibitor of ATP binding which prevents phosphorylation of intracellular kinase domain of associated RTK and subsequent signal transduction. The drugs may also inhibit other RTK in split kinase family including VEGF and PDGFR. Palladia (toceranib phosphate) is an oral TKI that blocks activity of multiple receptors and selectively target split kinase family of RTKs. It exerts antiangiogenic and antiproliferative effects. The oral bioavailability is 77%. Palladia is labeled for dogs with grade 2 or 3, recurrent cutaneous MCT, + regional LN involvement, and was FDA approved in June 2009. Palladia is 1st anti-cancer drug FDA approved for dogs. In the clinical field study of single agent Palladia (London 2009, Clin Cancer Research), this was a multi-center placebo- controlled, double-blinded study looking at the objective response (PR or CR) to single-agent Palladia @ 3.25mg/kg EOD. The biologic response rate was 59.5% for all dogs (blinded + open): CR 16%, PR 31.3%, and SD 12.2%. The odds ratio of OR was 6.5x higher in Palladia-treated patients vs. placebo. Grade 2 MCT had better outcomes than grade 3, and had a significantly longer time to progression (TTP) and significantly longer response duration. Palladia was effective with or without c-Kit mutation (positive: 69% response; negative: 37% response) Adverse Events (AE): GI side effects were most common AES, >10% Palladia dogs (during blinded phase). Neutropenia was the most common lab abnormality. From the study the recommended dose for MCT is 3.25 mg/kg EOD. It is recommend to give with or without food (I recommend with food), give in evening, and adjust dose based on biweekly assessments for 1st 6 weeks, then every 4 to 6 weeks. Dose reductions of 0.5 m/kg are recommended with a minimum dose of 2.2 mg/kg EOD. If AE occur, drug holidays for up to 2 weeks. It is important to not be complacent in monitoring. Clients must be educated if any side effects are noted, STOP medication, start just in case medications, and contact a veterinarian. Early recognition if side effects are critical when using Palladia!! TKI combination protocols are starting to be evaluated. Palladia given with vinblastine caused myelosuppression, and the dose of vinblastine was reduced significantly. The ORR of 71% is encouraging. In conclusion chemotherapy should be considered for: High grade/grade 3, dogs with distant metastasis, node metastasis, C-kit positive dogs, dogs with high proliferation scores, and for non resectable MCT in the neo-adjuvant setting. Dogs with multiple MCT in a short time period may also be considered for chemotherapy. Dogs with low grade/grade 1 or grade that have low proliferation scores and are c-kit negative can typically be managed with local therapy (surgery +/- radiation).

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Easy Ways to Improve Chemotherapy Treatment in Your Practice Sue Ettinger, DVM, DACVIM Dr. Sue Cancer Vet Tarrytown, NY

“Cancer” is a scary word that is often equated with death. There is often a visceral fear of cancer, and pet owners think cancer equals pain and suffering. There are many myths and misconceptions about chemotherapy in pets. Owners think cancer treatment will just make the patient sicker. But cancer is not a death sentence. With treatment, many cancer patients are not only living longer, but living well. Chemotherapy is well tolerated in the majority of dogs and cats undergoing treatment. Whether you are directly managing chemotherapy patients or sharing cases with an oncologist, there are simple tips and tricks to improve quality of life and minimize side effects in chemotherapy patients.

Chemotherapy Conventional chemotherapy Conventional chemotherapy is typically given at high dosages, known as maximum tolerated dose, or MTD. The goal is to kill the rapidly dividing cancer cells. But some normal cells that also have high turnover often can be temporarily damaged by MTD chemotherapy. The normal tissues that typically are most sensitive to chemotherapy are the bone marrow, hair follicles (alopecia), and the gastrointestinal lining. This is often referred to as “BAG”. As a result there is a break period to allow these cell populations to recover. MTD is typically given weekly to every 3 weeks. The overall toxicity rate is very low in veterinary chemotherapy patients. In my experience, only 15-20% experience side effects, and this is even less common in cats than dogs. The primary goal is to provide the best quality of life possible for as long as possible. As I say, live longer, live well. Most side effects are mild and medically manageable. Metronomic chemotherapy In contrast to MTD chemotherapy, metronomic chemotherapy is pulse or low-dose continuous chemotherapy. This is typically administered daily or every other day. The target is endothelial cells in that line tumor . The goal may be tumor is stabilized, but this prevents further growth and spread. Common chemotherapy drugs include Palladia, cyclophosphamide, and chlorambucil and also with NSAIDS. There is still much to be learned including best drugs, dose, schedule, tumor types, and toxicity. This can be considered for some dogs and cats with advanced metastatic disease.

Side effects Alopecia Alopecia (hair loss) is due to damaging the rapidly dividing hair follicle. In dogs, potentially affected breeds have continuously growing coats and include Poodles, Scottish Terriers, and Westies. In cats, alopecia is rare, but shaved areas tend to grow back more slowly (limb catheters, abdominal ultrasounds). Cats more commonly lose their whiskers. The good news is that hair and whiskers will re-grow once the treatments have completed. Occasionally, hair will grow back a different texture or color. In cats it is typically softer, aka the “chemo coat”. It is important to remember pets do not care about this cosmetic side effect, and it does not impact the quality of life. However, pet owners like to be advised about the whiskers and coat so they are not surprised. Gastrointestinal (GI) toxicity Gastrointestinal (GI) toxicity includes vomiting, , decreased appetite, . It typically 1 to 5 days after chemotherapy and is self-limiting – lasting on average 2-3 days. These side effects are less common in feline chemotherapy patients than dogs. I recommend being very proactive with nausea/anti-emetic drugs. I often will use Cerenia or preventatively and as needed. I recommend giving Cerenia at administration with the following drugs: doxorubicin, vincristine, vinblastine, carboplatin, mitoxantrone, dacarbazine, and the MOPP protocol. If the pet has nausea/vomiting event within 24 hours of administration, I will add Cerenia SQ or IV at the time of administration at the subsequent treatment. For oral chemotherapy being given at home, I advise the owner give oral Cerenia 1 hour before chemotherapy pill dosing. I always recommend oral Cerenia for 4 days after doxorubicin in dogs to prevent nausea and vomiting. If there are side effects with other chemotherapeutics, I also typically will add prophylactic medications to prevent side effects like nausea, vomiting or diarrhea as indicated. If the GI side effects are more severe in a patient, the drug type or dosage may be adjusted at subsequent treatments to minimize the chance of side effects recurring. Unlike dogs, I do not routinely use GI medications unless the cat had issues with a prior treatment or had GI clinical signs prior to treatment (i.e. GI ) For diarrhea, I typically send my patients home with metronidazole and a probiotic. Metronidazole is a synthetic nitroimidazole with antibacterial, anti-protozoal and anti-inflammatory properties and is commonly prescribed for acute and chronic diarrhea. It is

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metabolized and excreted by the liver, so take care with patients with impaired liver function. Neurotoxicity is associated with higher doses and chronic use, so I do not recommend chronic use. Dose: 15 mg/kg PO BID for 5 days Rx Clay is a good option for chronic diarrhea and patients needing multiple courses of metronidazole. Rx Clay is a calcium aluminosilicate (CAS), which is geological nanomaterial that adsorbs bacterial enterotoxins and increases reabsorption of intraluminal water in GIT

Vomiting and diarrhea Acute vomiting is typically associated with cisplatin, doxorubicin (Adriamycin), dacarbazine (DTIC), cyclophosphamide, actinomycin, 5-FU streptozoticin. This can typically be prevented with pre-treatment Delayed vomiting is more common in our patients. This is due to direct damage to rapidly dividing GIT cells (crypt cells) or via the centrally mediated CRTZ stimulated via gut vagal efferents. Delayed vomiting is most commonly 2 to 5 days post-chemo and seen with doxorubicin and the vinca alkaloids. Clinical signs include vomiting, diarrhea, anorexia, lethargy, weakness, + . For work up, I recommend CBC, chemistry panel, UA, +/- fecal floatation and cultures. If abdominal pain is present, consider AXR or AUS to rule out foreign body, obstruction, and intussusception. For patients with GI neoplasia, it can be challenging to differentiate chemotherapy side effects vs. disease, and a good history can be key. For outpatient treatment, I recommend NPO, food & water trial, bland diet, anti-emetics, antibiotics with severe diarrhea and a probiotic. Do not forget to discontinue oral chemotherapy or delay chemotherapy treatment. In addition, I recommend prophylactic therapy with the next chemotherapy. For inpatient, I add injectable antiemetics, IV fluid therapy, and IV antibiotics. An important note, I strongly encourage owners to NOT EUTHANIZE at this time. It is amazing with 1 to 2 days of good supportive care how quickly these patients improve. And with prophylactic therapy and a dose reduction, these patients can tolerate the same chemotherapy drug. Myelosuppression and neutropenia Bone marrow suppression most commonly results in a neutropenia but cats seem to be more tolerant than dogs. Neutrophils and platelets are at greatest risk due to the shorter circulating lifespan and shorter bone marrow transit times. Neutropenia is the dose- limiting toxicity in veterinary . How Myelosuppressive? Chemotherapy Drug Mildly to not , Elspar, cisplatin, chlorambucil, bleomycin, vincristine Moderately vincristine, vinblastine, cyclophosphamide, melphalan Highly doxorubicin, Lomustine, mitoxantrone, carboplatin, combination protocols In addition to the chemotherapy targeting rapidly dividing bone marrow stem cells, other mechanisms for neutropenia includes bone marrow infiltration with neoplastic cells (, advanced stage lymphoma, multiple myeloma) and increased consumption due to . When a chemotherapy drug is used that is known to have a high potential for bone marrow suppression (like doxorubicin, carboplatin and Lomustine), a complete blood count (CBC) is often checked after the treatment to check the expected nadir (low neutrophil count) and see if antibiotics and/or a dose reduction are needed. I recommend a nadir be checked with all chemotherapy drugs except L-aspariginase. The nadir typically occurs 7 days after chemotherapy administration. Pay attention to the neutrophil count, not the total white blood cell count. For some chemotherapy drugs the nadir is more variable such as carboplatin and Lomustine. For cats, the nadir is can occur 7 to 28 days after treatment. In dogs the nadir for carboplatin in day 10-14. Chlorambucil tends to cause delayed neutropenias and thrombocytopenias after chronic use. Subsequent doses of chemotherapy are adjusted based on the results of the CBC. Antibiotics may be prescribed as a preventive measure but its use is controversial. Common antibiotics are TMS and Clavamox. I recommend prophylactic use with the more myelosuprressive drugs (doxorubicin, carboplatin and Lomustine) or if the previous nadir was <1500 neutrophils. Unlike dogs, I do not routinely use prophylactic antibiotics unless the cat had issues with a prior treatment. In my experience, there is less than a 5% chance that a patient will need hospitalization. If this does occur, these patients are usually hospitalized for typically 24-48 hours with supportive care including IV fluids and antibiotics. In my experience most chemotherapy patients can successfully receive that drug again with a dose reduction. What to do at the nadir visit? In addition to running a CBC, it is important to get a good history, TPR (fever is so important in neutropenic patients), and a complete physical examination. I am always interested in knowing how the patient handled chemotherapy –did she eat well, any vomiting/diarrhea, did the owner use any nausea or diarrheal medications? For the exam, did he lose weight, was she febrile? The nadir CBC should not be a technician appointment to just pull the blood sample. The history and exam are very important.

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Pay attention to the neutrophil count, not the total white blood cell count. The nadir typically occurs 7 days after chemotherapy administration, but can vary (see above). I recommend antibiotics if the neutrophil count is <1500. If the patient has <1500 neutrophils and is afebrile and feeling well, I recommend managing as an outpatient. However, if the patient has <1500 neutrophils and is febrile and sick, I recommend admitting for supportive care. Remember a febrile neutropenic is an oncologic emergency. Also, I prefer that we get blood samples from the jugular veins for patients getting IV chemotherapy (unless thrombocytopenic). Save those peripheral veins for treatment please. Finally many times the oncologist has run a recent chemistry panel, so check with the oncologist, and try not to repeat unneeded blood work to keep costs down. Neutrophil count Fever, Plan (per uL) Systemic Signs 1500-2500 No Monitor +/- treatment delay 2 to 4 days <1500 No Oral antibiotics treatment delay Consider dose change <1500 Yes ATH for IVF & IV antibiotics treatment delay Dose reduction Sepsis Sepsis in chemotherapy patients is typically due to patient’s own flora - Gram negative from GI bacteria: E. coli, Klebsiella, Pseudomona; Gram positive from skin bacteria: Staphylococcus epidermitidis and aureus, Anaerobes from oral bacteria. Predisposing factors include neutropenia (infection risk well correlated with degree and duration), cellular immune dysfunction, humoral immune dysfunction, prolonged hospitalizations, indwelling catheters, and poor nutrition. History and clinical signs are typically straightforward - cytotoxic chemotherapy was administered typically 5 to 7 days ago. Remember, the febrile neutropenic patient is an oncologic emergency!!! In addition the patient may have an inability to mount an inflammatory response, so the lack of fever, pyuria, or radiographic changes of pneumonia does not rule out sepsis. Signs of illness are unrelated to absolute neutrophil count, but are related to an increased susceptibility to local and systemic when neutropenic. Gastrointestinal, urogenital, and respiratory infections are most common. is also possible The sepsis work up includes: CBC, Chemistry panel, UA & UCS (if >50,000 platelets). If respiratory signs are present, chest radiographs are recommended, and TTW should be considered. Blood cultures may be needed, but uncommon in my experience. Culture any catheters suspected as the infection source. Treatment for sepsis includes: IVF and broad-spectrum IV antibiotics. Neupogen is human recombinant G-CSF. The MOA is stimulation of proliferation & maturation of neutrophil precursors, and precursors to a lesser extent. It also primes neutrophil for cell killing & neutrophil migration. The benefit for the febrile & febrile neutropenic patient is contradictory, and in my experience, Neupogen is rarely needed. The recommended dose is 5 ug/kg SQ SID until neutrophil >1000. When should I lower chemotherapy dose? Dose Intensity is chemotherapy given at MTD & shortest possible interval. It is important to remember than small dose changes can have significant impact on cancer control. Dose reductions as small as 20% can decrease drug efficacy up to 50%. Dose reductions should not be considered lightly.

Don’t treat cats like small dogs when it comes to chemotherapy Some chemotherapy drugs are dosed differently in cats. In dogs, weight and body surface area are used to determine the carboplatin dose. In cats there is now a more accurate method to dose carboplatin in cats based on glomerular filtration rate, which is determined with an Iohexol clearance test. Side effects in cats are also different. Cardiotoxicity is a well-described adverse effect in dogs treated with doxorubicin, but it has not been reported in cats. Sterile hemorrhagic cystitis (SHC) is a relatively uncommon complication of cyclophosphamide in dogs and ifosfamide therapy in dogs and cats. SHC is typically associated with long-term use, but possible after single dose, and can progress to bladder . The incidence with cyclophosphamide has been reported to be 9% in dogs (7-24%), 3% in cats, and 24% in humans. Unlike dogs, concurrent administration of furosemide with cyclophosphamide is not recommended in cats. Mesna, which binds the SHC-inducing acrolein, is recommended for cats and dogs when administering ifosfamide.

Chemotherapy safety Chemotherapy requires careful prescription preparation, drug dispensing, drug administration, client education, and safe handing of patients by ALL staff. Chemotherapy exposure has been documented in nurses and pharmacy workers. It is important to protect your team, our clients, & follow protocols.

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To protect your staff, the following are recommended a hood, closed system transfer device, dedicated counting equipment, dedicated chemo fridge, and Personal protective equipment (PPE) including gloves, gowns, chemo mat, and eye protection. Closed system transfer device such as PhaSeal® are leak-proof and airtight closed system transfer devices. Studies show closed systems reduce contamination and should be combined with other safe handling practices Active drug & metabolites are excreted in urine & feces, and there is some in saliva but research six limited. In the hospital identify patients after chemotherapy and dispose of wastes separately. Spill kits should be on hand and stocked. Protect your entire staff and make sure staff is aware patient is getting chemotherapy. Special precautions are recommended for staff and clients that are pregnant, trying to become pregnant, breast-feeding, immunosuppressed, ir taking immunosuppressive medication. Recommend they talk to their physician. Protect your client and discuss safety tips including common sense precautions, good basic hygiene, and provide an information sheet. Recommend they wear gloves when handling urine, feces, or vomit for at least 72 hours after treatment and when cleaning litter box. Wash soiled bedding separately & 2 wash cycles before use again, use detergent to clean floors, carpets, or countertops, and wear gloves when cleaning It is safe to be around pets undergoing chemotherapy. Metabolites are far less active than original drug. Being around family members – human and other pets in the home - is an important part of a pet's life. Normal activities are safe, but owners need to be careful with excretions.

References Gustafson DL, Page RL. Cancer Chemotherapy. In: Small Animal Clinical Oncology. 5th ed. St. Louis Missouri: Elsevier Saunders; 2013: 157-179 Rodriquez CO. Chemotherapy. In: Cancer Management in Small Animal Practice. Saunders 2010. Page 101-121. Dhaliwal RS. Managing Oncologic Emergencies. In: Cancer Management in Small Animal Practice. Saunders 2010. Page 122-136. Chretin JD, et al, JVIM, 2007; 21(1):141-8. Rau SE, et al, JVIM 2010; 24(6):1452-7. Vaughan MA, et al, JVIM 2007; 1(6):1332-9

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Essential Tips for Splenic Masses Sue Ettinger, DVM, DACVIM Dr. Sue Cancer Vet Tarrytown, NY

Key points • Dogs with and splenic masses generally follow the “double two-thirds rule”: 2/3 have splenic neoplasia, and 2/3 of those have . So 1/3 do not have cancer! Hemangiosarcoma is not the only differential for a with a splenic mass. • Hemangiosarcoma (HSA) is the most common primary canine splenic cancer in dogs, and it is locally aggressive and highly metastatic. • The likelihood of increases with anemia, nucleated RBC, abnormal RBC morphology, or splenic rupture. • Prognosis for splenic masses cannot be determined without histology which usually requires surgery. A common clinical error is to assume HSA based on the presence of a splenic mass. Large masses are not necessarily malignant. Several splenic lesions have similar ultrasound and gross appearances. • Except for lymphoma, splenectomy is the treatment of choice for splenic tumors when there is no evidence of metastasis based on staging tests. Even at surgery, it is often impossible to distinguish various diseases based on gross appearance of the spleen or liver. • Dogs with HSA treated with local therapy and chemotherapy live longer than dogs without treatment and with local therapy only but 1-year survival rates are still low (10%). Chemotherapy is generally well tolerated in most dogs, and only a minority develops significant toxicity.

Who, what, where, why Splenic neoplasia can arise from any of the normal splenic tissues including blood vessels, lymphoid tissue, smooth muscle and connective tissues. Common splenic tumors include HSA, mast cell tumor, lymphoma and various sarcomas. Hematomas are the most common benign splenic masses. Splenic tumors usually occur in large breed dogs. Breeds most at risk are German shepherd dog, golden Retrievers, and Labradors. German shepherds also have a high prevalence of hyperplastic nodules and hematoma. Clinical signs are typically vague, non-specific and include enlarged abdomen, anorexia, lethargy, depression, vomiting, and diarrhea. Clinical signs also vary with how advanced disease is, so dogs may have acute and often dramatic acute signs including collapse and hypovolemic shock. In one study 80% of dogs with acute abdomen and no history of trauma had malignant cancer and 88% were HSA. Splenomegaly is readily detectable through abdominal palpation, radiography and ultrasonography.

Differentials diagnoses Hemangiosarcaoma is not the only differential for a dog with a splenic mass. A common clinical error is to assume HSA based on the presence of a splenic mass. Large masses are not necessarily malignant. Several splenic lesions including HSA, hemangioma and hematoma have similar ultrasound and gross appearances. Lymphoma (LSA) LSA that involves the spleen is most commonly part of multicentric LSA and typically is a diffusely infiltrative disorder. Some may occur as solitary splenic nodules, especially marginal zone lymphoma and mantle subtypes of the indolent form. Similarly acute and chronic can also diffusely infiltrate the spleen. Malignant (MH) MH is an uncommon cancer of atypical histiocytes and has progressive, multicentric involvement of multiple organs, including the spleen, liver, lymph nodes, and bone marrow. The Bernese mountain dog has a familial predilection. Mast cell tumors (MCT) Tumors of primary visceral organs including the spleen are rare in dogs. Visceral is typically preceded by a poorly differentiated cutaneous MCT. Splenic sarcoma Splenic sarcomas are non-angiomatous, non-lymphoid tumors of connective tissues and include fibrosarcoma, leiomyosarcoma, extraskeletal osteosarcoma, and undifferentiated sarcomas. A high mitotic index (MI) of >9 is a negative prognostic factor for survival. Splenic sarcomas tend to be fatal within 1 year. Splenic leiomyosarcoma have a high metastatic rate but dogs that survive the initial post-surgical period have a MST of 8 months. Hemangioma Hemangiomas are benign tumors of blood vessels. Surgery is curative. Non-neoplastic Hematoma, abscess, nodular , granuloma 419

Hemangiosarcaoma (HSA) HSA is an aggressive malignant cancer of transformed vascular endothelial cells. It causes local infiltration and rapid systemic metastasis. German shepherds and golden Retrievers are at greatest risk. Gross metastasis is present at diagnosis in more than 50% of cases. Excluding cutaneous cancers, it accounts for about 5% of primary cancers in the dog. Spleen is the most common primary site, but other common sites include right atrium, liver, skin and subcutis. HSA may be solitary, multifocal in an organ, or widely disseminated. Metastasis is typically hematogenously or via transabdominal transplantation. Metastasis is most commonly to the liver and lungs. Less common sites of metastasis include the omentum, mesentery, brain, muscle and bone. HSA is considered the most common metastatic tumor to the brain.

Diagnostic work up for HSA CBC and chemistry panel The likelihood of splenic tumor increases with anemia, nucleated RBC, abnormal RBC morphology, or splenic rupture. The anemia may be regenerative with splenic rupture depending on the duration. Neutrophilic may also be present. Other abnormalities include Howell-Jolly bodies, poikilocytosis, acanthocytosis, schistocytosis and/or thrombocytopenia. Thrombocytopenia is common in 75-97% cases and rages from mild to severe. A coagulation panel should be run if HSA is suspected. Imaging Three-view chest radiographs are mandatory to rule out pulmonary metastasis and pleural fluid. Three-views significantly decreases the false-negative rate. Abdominal ultrasound confirms the mass and allows detection of abdominal effusion, defines splenic architecture, and provides detailed evaluation of the abdominal organs and is less affected by abdominal effusion than radiographs. FNA and cytology Ultrasound-guided FNA is relatively simple, cost-effective and typically a safe procedure. It is most helpful for cases where the diagnosis eliminates the need for surgery, such as lymphoma. For diffuse splenomegaly, the spleen is accessible for cytology. But even with ultrasound-guidance, if non-representative tissues are sampled, you may get a false negative of benign or reactive. In one study, only 61% of cases did cytology match histologic diagnoses. FNA is not recommended for mixed echogenicity masses suspicious of HSA as the masses are often extremely friable so there is an increased risk of hemorrhage in addition to the low diagnostic yield due to hemodilution. HSA effusions are serosanguinous or frank blood and usually do not clot. Unfortunately cytology is typically non-diagnostic. Cardiac evaluation Since 25 to 45% of dogs with splenic HSA have concurrent right atrial HSA, an echocardiogram is recommended. In my experience this is lower at presentation. Arrhythmias can occur with benign and malignant lesions.

Treatment modalities for HSA Treatment pearls Treatment for HSA is ideally both local and systemic. Chemotherapy improves the MST, but HSA is still a frustrating cancer for owners and veterinarians with shorter survival times than many malignant cancers in dogs. The majority of dogs tolerates chemotherapy quite well and will maintain a good to excellent quality of life even during chemotherapy. Treatment: Surgery Except for lymphoma, splenectomy is the treatment of choice for splenic tumors when there is no evidence of metastasis based on staging tests. Even at surgery, it is often impossible to distinguish various diseases based on gross appearance of the spleen or liver – including hematoma, nodular hyperplasia, hemangioma and HSA. Ideally the entire spleen should be submitted fresh on cold packs or in formalin. Biopsy of normal liver is controversial and may not be useful. The abdomen should be thoroughly explored and any suspicious lesions removed or biopsied. About 25% of dogs develop arrhythmias post-op. An ECG should be monitored during and after surgery, and they usually resolve within 24-48 hours. Treatment: Chemotherapy The goal of chemotherapy is to achieve is to delay the metastatic disease that develops quickly after splenectomy. Since chemotherapy improves the MST, it is considered part of the standard of care. Single agent doxorubicin and combination protocols are most common. Recently low dose oral chemotherapy (metronomic) was comparable to conventional doxorubicin. This protocol included low dose cyclophosphamide, piroxicam and etoposide. Current studies are evaluating whether conventional chemotherapy followed by maintenance metronomic chemotherapy for VEGF-receptor kinase inhibitors such as tocerinib will improve outcome.

Prognosis for has Overall the prognosis with surgery alone is poor and reported MST in dogs treated with surgery alone ranges from 1 to 3 months, and less than 10% survives 1 year. Adjunctive chemotherapy improves the MST to 4 to 6 months, and doxorubicin-based protocols are the

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mainstay. Stage I, non-ruptured tumors may have an improved prognosis when chemotherapy is administered after surgery. Low grade tumors may also have a better prognosis. Additional resources Thamm DH. Hemangiosarcaoma. In: Small Animal Clinical Oncology. 5th ed. St. Louis Missouri: Elsevier Saunders; 2013: 679-688. Schoeman JP. Splenomegaly. In Clinical Veterinary Advisor Dogs and Cats. 2nd edition. St. Louis Missouri: Elsevier Mosby; 2011: web Johnson KD. Splenic Tumors. In Cancer Management in Small Animal Practice. Saunders 2010. 264-268

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Let’s Talk About Cancer: Breaking the News Sue Ettinger, DVM, DACVIM Dr. Sue Cancer Vet Tarrytown, NY

“Your pet has cancer.” This may be one of the hardest things you will have to tell an owner. Breaking bad news is stressful and unpleasant, and has been described as “dropping a bomb.” But unfortunately you will have to drop the cancer bomb on your often- unsuspecting clients many times throughout your career.

Delivering bad news Delivering bad news is a complex communication task that you may have to do thousands of times. It is stressful for clinicians and veterinary team members to carry the burden of responsibility for communicating bad news. Complicating factors include our experience (or inexperience) giving bad news, the relationship with the client and their pet, and often the limited treatment options. For the client, their response is affected by their relationship to their pet, severity of the diagnosis, past experiences with other pets or human family members with cancer and illness, other stressors in their life, and their support system. The manner in which bad news is delivered is key to the owners’ understanding and to their satisfaction with their veterinarian.

Lack of training In veterinary and technician school, cancer communication training varies with regard to content, duration and methods. There is often a skills gap between veterinary school curriculum content and the actual skills to be successful in practice. The specific lack of training opportunities appears to play a major role in leading to this problem. As a result, many veterinarians and team members feel unprepared for difficult conversations about cancer. As veterinarians, we know the communication between veterinarian and veterinary team with the client is critical to optimal patient care. Yet there is a lack of guidelines and training to help the veterinary team and clients broach difficult conversations about diagnosis, prognosis, and definitive and palliative treatment options for pets diagnosed with cancer. Many of us are stressed and unsure on how to initiate these conversations and talk about cancer with our clients.

Here are my 3 tips for good communication with clients receiving bad news 1. Aware 2. Where 3. How Be aware Be aware of the cancer communication challenges. Since the cancer diagnosis is typically made by the primary care veterinarian, the primary care veterinarians often have the more difficult job compared to the oncologist, in my opinion. You are breaking the bad news - dropping a bomb often on unsuspecting clients. But primary care veterinarians also typically have a relationship with the client, which can be very helpful during these challenging conversations. On the other hand, when the client visits the oncologist, the owner usually knows cancer is the diagnosis, and the focus is treatment options and decision making, but there is no pre-existing relationship, familiarity, or trust. This may be the case in the primary care setting with a new client. Many barriers currently prevent veterinarians and clients from engaging in cancer conversations and optimal cancer care planning. To address barriers to advanced cancer care planning, we must first identify the challenges. These will vary from case to case For the veterinarian and team, challenges may include general discomfort in talking about cancer and death, lack of training, shortness of time, practice culture, feelings of responsibility for cancer or a late diagnosis, perception of failure, unease with death and dying, uncertainty of outcome, impact on relationship with client, and the worry about patient quality of life (QOL), about client response, about costs, and about the veterinarian’s own response. For the client, conversations are challenging, as clients are often emotional and dealing with their feelings of self-blame, guilt, anxiety, fear, and frustration. There is the unease with death and dying, anticipatory grief, and concerns about the effect on human- animal bond. The client is also concerned for the pet’s QOL, the costs, the time required to treat the cancer. Where you give your news When saying “Your pet has cancer”, be aware of where you deliver the bad news. Too many clients hear those fateful words with less than an appropriate manner in less than an appropriate setting. A common mistake includes having the conversation in a space with no

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privacy, such as the waiting room or in the treatment area (especially of the pet belongs to a hospital employee). The client should be told ideally in person and in a private location such as an exam room. In reality, many of these conversations happen over the phone after test results are finalized after the pet’s appointment. This can make the conversation harder because we lose the opportunity to make a connection and make eye contact. I am trying to move towards giving news in person when possible. If you cannot have the conversation in person, be aware of the techniques you will lose, and add other tips such as empathetic responses. How do you give your information? Poor communication can lead to general dissatisfaction and a loss of trust from the client. Common mistakes include having a conversation that is too short, explaining the cancer as a monologue and not discussing a treatment plan. There are 2 methods for giving information (Silverman). The first method is called Data Dump, and is often nicknamed the Shot-put technique. The veterinarian does most of the talking like a monologue, and the client is more passive. The intent is on delivery of information, but it is often too much information for the client to absorb and too challenging to receive the message. A better method is the collaborative approach, is often nicknamed the Frisbee technique, where the conversation goes back and forth – you elicit feedback to how the client perceives and understands the information and adjust the conversation to stay on target. This reciprocal interaction focuses on a dialogue. The delivery is given in small pieces, and the emphasis is on eliciting client feedback. By adding open-ended questions to the conversation, we make sure we are all on same page with cancer information.

The spikes protocol for delivering bad news One useful method that I like is the SPIKES protocol for disclosing unfavorable information to human cancer patients about the illness (Baile). The authors describe the six-step protocol as straightforward and practical. Oncologists, oncology trainees, and medical students who have been taught the protocol have reported increased confidence in their ability to break bad news. Although I am typically not breaking the initial news of the cancer diagnosis, I often have to report cancer recurrence, failure of treatment to affect progression, unwanted side effects like neutropenia, and metastasis. I have personally been incorporating the six steps in my own clinical practice, and can report that I am more comfortable and confident as well. Not every conversation of breaking bad news will require all 6 steps, but when they do, they are meant to follow the sequence. Setting up the interview To prepare for the stressful task, review your plan for breaking the bad news and mentally rehearse what you are going to say and where you are going to say it. Remember it is normal to have negative feelings, feel frustrated or feel responsibility. This information may be sad and devastating but the information will allow the family to plan their pet’s future. • Arrange for privacy. An exam room is ideal. • I always involve significant others. It’s great to have an extra set of ears. Before I start, I ask the client if they want to conference call in a family member, or even record the conversation on their smartphone. • Sit down to relax the client. It is also a sign you are not in a rush and focused on them. Remove physical barriers such as the exam table between you and the client. • Make a connection with eye contact, or appropriate touching the patient on the arm or hold a hand if the client is comfortable. Sometimes I ask the client if they need a hug – they usually do. Assessing the client’s perception Before you tell the client medical information, we need to gather information. It is very helpful to identify the client’s understanding and help the client identify concerns. Use open-ended questions to try to get an accurate picture of what the client knows and their feelings. Start questions with: how, what, and tell me. I may start with, “What have you been told about Bear’s lymphoma?” of “What have you been told about Oscar’s chest X-rays?” I find that these questions allow me to correct misinformation such as chemotherapy is not well tolerated in pets. I can also tailor the bad news to the patient’s level of understanding whether they have some medical background or none. Elicit the client’s perspective. Does the client have a previous experience with cancer in people or another pet? It is important to identify misconceptions of cancer and barriers to care. Examples are “What are you goals with treating Bo’s cancer?” “What are your hopes?” and “What are your fears?” Other examples are “What other questions do you have?” or “Anything else you’d like to discuss?” Obtaining the client’s invitation Some clients want full information for diagnosis, prognosis and details of the illness, but some do not. I have found that some may want more information later. If clients do not details, offer to pick up the conversation in the future or talk to a relative. You may want to get the conversation completed, but if the owner is not ready, you will end up repeating it again anyway.

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It is also important to determine what degree the client wants information, and be aware this may change with time. Since many clients are overwhelmed in the beginning, it is often helpful to start with the big picture and ask what they know already and to what additional information they are seeking. Giving knowledge and information to the client To lessen the shock it helps to warn that bad news is coming. When I walk in, I sit down and say, “Unfortunately I have some bad news.” Then pause. Let them get ready for the news. Then when explaining, remember to use non-technical terms, such as spread instead if metastasis, and sample of tissue over biopsy or fine needle aspirate. “Chunks and check” is very helpful when having cancer conversations. You give information in small chunks, and then follow with checks for understanding. This is less lecturing and aims to increase recall, understanding and commitment. Use open-ended questions like: “What questions do you have?” or “What part of the plan is most difficult?” Addressing the client’s emotions with empathetic responses One of the biggest challenges is responding to the client’s emotions, which can range from silence, disbelief, crying, denial, or anger. Let client express feelings, and express empathy: identify and acknowledge clients emotions. Put yourself in their shoes and communicate that you know where they are coming from. Examples: “I can only imagine how hard this is. Nemo has been part of your family for so long.” “I can see how upsetting this is for you. I was also hoping for different results.” Clients will often be shocked and feel alone. Offer partnership and use inclusive language like let’s, we, our, us, such as “We’ll work together for Teddy. “ Asking permission during the conversation will allow you to assess the client’s readiness to take next step with questions like: Would you like to schedule surgery? Are you ready to start chemotherapy? Combining empathic, exploratory, and validating statements is one of the most powerful ways to provide support, as it reduced the client’s isolation, expresses solidarity and validated the client’s feelings.

Strategy and summary It is useful to take time to reflect what the client heard, to repeat key aspects of diagnostics and treatment, and to provide a summary at end of appointment. For example, “I recommend these tests and this treatment for Bo’s oral melanoma but there are options. What questions do you have?” Clients who have a clear plan are less likely to feel anxious and uncertain, and it helps to check the client’s understanding, or misunderstanding of your conversation and the treatment options. Consider a referral to a specialist, and address pain control and relief from clinical signs. “I don’t have time for this!” I know what you are thinking. But core communication skills actually save time and allows for more efficient veterinarian-client- patient interaction. If you spend time to build a relationship early, it will pay dividends through diagnosis and treatment. It takes practice, but even adding one or 2 steps will improve the experience for you and the client. In addition, physicians who are comfortable in breaking bad news may be subject to less stress and burnout. Less stress and less burnout are things we all could use.

Discussing prognosis There are a few approaches to discussing prognosis – realism, optimism and avoidance. The first is realism. Interestingly, in people, 20% of patients do not want full prognosis information. Second is optimism. If overly optimistic, clients may lose opportunities to fulfill last wishes, prepare themselves and family, and spend quality time with their pet. With avoidance, you may appear evasive or dishonest. In addition, the veterinarian risks the trust and relationship with client, and the client could compromise pet’s care. Do not make assumptions about what the client wants to know. Ask. “How much would you like to know about course of Myles’ lymphoma?” Some like details or the big picture. This is a good time to use chunk and check. Balance hope and reality. The median survival time can be helpful. Acknowledge the client's emotional reaction and remember to compose yourself, pace yourself, and allow time to reflect.

First reaction Remember the client’s initial reaction may be to not treat at all. It is okay not to treat after we provide information about the diagnosis, treatment options and prognosis. We must provide accurate information about cancer and a range of treatment options. We can replace misperceptions and fear with knowledge and hope and educate the client that pets with cancer can live longer, and live well – not only after treatment, but during treatment too. Many clients change their minds after considering the information. The manner in which bad news is delivered is key to the owners understanding, to their satisfaction with their veterinarian, and often their willingness to pursue treatment options or a referral.

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Summary Poor communication can lead to general dissatisfaction and a loss of trust. Common communication mistakes include having the conversation in a space with no privacy, having a conversation that is too short, and having no treatment plan to discuss. Remember the 3 tips: be aware of the issues for you and the client, where will you tell them, and how will you tell them. The 6-steps of the Spikes method will allow you to gather information, determine the client’s knowledge and expectations, support the client’s emotional response through empathy, and come up with a strategy and plan. When saying, “Your pet has cancer”, stop, mentally rehearse, think empathy and respect. Demonstrate appropriate nonverbal behavior: This can be helped with an attentive body posture, sit at same level, sit close, and maintain good eye contact. Use a slow pace, lean forward, reach out to touch. Go to a private location, have sufficient time and attention, be sensitive, and be flexible. There are inevitable differences among clients, but we the veterinary team can improve the complex and stressful task of breaking news for our clients and ourselves.

References Back AL, Arnold RM. Discussing Prognosis: “How Much Do You Want to Know?” Talking to Patients Who are prepared for explicit information. J Clin Oncol 24:4209-4213, 2006a Baile WF, Buckman R, Lenzi R, et al. SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer. Oncologist. 2000;5(4):302-11 Fleming, J.M., Creevy, K.E. and Promislow, D.E.L. (2011), Mortality in North American Dogs from 1984 to 2004: An Investigation into Age-, Size-, and Breed-Related Causes of Death. Journal of Veterinary Internal Medicine, 25: 187–198. doi:10.1111/j.1939-1676.2011.0695.x Miyaji N. The power of compassion: truth-telling among American doctors in the care of dying patients. Soc Sci Med 1993;36:249-264. Drop bomb Ramirez AJ, Graham J, Richards MA et al. Burnout and psychiatric disorder among cancer clinicians. Br J Cancer1995;71:1263-1269. Shaw JR. Relationship-Centered Approach to Cancer Communication. In: Small Animal Clinical Oncology. 5th ed. St. Louis Missouri: Elsevier Saunders; 2013: 272-279. Silverman J, Kurtz SM, Draper J. Skills for communicating with patients, Abingdon UK 2005 Radcliffe Medical press

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Osteosarcoma Survival Guide Sue Ettinger, DVM, DACVIM Dr. Sue Cancer Vet Tarrytown, NY

Key points • Osteosarcoma (OSA) is the most common primary canine bone cancer in dogs, and it is locally aggressive and highly metastatic. • The majority of dogs with appendicular osteosarcoma have no evidence of metastasis at diagnosis, but most will likely succumb to metastasis. • Early diagnostics are key. If you are presented with a large- or giant-breed dog that is lame and has swelling at metaphyseal site, it is osteosarcoma until proven otherwise, and do radiographs promptly. • To determine the best treatment plan for a patient and owners, it is important to understand efficacy of the various protocols, the potential toxicities, and prognostic factors. • Dogs treated with local therapy and chemotherapy live significantly longer than dogs without treatment and with local therapy only, and chemotherapy is generally well-tolerated in most dogs. Only a minority develop significant toxicity.

Who, what, where, why What Osteosarcoma is the most common primary bone cancer, accounting for 85% of all skeletal cancers and 5% of all neoplasia. OSA is a malignant mesenchymal tumor of primitive bone cells that produce ECM of osteoid. The biologic behavior is aggressive locally and highly metastatic. At the primary site, there may be bone lysis or bone production or both, soft tissue swelling, and pathologic fracture (not negative prognostic). While OSA is highly metastatic, <10-15% have detectable metastasis at diagnosis, but 90% die within 1 year with amputation alone due to metastasis Who OSA is estimated to occur in > 10,000 dogs per year, but this is likely an underestimate. It typically occurs in middle aged and older dogs, but there is a small peak at 1.5 to 2 years old. Rib OSA occurs in younger adults (5 y.o.). OSA is common in large and giant breeds with increasing weight and height. In the U.S., breeds most at risk are St Bernard, Great Dane, Irish Setter, GSD, Rottweilers, Dobies, and Golden Retrievers. The dog SIZE IS MORE IMPORTANT than breed. The risk of OSA is 60 times higher in dogs weighing > 30 kg, and 8 times higher in dogs weighing 20-30 kg. Appendicular OSA accounts for 95% of all cases in dogs >40 kg but only 40-80% of all cases <15 kg. Axial OSA can occur in any breed and at any location. Why Large and giant-breed dogs are predisposed. Body size (increasing weight and more specifically height) appears to be most predictive factors for OSA, and it is more important than breed. Hereditary basis is suspected based on the large breed prevalence. The most thoroughly described mutation that contributes to formation and/or progression is p53. Additional genetic factors studied are RB and PTEN tumor suppressor . OSA is more prevalent in males than females, but in the St Bernard, Great Dane, and Rottweilers, females outnumber the males, and females more affected by axial (except rib and spine). Sex hormones also appear to have a protective role. In Rottweilers neutered before 1 yo, 1 in 4 developed OSA and more likely than intact dogs. OSA has also been associated with fractures, metallic implants, chronic osteomyelitis and ionizing radiation. Where 75% of OSA is appendicular, and 25% is in axial bones. It typically occurs in the metaphyseal region of long bones, towards the knee and away from the elbow, front limbs are two times more affected than hind limbs. The most common sites are the distal radius bad proximal humerus, while in the hind limbs, OSA lesions are evenly distributed among the distal femur, distal tibia, and proximal tibia. The proximal femur less common and OSA distal to carpus and hock is rare. In the axial location: 27% mandible, 22% maxilla, 15% spine, 14% cranium, 10% ribs, 9% sinonasal, and 6% pelvis. Multicentric is uncommon reported in <10% cases. Extraskeletal OSA is rare and some reported sites include mammary, SQ, spleen, GIT, eye, and kidney. What do we see? Most dogs appear in pain, and many are presented with progressive lameness. Palpable swelling may or may not be present. Acute severe swelling is typical with pathologic fracture, but only 3% pathologic fractures due to OSA. If you are presented with a large- or giant-breed dog that is lame and has swelling at metaphyseal site, it is OSA until proven otherwise and do radiographs promptly.

Diagnostic work up When taking radiographs, take good quality lateral and craniocaudal views. The abnormalities vary from mostly lysis to mostly osteoblastic. Common features include cortical lysis, soft tissue extension and swelling, new bone extension in sunburst pattern, 426

Codman’s triangle deposition of new bone on cortex at periphery. While OSA does not cross joint, it can invade adjacent bones. Radiographic changed can be similar to fungal osteomyelitis. A presumptive diagnosis is based on signalment, history, PE, and radiographs. Differentials include other primary bone (CSA, FSA, HAS, HS), metastatic bone cancer (usually diaphyseal), multiple myeloma or LSA of bone, systemic mycosis, bacterial osteomyelitis, bone , and healing bone injury.

Preliminary diagnosis Cytology While cytology is not definitive, it is supportive and can distinguish malignant vs non-malignant with an accuracy of 70-85%. In diagnostic samples, ALP staining can differentiate OSA from other sarcomas. Ultrasound-guidance can be helpful to aid sample collection. Pre-op biopsy is not required in cases with classic signalment, history, PE/location, and radiographic appearance, there is little possibility of fungal or bacterial osteomyelitis, and the owners are willing to treat aggressively. On the other hand, biopsy is recommended if there is non-diagnostic cytology, the owner wants confirmation, or it is not a classic case. Always submit larger specimen at surgery to confirm. When doing pre-op biopsy, plan carefully if limb spare is option so contaminated tissue is removed. There is also 10-20% false negatives rate. The open incisional approach collects a large sample but post-surgical complications include hematoma, seeding, infection, fracture, and breakdown. The trephine technique is 94% diagnostic but increases the fracture risk. Closed needle biopsy can be done with a Jamshidi and is 92% accurate for tumor diagnosis and 83% accurate for tumor subtype, but accuracy is dependent on experience and comfort level. In some case, repeated attempts may yield “reactive bone”. Biopsy at CENTER of lesion, and incision and biopsy tract should be planned that will be removed a definitive surgery. Fluoroscopy or CT-guided biopsy can be useful. Samples collected from the peripheral bone lesion are more likely to be non-diagnostic and contain reactive bone. Staging included local LN FNA, Orthopedic exam for bone mets, 3-view chest radiographs or chest CT. Treatment recommendations and prognosis are based on plain radiographs, not advanced imaging. Less than 5% of dogs have LN metastasis. Bone survey radiographs are not typically recommended unless there are suspicious or painful lesions. I involves taking a lateral of all bone and VD of the pelvis and can be considered to rule out bone metastasis and 6% of dogs have bone metastasis detected (vs 4% chest). Bone scans have conflicting reports of usefulness. AUS is not recommended for OSA staging, but can be considered if determining is the bone lesion is a metastatic lesion or there are abnormalities on the chemistry panel. CT is recommended for axial tumors. Prognostic factors For appendicular OSA, the MST with surgery alone is 4 to 5 months. Well-established negative predictors include young age (<5 years old), large tumor size, humerus location, and high histologic grade. Other factors include small body size, larger tumors, extraskeletal tumors, percent bone necrosis, mitotic index, and over metastasis (lungs, LN) For non-appendicular, the head locations (mandible, maxilla, skull) are locally aggressive but have a lower metastatic rate (37%). With skull surgery alone, the MST is longer than limb at 7 months. The 1-year survival with mandibulectomy is 71%, but the MST is 5 months for maxillectomy. Following rib resection, the MST is 3 month, and 8 months for surgery and chemo. Stage III dogs with measurable metastasis have a worse prognosis with a MST of 2 months. Dogs with bone metastasis do better than lung (4 m vs 2 m), and LN metastasis is a negative prognostic factor (2 m vs 8 months) Dog with elevated ALP have shorter DFI and ST. Remember, prognostic factors cannot predict an individual’s response.

Treatment modalities Treatment pearls Treatment for OSA is ideally both local and systemic. Since chemotherapy significantly improves the MST, it is considered part of the standard of care. The majority of dogs tolerates chemotherapy quite well and will maintain a good to excellent quality of life even during chemotherapy. Treatment: Surgery Surgical options include amputation or limb spare techniques to address the primary tumor. Amputation is the standard treatment for appendicular OSA. It is palliative and a very effective way to remove the source of pain, but amputation alone does not increase survival (other than preventing pain-related death) and most dogs succumb to metastasis. While we as veterinarians know that amputation is well-tolerated, many owners are shocked by the procedure and often reluctant to consider the radical procedure. It is important to screen the patient well and rule out concurrent musculoskeletal and neurologic abnormalities. Even middle-aged and older large-breed dogs with moderate arthritis are typically candidates. Owner satisfaction is typically excellent post-op, and most dogs compensate well,

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Surgical limb-spare procedures allow the preservation of limb function, and are an alternative when amputation is not physically an option or is declined by the owner. Limb-spare procedures do not increased survival times and systemic therapy is still recommended after the delay metastasis. There are various limb-spare procedures described but the techniques involve surgical resection of the effected bone and replacement with a bone implant, bone plating and arthrodesis to stabilize the joint. Since residual disease likely remains, the region is treated with radiation, IA cisplatin or chemotherapy impregnated beads. Distal radius and ulnar lesions are most amenable. These techniques have similar survival times but have much higher complication rates. Treatment: Radiation Like surgery, radiation is a local treatment option. Palliative radiation can be very effective for bone tumors, and is a good option if amputation is declined. Most dogs (75 to 90%) respond favorably and analgesia is improved. There is variation with duration of analgesia and most typically lasts 4 to 6 month but it can be durable for greater than 1 year, and palliative radiation can be combined with adjuvant IV chemotherapy. Stereotactic radiosurgery (SRS, aka stereotactic radiation therapy (SRT) is an alternative limb-spare technique for local control. SRS delivers extremely precise high dose radiation with multiple beams within submillimeter accuracy. Less normal tissue that surrounds the tumor is irradiated, so there are fewer radiation side effects, higher dose to tumor, and fewer treatments (typically 3). For OSA, preliminary results are encouraging with MST of approximately 1 year, when combined with chemotherapy for systemic disease. One type of SRS is called CyberKnife Radiosurgery, which I did with our radiation oncologist for 7 years at my previous practice. OSA was the 3rd most common tumor we treated (after brain and nasal tumors). Not every dog with appendicular OSA is a candidate for SRS, especially if there is more bone destruction and increased risk of pathologic fracture. CT-based prognostic factors can help predict the likelihood of fracture. Treatment: Chemotherapy The goal of chemotherapy is to achieve is to delay the metastatic disease that develops quickly after amputation or limb-spare procedure. Since chemotherapy significantly improves the MST, it is considered part of the standard of care. For appendicular OSA, the MST with surgery alone is 4 to 5 months, with 90 to 100% mortality rate in one year. With chemotherapy the 1-year survival rate is 40-50% and 20-25% of dogs are alive at 2 years. Most studies have evaluated doxorubicin, cisplatin, or carboplatin in varying combinations. Choice of protocol (single vs combination) does not result in significant differences in DFI or ST, the carboplatin protocol resulted in a lower proportion of dogs experiencing side effects, and helpful in maintaining high quality of life during treatment. Unfortunately, 95% of dogs will eventually succeed to metastasis. Other treatment options Other treatment options include bisphosphonates, immunotherapy, and COX-2 inhibitors. Pain control for the patients is a priority, Bisphosphonates are osteoclast inhibitors than inhibit bone resorption and are used in human patients with diffuse skeletal metastasis. Approximately 30% dogs have decreased pain. Direct cytotoxicity to has also been reported suggesting interaction with radiation therapy and/or chemotherapy. A canine OSA vaccine is currently being developed by Aratana. This is a recombinant HER2/neu expressing Listeria therapeutic vaccine being studied at UPenn. In a recent study by Dr Mason, 18 dogs were treated with amputation, 4 doses of carboplatin, and the vaccine. The MST has not been reached but 11 of 18 dogs surpassed the MST of the control group (318 days). Adverse effects were mild to moderate and included fever, lethargy, nausea and vomiting. Overall OSA is the most common primary is dogs. The biologic behavior is aggressive locally and highly metastatic, so its therapy requires both local and systemic treatments. For appendicular OSA, amputation addresses the local disease and is palliative. The MST with surgery alone is 4 to 5 months, with 90 to 100% mortality rate in one year. The ability to control the progression of OSA metastasis remains the challenge for our patients, and systemic chemotherapy is the backbone for therapy. With chemotherapy, the 1- year survival rate is 40-50% and 20-25% of dogs are alive at 2 years. Well established prognostic factors include adjuvant chemotherapy, low grade (rare for OSA), and normal total and bone ALP. Dogs treated with chemotherapy live significantly longer than dogs only treated with local therapy, and chemotherapy is generally well-tolerated in most dogs.

Additional resources Ehrhart BP, Ryan SD, Fan TM. Tumors of the Skeletal System. In: Small Animal Clinical Oncology. 5th ed. St. Louis Missouri: Elsevier Saunders; 2013: 463-503. Bailey DB. Osteosarcoma. In Clinical Veterinary Advisor Dogs and Cats. 3rd edition. St. Louis Missouri: Elsevier Mosby; 2015: 740-742 Ruslander D. Tumors of the Musculoskeletal System. In Cancer Management in Small Animal Practice. Saunders 2010. 333-342 Selmic LE et al. Comparison of carboplatin and doxorubicin-based chemotherapy protocols in 470 dogs after amputation for treatment of appendicular osteosarcoma. J Vet Intern Med. 2014 Mar-Apr ;28(2):554-63. doi: 10.1111/jvim.12313. Epub 2014 Feb 10

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Ready, Set, Go Pink: The Veterinary Mammary Cancer Edition Sue Ettinger, DVM, DACVIM Dr. Sue Cancer Vet Tarrytown, NY

Key points • Mammary tumors are one of the most common tumors in dogs and cats, but the disease varies considerably. • A simple rule for dog mammary tumors is that 50% are benign, 50% are malignant, and approximately 50% of those will metastasize. So 75% of dogs with mammary tumors will be cured with surgery. • Mammary tumors in cats are generally malignant (80-90%), with adenocarcinomas most common. • Half of cases in dogs and cats will present with multiple masses. Dogs can have concurrent benign and malignant masses, so all excised lesions must be submitted for histology. Cats are less likely to have concurrent benign and malignant lesions. • Even though complete surgical excision is the goal for dogs and cats, surgical recommendations are different in dogs and cats. For dogs lumpectomy or simple mastectomy is recommended. For cats, unilateral or bilateral is recommended. • For intact female dogs, unilateral mastectomy reduces the likelihood of subsequent ipsilateral tumor development.

Canine mammary tumors (CMT) Who, what, where, why Middle-aged (9-11 years old) female intact dogs are most often affected, with an increased incidence beginning at about 6 months of age. The incidence is about 2 in 1000. Male dogs are not completely protected, and 1% occur in male dogs and may be associated with hormonal abnormalities such as estrogen-secreting Sertoli cell tumors. Breeds most at risk are English Springer, Brittany and Cocker spaniels, toy and miniature poodles, English setters, pointers, German shepherd, Maltese, Yorkshire Terriers, and dachshunds. Mammary tumors in small breed dogs are more likely benign than those that develop in large breed dogs (25-58%). Timing of OHE It is well accepted that spaying dogs before 2.5 years of age is protective against the development of cancer. Schneider et al showed the risk rose to 26% for dogs spayed after the second heat, compared to 0.5% and 8% if spayed before 1st or 2nd estrus, respectively. The protective effect is not seen after 2 estrus cycles, likely because the sex steroid hormones have already had their primary effect on target cells. Intact females and females spayed after 2 years of age have a sevenfold greater risk of neoplasia compared to those spayed before 6 months of age. In European countries, mammary tumors represent 40-70% of all tumors in female dogs. Hormone therapy with progesterone and/or estrogen can lead to a 2-fold increase of both benign and mammary tumors. A genetic factor seems to be present, but a common mutation is yet to be identified. The following mutations have been found in select tumors: p53, Her-2/neu, and BCRA 1,2. Mammary masses are often incidental findings during routine wellness exams in older intact females, or owners find them. Owners should be encouraged to palpate their dogs monthly for skin and subcutaneous masses – see section on See Something, Do Something (SSDS) below. The caudal glands are more frequently affected. Half of cases will present with multiple masses. These may be simultaneous primary masses or regional extension or metastasis. Lymphatic drainage is complex and nodal metastasis can occur to inguinal, sternal or . Lymphadenomegaly, , skin ulceration and fixation to underlying tissue suggest malignancy. Estimated malignancy rates vary from 30-50%. Inflammatory Mammary (IMC) is a unique form that is often confused clinically with mastitis and presents with warm tissues, erythema, lymphedema, ulceration, and pain.

Diagnostic work up Measure the primary tumor(s) and describe if it is fixed, ulcerated, and invasive into surrounding tissues. Cytology of the tumor FNA may help to distinguish non-mammary tumors such as MCT or lipomas, but cytology alone is typically not helpful to determine if the mammary tumor is benign or malignant. Regional evaluation Lymph nodes should also be evaluated for metastasis and staging. Palpation alone is not adequate, and pre-operative cytology of palpable lymph nodes is recommended to determine disease extent. Metastasis may be present in lymph nodes that palpate normally.

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Histology Biopsy (incisional or excisional) and histology are required for a diagnosis. Patients can have concurrent benign and malignant masses, so all excised lesions must be submitted for histology. The most common malignancy is complex carcinoma. Histology of is based on tubule formation, nuclear pleomorphism and mitotic index and is prognostic. Mixed mammary tumors typically consist of epithelial, myoepithelial and mesenchymal tissues. Imaging In addition to a minimum database (CBC, chemistry panel and urinalysis), imaging is recommended, as approximately 50% of malignant mammary tumors will metastasize. Three-view chest radiographs and abdominal ultrasound are important to rule out pulmonary metastasis and distant visceral metastasis. Three-views significantly decreases the false-negative rate. Metastasis is typically to regional lymph nodes and lung, but liver, abdominal lymph nodes, and bone may also be involved. Advanced imaging such as CT scan can be considered, as it is more sensitive to detect distant metastasis. A coagulation profile is recommended in cases of IMC to rule of DIC. Clinical staging • Tumor (longest diameter): T1 <3 cm, T2 3-5 cm, T3 >5 cm • Regional lymph node: N0 no metastasis, N1 metastasis detected • Distant metastasis: M0 no metastasis, M1 metastasis detected Stage T N M grouping I T1 N0 M0 II T2 N0 M0 III T2 N0 M0 IV T1-3 N1 M0 V T1-3 N1 M1

Treatment modalities for CMT Treatment: Surgery Surgery is the treatment of choice for mammary tumors when there is no evidence of distant metastasis based on staging tests. The type of surgery in dogs is not prognostic for survival as long as margins are complete based on histology. Surgery can be minimal as long as the excision is adequate. Most commonly, this will be a lumpectomy for small lesions (<0.5 cm) or a partial mastectomy. It is recommended to always remove the inguinal LN with caudal gland tumors and the axillary LN only if metastasis is recommended. An exception to the rule is if the dog is intact (and staying intact.) In a 2008 study, 58% of intact dogs who underwent a regional mastectomy developed a second mammary tumor in the ipsilateral chain, and 75% were malignant. In these cases, unilateral radical mastectomy should be considered. The effect of ovariohysterectomy (OHE) at the time of mammary tumor excision is controversial. The concern is that ER (estrogen receptor) positive tumors would benefit from the hormone ablation effects of OHE. Two studies have demonstrated survival advantage of OHE. In one study, dogs that were spayed within 2 years of mammary tumors or at time of tumor excision survived 45% longer than FI dogs or spay was greater than 2 years. Another study showed that spayed dogs were more likely to survive at least 2 years after surgery, especially for complex carcinomas. A practical issue is you may not know if the mass is benign or malignant at the time of surgery. But if malignancy is suspected, OHE should be recommended. Treatment: Chemotherapy The goal of chemotherapy is to achieve is to delay the metastatic disease in high risk patients, including high grade tumors and those with tumor emboli on histology. Various protocols have been adapted from human oncology, and often include doxorubicin, 5-FU (5- fluoroucil) cyclophosphamide, mitoxantrone, paclitaxel and carboplatin. Additional studies are needed to confirm the role of chemotherapy. COX-2 inhibition with NSAIDs may also have an anti-cancer activity Treatment: Radiation Unfortunately there is little information about radiation for CMT, despite its important role in the treatment of in women. Treatment: Hormone therapy It is relatively difficult to perform estrogen and progesterone assays on mammary tissue in practice, so hormone therapy has not been widely used for CMT. OHE can accomplish hormone ablation. is used in women with ER-positive tumors, but there have only been a few reports in a handful of dogs and results have been mixed. In addition there can be estrogen-like side effects. Treatment: Inflammatory mammary carcinoma (IMC) Surgery is contraindicated in dogs with IMC and surgery often leads to dehiscence, DIC (in up to 26% of cases), and of the ventrum and limbs. These tumors often have high levels of COX-2 expression and may benefit from NSAIDs. Unfortunately the overall the prognosis is poor for dogs with IMC.

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Prognosis for CMT The overall mean survival time is 439 days (14.6 months). When comparing benign to malignant tumors, the median survival time (MST) is approximately 16 months for malignant tumors vs. for benign tumors 26 months. For malignant tumors, the prognosis is quite variable and ranges from surgical cure to metastasis and/or recurrence in the 1st year. Of the malignant tumors, a better prognosis is associated with carcinoma in situ and adenocarcinomas. Of the carcinomas, solid carcinomas (MST = 6.5 months) have a worse prognosis that tubular or papillary carcinomas. Other tumors with poor prognosis are mixed malignant tumors (carcinomasarcoms MST 18 months) and SCC. Sarcomas (MST = 10 months) and IMC have the worst prognosis. In addition to histology, additional prognostic factors include: skin ulceration, invasive growth or fixed to adjacent tissue (29 months vs 12 months), increased age, GSD breed, advanced stage, tumor size >3 cm, high grade, nodal metastasis, not spayed, and vascular and/or lymphatic invasion, and male gender. Higher clinical stage at diagnosis is also associated with a worse prognosis (larger tumors, LN involvement, distant metastasis)

Feline mammary cancers (FMC) Who, what, where, why Feline mammary tumors are the third most common tumor (after skin tumors and lymphoma), representing about 20% of tumors in the female cat. Cats are typically middle-aged with a mean age is 10-12 years. Siamese cats may develop at an earlier age. Unlike dogs, malignant tumors are more common (85-93%) with malignant epithelial carcinomas/ACA the most common (80%). Unlike dogs, mixed tumors are rare. Like dogs, mammary tumors are rare in males (1-2%). Metastasis rates ranging from 25-100% have been reported. Metastasis is common (80%), typically to lungs, pleura and LN. Skeletal metastasis is less common in cats than dogs and people. Siamese cats are two times more likely to develop and have a higher incidence of tumors with lymphatic invasion. Persians have a higher incidence of benign tumors. While a genetic factor has not been identified, some and molecular markers have been shown to have abnormal expression: p53, Her-2, VEGF, cyclin A, COX-2. As with dogs, mammary masses are often incidental findings during routine wellness exams in older intact females, or owners find them. Owners should be encouraged to palpate their cats monthly for skin and subcutaneous masses – see section on See Something, Do Something (SSDS) below. Like dogs, half of cases will present with multiple masses and both chains can be affected. Tumors can be discrete or infiltrative, soft or firm, ulcerated and may be fixed to underlying tissues. Ulceration is common in cats and suggestive of malignancy. Timing of OHE Like dogs, OHE reduces the risk of cats developing mammary tumors. Cats spayed before 6 months had a 91% reduction, between 7- 12 months had an 86% reduction, but if spayed between 13-24 months, the reduction was only 11%. The protective effect is not seen after 2 years of age in cats. Based on this, it may be beneficial to spay cats prior to 1 year of age. Hormone therapy with progesterone and/or estrogen can lead to a 3-fold increase of both benign and mammary tumors.

Diagnostic work up in cats The work up is similar as dogs including measure tumor (Size is the most reliable prognostic factor for cats), evaluate LN, imaging (chest radiographs and abdominal ultrasound), and histology of the tumor. Incisional biopsy can be considered if a benign tumor is suspected, but in most cases, histology is performed on tissue removed at radical mastectomy. Like dogs, advanced imaging such as CT scan can be considered, as it is more sensitive to detect distant metastasis. Clinical staging in cats • Tumor (longest diameter): T1 <2 cm, T2 2-3 cm, T3 >3 cm • Regional lymph node: N0 no metastasis, N1 metastasis detected • Distant metastasis: M0 no metastasis, M1 metastasis detected Stage T N M grouping I T1 N0 M0 II T2 N0 M0 III T1, T2 N1 M0 T3 N0, N1 M0 IV T1-3 N0, N1 M1

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Treatment modalities for cats Treatment: Surgery Surgery is the first treatment of choice for mammary tumors when there is no evidence of distant metastasis based on staging tests. Unlike dogs, adjuvant chemotherapy is typically part of the recommended treatment protocol. The type of surgery in cats is different than dogs. The recommended surgery is radical mastectomy, and staged bilateral radical mastectomy is recommended if bilateral disease is present. Radical mastectomy reduces the risk of local recurrence. Local recurrence is >50% with incomplete resections. Underlying muscle and fascia should be removed en bloc. It is recommended to always remove the affected LN with the chain. In cats with unilateral disease, the benefit of bilateral surgery is not clear. Treatment: Chemotherapy The goal of chemotherapy is to achieve is to delay the metastatic disease in high-risk patients, including cats with poor prognostic factors. Additional studies are needed to determine the best protocols and survival advantage. Various protocols often include doxorubicin, cyclophosphamide, and carboplatin. Treatment: Radiation Unfortunately there is little information about RT but can be considered as palliation for non-resectable tumors. Treatment: Hormone therapy Most malignant tumors in cats are estrogen and progesterone negative so hormone therapy is ineffective.

Prognosis for cats • 1-year survival: 33-50% surgery alone, 59% with adjuvant chemotherapy • 2-year survival: 15-20% surgery alone, 37% with adjuvant chemotherapy Prognostic factors Size matters! Size is the most reliable prognostic factor for cats. (And gender too.) MST based on tumor size with surgery alone: • <2cm: > 3 years with mastectomy for females, 14 m for males • 2-3 cm: 1-2 years for females, 5.2 months for males • 3 cm: 4-6 months for females, 1.6 months for males • Surgery type: radical mastectomy decreases recurrence locally • Histology: complex carcinoma MST 33 months vs 15 months for other carcinomas • Grade: higher grade, shorter ST • Lymphatic invasion • Higher clinical stage at diagnosis is also associated with a worse prognosis • IMC has a similar poor prognosis in cats.

Don’t monitor the bump or lump. Why wait? Aspirate. ® Visual monitoring of skin and subcutaneous masses is not enough. Even the most experienced veterinarian or oncologist cannot look at or palpate a mass and know whether it is malignant or not. Cancer is a cellular diagnosis. It is always recommended to evaluate masses that are growing, changing in appearance, or irritating to the patient. But these guidelines are not enough.

“See something do something. Why wait? Aspirate. Dr. Sue Cancer Vet®” (SSDS) provides guidelines for evaluating superficial masses in dogs and cats. These apply to masses along the mammary chain as well. These guidelines will increase client awareness and will promote early cancer detection, diagnosis, and early surgical intervention. In veterinary medicine, most skin and subcutaneous tumors can be cured with surgery alone if diagnosed early when tumors are small. See something When a skin mass is the size of a pea (1 cm) and has been present for at least 1 month, Do something Aspirate or biopsy, and treat appropriately! Why diagnose early? Obtaining a definitive diagnosis with cytology or biopsy early and before excision will lead to improved patient outcomes for superficial masses. When smaller, superficial tumors are detected early, surgery is likely curative – this is especially true for benign lesions and tumors that are only locally invasive with a low probability of metastasis. If tumors are removed with complete surgical margins, the prognosis is often good with no additional treatments needed. 1. Pet owners need to be aware of the “pea” size requirement to have masses evaluated. 2. Veterinarians must measure and document the size of the mass in order to compare growth. 3. If > 1 cm (or size of large pea) and present for a month, the mass should be aspirated or biopsied. 4. Knowing the tumor type prior to the FIRST surgery will increase success of a curative-intent surgery

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Additional resources Henry CJ. Mammary Tumors. In Cancer Management in Small Animal Practice. Saunders 2010. 275-282. Malone EK. Mammary Gland Neoplasia, Cat. In Clinical Veterinary Advisor Dogs and Cats. 3rd edition. St. Louis Missouri: Elsevier Mosby; 2015: 633-635 Malone EK. Mammary Gland Neoplasia, Dog. In Clinical Veterinary Advisor Dogs and Cats. 3rd edition. St. Louis Missouri: Elsevier Mosby; 2015: 635-637 Schneider R, et al. Factors influencing canine mammary cancer development and post surgical survival, J Nat Cancer Inst 43 (6): 1249, 1969 Novosad CA, et al. Retrospective evaluation of adjunctive doxorubicin for treatment of feline mammary gland adenocarcinomas: 67 cases, J Am Hosp Assoc 42:110, 2006.

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Cancer Tools You Can Use Tomorrow: Canine Lymphoma Sue Ettinger, DVM, DACVIM Dr. Sue Cancer Vet Tarrytown, NY

Key points • Lymphoma is a common canine cancer and is a systemic disease that requires chemotherapy in almost all cases. • The majority of dogs achieve a complete remission with chemotherapy (approximately 80%). Higher remission rates are typical with CHOP multi-agent chemotherapy protocols. • Early accurate diagnostics and careful staging are keys to proper clinical decision-making. • To determine the best protocol for a patient and owners, it is important to understand efficacy of the various protocols, the potential toxicities, and prognostic factors. • Dogs treated with chemotherapy live significantly longer than untreated dogs, and chemotherapy is generally well- tolerated in most dogs. Only a minority develops significant toxicity. • The diagnostic and treatment choices can be confusing and overwhelming. In this talk, we will take “My 3 P’s” approach – prognostic, practical and pertinent.

Biology of lymphoma Lymphoma is a collection of cancers arising from the malignant transformation of lymphocytes. Even though lymphoma is clinically a diverse group of , the common origin is the lymphorecticular cells. Lymphoma is one of the most common canine cancers, accounting for 7-24% of all canine tumors and 85% of hematopoietic tumors. Dogs of any age, gender, and breed can be affected with lymphoma. Affected dogs are typically middle aged to older dog.

Anatomic classification Multicentric (PLN) is the most common form, accounting for 80% of lymphomas. Most dogs are typically asymptomatic, and 20- 40% are clinical (substage b) with anorexia, lethargy, fever, V/D, weight loss, melena Gastrointestinal (GI) involvement is less common accounting for only 5-7% of LSA cases. It is more common in males, and Boxers and Shar-peis over-represented. Weight loss, anorexia, panhypoproteinenemia, are common. It typically involve multifocal & diffuse of submucosa & lamina propria layers of small intestine. Phenotypically, GI LSA is typically T-cell. Histologically, can be challenging to distinguish from lymphoplasmacytic enteritis (LPE). In GI LSA, lymphocytic and plasmacytic inflammation can be adjacent or distant to the neoplastic population of cells. There is also the question of whether LPE a pre- lymphoma change? Mediastinal forms are also less common, accounting for only 5% of LSA cases. It typically involves the cranial mediastinal LN and/or , but 20% multicentric LSA have cranial mediastinal LN involvement. Hypercalcemia is most common with this form. In one study of 37 hypercalcemic dogs, 16 dogs (43%) had mediastinal lymphoma. Phenotypically, mediastinal LSA is typically T- cell Cutaneous LSA can be a solitary lesion or generalized lesions, and may have oral mucosa lesions, +/- extracutaneous involvement of LN, liver, spleen, BM. This form is referred to epitheliotrophic form or as mycosis fungoides. It is more common in dogs than cats. The immunophenotype is typically T-cell (CD8+). In contrast, B-cell cutaneous LSA spares the epidermis and papillary dermis and affects the deeper dermal layers.

Clinical appearance Historic findings The most common complaint is generalized lymphadenomegaly. Owners commonly report that lymph node size is rapidly increasing – over days to 1 to 3 weeks. In the early stages, dogs appear healthy and are not showing clinical signs. When present, clinical signs tend to be nonspecific and include vomiting, diarrhea, melena, anorexia, fever, and weight loss (substage b). Common examination findings Lymphoma can be indolent or aggressive, solitary or multicentric, or node-based or associated with any organ. Non-painful generalized lymphadenomegaly is most common physical exam finding. Multicentric lymphoma involving the peripheral lymph nodes is most common, accounting for 80% of patients. Most dogs are “healthy” substage a. T-cell dogs tend to be sick (b). In dogs, multicentric LSA is generally the NHL (non- Hodgkin’s LSA) form. Hepatosplenomegaly is common. Diffuse pulmonary infiltration has been reported in 27-34% based on CXR but on BAL, lung involvement may be higher. The lack of generalized lymphadenomegaly does not eliminate the possibility of

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lymphoma, as some dogs will have internal involvement only (i.e. hepatosplenic form, GI). Another scenario that can lead to confusion is hypercalcemia, often without peripheral lymphadenomegaly so lymphoma is not suspected.

Preliminary diagnosis Cytology Confirmation of lymphoma starts with fine needle aspirate of an affected lymph node. Cytology is minimally invasive, less expensive than biopsy, and typically provides rapid results, in 1 to 2 days. Cytology reveals monomorphic abnormal lymphocyte populations. Cytology does not provide complete classification, grading, or phenotype. Avoid reactive LN, such as the mandibular LN.

Diagnostic work up The minimum tests required for treatment are cytological confirmation (lymph node or affected organ), CBC, chemistry panel and urinalysis. The next diagnostic I encourage owners to submit is phenotyping to determine B vs T-cell subtype. Phenotyping is typically determined with immunocytochemistry from aspirates, immunohistochemistry from biopsy, or flow cytometry or PARR from aspirates. If there is a peripheral lymphocytosis on CBC (stage V), flow cytometry can be submitted on a whole blood sample to determine phenotype. Phenotype is the best independent prognostic factor; prognosis is worse with T-cell than B-cell. Lymph node biopsy is ideally performed for histologic grading but is often only collected when cytology was inconclusive. Baseline chest radiographs and abdominal ultrasound are recommended for staging purposes to determine extent of disease. While stage is prognostic, I also find it valuable to have these baseline imaging tests to be able to compare treatment response or progression. Bone marrow cytology is also considered part of the basic staging but it is often not done is the majority of cases, factoring in the additional cost and sedation for most cases. Bone marrow cytology is of less clinical utility in most cases. However, if there are cytopenias and/or a lymphocytosis, a bone marrow should be considered to identify bone marrow involvement. To stage or not to stage? Complete lymphoma staging includes lymph node cytological confirmation, CBC, chemistry panel, urinalysis, lymph node histology, urinalysis, thoracic radiographs, abdominal ultrasound, bone marrow cytology and phenotyping. These tests are useful and informative, as they provide prognostic factors and a baseline for a patient’s response. These tests can also help determine if there large tumor burden and risk for acute tumor lysis syndrome with induction chemotherapy. Still, we must consider the owner’s financial issues. While it is ideal to perform all the tests, we can also consider each test on a case by case basis and help the owner make an educated decision. We can treat without but review pros and cons with the owner and let owner make educated decision and maybe choose more important tests for that dog. Histology NIH WF & Kiel System most useful, and both describe architecture and cell morphology, including mitotic index, cell size, and cell shape. Why do I care about histology? It’s prognostic. Positive: Low grade LSA, Including mantle-zone, follicular, T-cell. But low grade LSA may only partially respond to chemotherapy and is often incurable. Negative: intermediate and high grade LSA BUT have a high mitotic rate & are more likely to completely respond to chemotherapy. Phenotype 60-80% of LSA are B-cell, and this is an important positive predictor, associated with higher rate of CR, longer remission, increased ST, and most high grade are B-cell. Breed prevalence with B-cell includes Cockers and Dobies. Goldens have equal B and T-cell. 10- 38% of LSA are T-cell, and this is an important negative predictor, associated with lower rate of CR, shorter remission, shorter ST, and tends to be associated with hypercalcemia. Boxers are over-represented. Flow cytometry (FCM) involves staining live cells with labeled antibodies that bind to cell surface . These live cells are suspended in liquid (saline, tissue culture media). Different types of lymphocytes express different proteins. Flow cytometer tells us how many cells of each type are present and can determine the lineage of the cells present. Flow could not identify LSA in 30% of newly diagnosed cases PARR PCR Antigen Receptor Rearrangement is a polymerase chain reaction (PCR) assay that amplifies DNA with PCR primers in the dog or cat. It tells us if the majority of cells in the sample are clonal: same original clone - most consistent with neoplasia, or from multiple clones/polyclonal - lymphoid proliferation - most consistent with a reactive process, It is useful to determine: whether lymphoid neoplasia, phenotype (B vs. T), and to monitor for MRD in treated patients, It must be interpreted with history, clinical signs, cytology, flow cytometry, IHC. For sensitivity & specificity, both are ~90% in dogs, and it is more sensitive for circulating cells > blood, bone marrow. In cats, it is better for T cell (89%, 80%) vs B-cells (60%, 70%). FCM and PARR are NOT useful for neutrophilia to r/o chronic myelogenous leukemia, when hypercalcemia is only sign, not helpful on LN, fluid, etc., or as a screening test for healthy dogs and cats without clinical signs.

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Prognostic factors There are many prognostic factors, but the more significant predictors include: • Phenotype: B-cell is better than T-cell. 60-80% are B-cell and this is associated with higher rated of CR, longer remission rates, and increased ST. Most high grade LSA are B-cell. • Histologic grade: high grade has better CR rate than low grade, but low grade often has comparable survival times with less intensive chemotherapy protocols. • Administration of prednisone prior to chemotherapy is a negative predictor • Substage: clinically healthy dogs tend to do better than sick dogs • Higher stage (stage IV and V) tend to do worse than lower stage (I to III) • Hypercalcemia: negative predictor due to association with T-cell phenotype • Mediastinal mass: negative predictor due to association with T-cell phenotype Remember, prognostic factors cannot predict an individual’s response, and lymphoma is typically treatable and rewarding to treat for the patient, owner and the veterinarian.

Treatment modalities Treatment pearls Chemotherapy is the mainstay of therapy to promote a rapid, durable and complete remission (CR), while maintaining a good to excellent quality of life even during chemotherapy. Complete remission is complete disappearance of all detectable lymphoma and resolution of clinical signs. Lymphoma is typically rewarding to treat with high response rates, and most dogs tolerate chemotherapy quite well. Treatment Chemotherapy The goal of therapy is to achieve a complete remission and a good to excellent quality of life. Dogs that respond and achieve CR are usually free of clinical signs of lymphoma and live longer and live well. Only a minority develops significant toxicity or do not respond to therapy. Most patients are treated on an outpatient basis. Newly diagnosed lymphoma patients that are sick (substage b), dehydrated, and have a large tumor burden (advanced stages) are at increased risk for acute tumor lysis syndrome with induction chemotherapy. In such cases, the dogs should be admitted for IV fluid therapy, supportive care, and intensive monitoring prior to chemo and for 24 to 72 hours after. Combination chemotherapy provides improved remission rates and duration in comparison to single agent protocols. Multi-agent CHOP protocols are the most successful, with complete remission rates of > 80% and remission durations of typically 6-11 months. Median survival times (MST) are 1 year when followed by rescue protocol, and 25% of dogs are long term survivors > 2 years. There are numerous CHOP protocols that vary in drug dosages, scheduling, and dose intensity. The UW-Madison protocol is often recommended for owners choosing a combination protocol for its high complete remission rates, higher remission duration, and lower morbidity and mortality rates. Commonly used UW protocols are the 25 and 19 week protocols Multi-agent CHOP protocols typically combine vincristine, cyclophosphamide, doxorubicin and prednisone. Recent studies suggest the inclusion of l-aspariginase at induction does not significantly impact remission duration or survival times and can be omitted and saved for the rescue protocol. Additionally recent studies suggest there is no survival benefit of maintenance phase. Most current protocols are discontinuous without a chronic maintenance phase and provide comparable remission durations. It is thought the period without chemotherapy may lead to greater responsiveness at relapse by lack of selection of resistant cells. For some clients, alternative protocols are elected over the multi-agent CHOP protocol due to budget, toxicity profile on par with clients’ willingness to assume risks of chemo, and schedule and time commitment. In some cases, it is to avoid drugs that target a patient’s weakness or concurrent illness. For example Lomustine is avoided with liver dysfunction and doxorubicin can cause cardiotoxicity so should be used cautiously in dogs with some pre-existing cardiac disease. Alternative chemotherapy protocols include COP (vincristine, cyclophosphamide, and prednisone), single agent doxorubicin for B- cell lymphoma, and single agent Lomustine for T-cell lymphoma. These protocols generally have lower response rates ranging from 50-80% and shorter remission durations of 6 to 7 months. New therapies for lymphoma include monoclonal antibodies and a lymphoma vaccine. It is hopeful these new therapies will increase survival times. If chemotherapy is declined If chemotherapy is declined, another option is single agent steroids. Typical response rates are 50% with duration of 2 to 3 months. Prednisone should not be started prior to chemotherapy since it may decrease response rate to chemotherapy started after the steroids. Pre- chemotherapy steroids use is associated with shorter remission and survival times due to induction of multi-drug resistance. If staging tests are done after prednisone is started, higher stage patients may appear to be lower stage (down-stage). Without chemotherapy the prognosis for lymphoma is poor, with MST of 1 month. 436

Relapse The majority of lymphoma patients relapse as there is the emergence of tumor clones that are more resistant to chemotherapy, or survival-of-the-fittest lymphoma cells. These MDR (multi-drug-resistance) clones are more likely to express MDR-1 that encodes for protein transmembrane pump associated with multidrug resistance. Other reasons for relapse include inadequate chemotherapy dosing, inadequate chemotherapy frequency, or failure to achieve high chemotherapy concentrations at certain sites, such as the CNS. When a patient relapses, I recommend reintroducing the initial protocol if it was successful, meaning the expected remission duration was achieved. For example, if a dog relapses one month after completing a CHOP protocol I will not recommend restarting front-line chemotherapy. However if the dog was off chemotherapy for 4-5 months with a 1st remission of 9-10 months, I will recommend restarting the induction protocol as re-induction rates of 90% can be expected. Remember there is a cumulative dose of doxorubicin, so doxorubicin is typically replaced after a total of 6 doses.When a dog no longer responds front-line chemotherapy, rescue protocols are recommended. There is decreased likelihood of response (30-50%) and shorter remission durations, typically half the length of the initial remission. Still some patients experience long-term re-inductions. Some commonly used protocols include MOPP, doxorubicin or mitoxantrone with DTIC, Lomustine/l-aspariginase/prednisone, and single agent Lomustine. Other treatment options Other treatment options include localized radiation for local disease, such as nasal or CNS lymphoma. Palliative radiation can be used for bulky localized disease such as rectal, bone or mandibular lymph nodes. The addition of half body radiation to multi-agent chemotherapy improved ST and remission duration in some studies, but there is increased costs and toxicity to balance. Whole body radiation is used in combination with bone marrow transplants. More recently, monoclonal antibodies have been introduced as targeted therapy for both T- and B-cell canine lymphoma, but efficacy and administration schedule are still being worked out. Canine remission times on CHOP have plateaued at about 9 months. In human monoclonal antibodies are standard of care. Before rituximab, results of CHOP-based chemotherapy plateaued in human medicine. Since its launch in 1997 it is the standard of care for non-Hodgkin’s lymphoma in humans and the addition of rituximab to standard CHOP has increased overall survival by 55%. Recheck frequency After completion of chemotherapy, I recommend monthly rechecks to evaluate for relapse, especially at time of expected relapse depending on the protocol elected. In addition to physical exam, monitoring with lymph node palpation, cytology, chest radiographs, ultrasound, and advanced diagnostics can be helpful. Recently blood tests have been evaluated to look for molecular markers to detect early relapse before clinically detectable. The Canine Lymphoma Blood Test (cLBT, Avacta) has recently been shown to detect relapse earlier, and the lowest score during treatment was prognostic for ST and TTP. (Alexandrakis, 2014). Overall Lymphoma is one of the most successfully treated cancers in dogs, and many patients with lymphoma outlive animals with other noncancerous diseases such as kidney, heart, and liver disease. Dogs treated with chemotherapy live significantly longer than untreated dogs, and chemotherapy is generally well-tolerated in most dogs.

Additional resources Vail DM, et al. Hematopoietic Tumors, Canine Lymphoma and Lymphoid Leukemia. In: Small Animal Clinical Oncology. 5th ed. St. Louis Missouri: Elsevier Saunders; 2013: 608-638. Williams LE. Lymphoma, Dog (Multicentric) in Clinical Veterinary Advisor Dogs and Cats. 2nd edition. St. Louis Missouri: Elsevier Mosby; 2011: 675-678 Bryan JN. Lymphoma. In Cancer Management in Small Animal Practice. Saunders 2010. 343-350 Alexandrakis I, et al, Vet Comp Oncol. 2014. Vaughan MA, et al, JVIM 2007; 1(6):1332-9

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Cancer Tools You Can Use Tomorrow: Feline GI Lymphoma Sue Ettinger, DVM, DACVIM Dr. Sue Cancer Vet Tarrytown, NY

Key points Lymphoma (LSA) is one of the most commonly occurring cancers in cats. Lymphoma is a systemic disease that requires chemotherapy in almost all cases. Outcomes for treated cats are less predictable than dogs, but cats tend to tolerate chemotherapy better than dogs. Treated cats live longer, and chemotherapy is generally well-tolerated. The diagnostic and treatment choices can be confusing and overwhelming. In this talk, we will take “My 3 P’s” approach – prognostic, practical and pertinent.

Biology of lymphoma Lymphoma is collection of cancers arising from the malignant transformation of lymphocytes and is a diverse group of neoplasms with the common origin of the lymphorecticular cells. In contrast to dogs, feline lymphoma most commonly affects the gastrointestinal (GI) tract. Lymphoma is one of the most common feline cancers, reported at 30% of all cancers. In the FeLV era from the 1960-1980s, lymphoma accounted for 50-90% of hematopoietic tumors. However, there was a shift after the 1990s, also called the post FeLV-era. With the aid of FeLV diagnostic assays and elimination regimens in 1970s and 1980s, there was a dramatic decline in FeLV- associated LSA. Still lymphoma prevalence is increasing, especially the alimentary form.

Etiology Viral In the FeLV era of the 1960-1980s, two-thirds of lymphoma was associated with FeLV antigen. FeLV-positive cats had a 62 fold increased risk. This form was predominantly seen in younger cats, was the mediastinal form, T-cell, and the virus had a direct role in tumorigenesis. Being FIV-positive increased lymphoma incidence by 5-6x. In contrast to FeLV, FIV has an indirect role secondary to immunosuppressive effects and is associated with B-cell and the extranodal form. Cats that are both FeLV and FIV positive have an increased risk of 77 fold Immunosuppression FIV has an indirect role with lymphoma secondary to immunosuppressive effects. Ten percent of feline renal transplants develop lymphoma following transplant and associated immunosuppressive therapy. Environmental Environmental tobacco smoke (ETS) has been reported to increase the risk of LSA by 2.5 to 3.2 fold. Genetic and molecular factors The predisposition of oriental breeds suggests a heritable risk, but this is still being investigated Chronic inflammation While definitive proof is lacking, there is growing evidence of the link with chronic inflammation and lymphoma, in particular with and intestinal LSA. This has been as area of interest with IBD and GI LSA. Diet and GI LSA While definitive proof is lacking, the diet changes over last 20 years in response to diseases such as urinary tract and the increase in GI LSA has led to the suggestion of a link, but more studies are needed.

Signalment Lymphoma can occur in cats of any age, any sex, any breed. The median age is 11 years, and a male predisposition is reported and intact females are at decreased risk, suggesting a protective benefit of sex hormones. Overrepresented breeds include Siamese cats, Manx, and Burmese. Signalment varies with anatomic site and FeLV status.

Pathology and behavior For the alimentary/GI from, the LSA typically involved the intestines alone or intestines, lymph nodes (LN), and liver. In the GI tract, it can be solitary vs diffuse. 55% of GI tumors are LSA. Siamese are at increased risk. The GI form typically occurs in aged cats of 12 to 13 years old. The small intestines are four times more affected than the large intestines. Enteropathy-associated T-cell LSA (EATL) has 2 forms. EATL Type I is intermediate to large B-cells, high grade, lymphoblastic lymphoma. This form often has a palpable mass. EATL Type II is called small cell, low grade, lymphocytic lymphoma. This form is more diffuse throughout the GIT and T-cell is more common.

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Clinical appearance Alimentary/GI For low grade small cell LSA, clinical signs include weight loss (83-100%), V/D (73-88%), anorexia (66%), and icterus (7%). 70% have abnormal palpation on exam, either thickened GI or a palpable mass 33%. The history is usually chronic over several months, with a median 6 months. For high grade LSA, the clinical signs are similar but icterus is more common and the onset is more rapid – days to weeks. A palpable mass is common. Rarely the cat will present with acute abdomen due to obstruction or perforation.

Diagnosis and staging Basic diagnostics include CBC, chemistry panel, and UA. For the GI forms, 23% have panhypoproteinemia and 76% are anemic. Test for FeLV/FIV status. Diagnosis typically made with cytology or histology of a LN or organ. Cytology may be inconclusive and be reported as benign hyperplastic and reactive, and histology will be needed. Other diagnostics may include abdominal ultrasound (AUS) and chest radiographs. Bone marrow cytology may be recommended especially for cases with anemia, leukopenia, or cellular atypia. Phenotype can be determined with PARR 80% sensitive or flow cytometry. For high grade large cell (EATL type I), the diagnosis is typically more straightforward with GI masses, enlarged mesenteric LN, or liver involvement. The diagnosis is typically made with abdominal ultrasound and cytology/histology. Surgery is less commonly needed. For low grade small cell (EATL type II), intestinal thickening is often modest or absent and similar to IBD. Cytology alone is often insufficient and will come back as benign hyperplasia. To confirm the diagnosis, AUS and histopathology are typically needed, and may require phenotype and clonality. It can be challenging to distinguish low grade vs IBD with abdominal ultrasound. With low grade GI LSA, 60-90% have an abnormal AUS with 50-70% diffuse SI thickening, predominantly muscularis propria and submucosa layers. Mesenteric lymph nodes are abnormal in 45-80%. Focal GI masses are uncommon. For IBD, 10-50% have diffuse SI thickening and mucosal thickening more common. The incidence of mesenteric LN lymph nodes is lower at 15-20%, and other abnormal organs are typically normal. Cytology is rarely useful for distinguishing low grade GI LSA vs IBD. The debate rages on regarding endoscopy vs full thickness biopsy (laparotomy vs laparoscopy). On histopathology, lymphoma typically has lymphoid infiltration beyond mucosal layer, epitheliotrophism, heterogeneity, and lymphocyte nuclear size consistent with malignanct. If diagnosis is still equivocal, phenotype or PARR is recommended.

Feline chronic small bowel disease (CSBD) This study highlights that CSBD often is often considered normal by cat owners. Excuses include: “He just eats fast”, “She is a nervous cat”, “He has a sensitive stomach”, “She gets hairballs”, “He’s always done this.” CSBD includes IBD and enteropathy- associated T-cell LSA (EATL) type 2. EATL type 2 most common infiltrative GI LSA in cats, and treatment is different than IBD. In this study, the authors looked at the association of clinical signs and disease in 100 cats that had an AUS of small bowel >0.28 cm in > 2 locations. These cats had >1: vomiting >2x /month for at least 3 months, several weeks of small bowel diarrhea, and weight loss > 0.5 kg in last 6 months. Interestingly, 26 cats were getting wellness exam. 65 cats did not have surgery and were excluded. Clinical signs included weight loss 70%, vomiting >2x 61%, diarrhea 11%, and V/D 13%. 92% had at least 1 AUS measurement >0.3 cm, 8 cats 0.29-0.29 cm, and 76 cats 1 measurement <0.28 cm. 99 of 100 had cats had IBD or LSA. Only 1 cat had normal histology. 49% had IBD/chronic enteritis. 46% had LSA (n=44 EATL type2).Cats <8 years old had enteritis, and cats > 8 years old enteritis or cancer. The 1 normal cat was 5 years old. Cats with GI clinical signs are common and should undergo diagnostics. Do not let clients make excuses, and get a good history. Chronic vomiting is often considered normal, but vomiting is not normal! Clinical signs should trigger abdominal ultrasound. One of the common excuses is vomiting hairballs is normal. Is vomiting hairballs is normal? Does chronic small bowel disease slow bowel movement and predispose to formation?

Treatment Treatment: Dogs vs cats There are less feline data than for canine LSA. Papers often lump together small number of cases of multiple subtypes of various anatomic, phenotype and histologic grades. Outcomes are less predictable in cate and there is greater variation in histologic type and anatomic location in cats. But cats tolerate chemotherapy well and better than dogs. Febrile neutropenia is rare. Most owners happy they chose to treat and the QOL improves. Which protocol? For intermediate and high grade/EATL I, there is an overall response of 50-80%, a median remission of 4 months, and a median survival 6 months. Cats that achieve a complete remission have a MST of 1 year. I typically recommend a CHOP multi-agent protocol

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such as the UW 25 week protocol. When using doxorubicin in cats, I use a lower dose (1 mg/kg). Cardiac toxicity is not clinical problem in cats in contrast to dogs, and renal function (BUN, Cr, USG) should be monitored in cats when giving doxorubicin. In dogs, data supports shorter maintenance-free protocol, but there is no data in cats, and some cats may need chronic chemotherapy. An alternative protocol is the COP protocol with reported complete remissions of 50-70%. This is commonly used in used in Europe with similar results to CHOP in 1 study. While the protocol requires less frequent visits, it is a longer 1 year protocol. Other studies support the addition of doxorubicin to COP for durable responses. For single agent options, Lomustine can be given at 50-60 mg/m2 every 4-6 weeks, which is given at a lower dose and less frequently than dogs. Single agent doxorubicin is cats is less successful with complete remission rates of <50%. For low Grade/ EATL type II, less aggressive chemotherapy protocols are typically used. Oral chlorambucil (Leukeran®) can be dose with pulse dosing (20mg/m2 every 2 weeks or 15 mg/m2 for 4 days every 3 weeks) or with chronic dose (>4 kg start @ 2 mg PO q 2 day, maintenance q 3 days; <4 kg start @2 mg PO q 3 day, maintenance q 4 days). For cats I prefer prednisolone, typically at 1 - 2 mg/kg orally daily and reduce to 0.5 to 1 mg/kg daily. In some cases, prednisolone may be discontinued. For relapsed cases, cyclophosphamide, Lomustine, and vinblastine are recommended. For severe or refractory cases, I will used CHOP or COP protocols Nutrition for EATL type II With evidence of role of inflammation and many have concurrent IBD, there is thought to consider transition to a novel protein diet and add probiotics. I also recommend running B12 levels, and supplementing as indicated Prognostic factors The prognosis and response in cats is more variable than in canine lymphoma. Prognostic factors include anatomic location, achieving a CR, FeLV status, substage, and a multi-agent protocol (CHOP vs COP?). Factors that are NOT prognostic in cats include stage and immunophenotype, age, weight, gender, and FIV For GI forms, the prognosis is overall extremely variable. For EATL type I, response rates are 50-75%, median remission duration is 4-6 months, and expected survival is 6-8 months. 15-25% can live 1-2 years. For EATL type II, remission is generally defined as improvement or resolution of clinical signs, And 70%-85% will respond for a median survival time of >2 years.

References Vail DM. Feline Lymphoma and Leukemia. In: Small Animal Clinical Oncology. 5th ed. St. Louis Missouri: Elsevier Saunders; 2013:638-653. Williams LE. Lymphoma, Dog (Multicentric) in Clinical Veterinary Advisor Dogs and Cats. 2nd edition. St. Louis Missouri: Elsevier Mosby; 2011: 675-678 Norsworthy GD, et al, JAVMA 2013, 243 (10): 1455-1461.

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