Cancer Flashcards

Question

Although combination chemotherapy could potentially be more toxic to normal cells, patterns of toxicity vary between drugs. Judicious scheduling of chemotherapeutic agents so that their toxicities do not overlap appears to improve tumor kill without compounding toxicity. For example, drugs that do not produce significant bone marrow suppression (such as ................... or ...................) may be scheduled to be given 1 week after a myelosuppressive agent (....................., ...................) or even on the same day in combination.

Answer 1

For example, drugs that do not produce significant bone marrow suppression (such as vincristine or L-asparaginase) may be scheduled to be given 1 week after a myelosuppressive agent (doxorubicin, cyclophosphamide) or even on the same day in combination.

Answer 2

No; so doses should not be reduced. To reduce risk of drug resistance, it is important not to administer drugs at subtherapeutic doses; the highest dose intensity possible should be delivered. It is also important not to modify the planned doses or schedule in anticipation of a toxicity that has not occurred. . It is also important not to change the protocol for short-term or non–life-threatening toxicities such as mild emesis or diarrhea. On the other hand, if tumor growth occurs, it is not good practice to continue the same treatment protocol at the same doses. Instead, an alternative, non–cross-resistant regimen should be used.

Answer 3

As the tumors grow, the growth fraction decreases, the cell cycle time increases, cellular heterogeneity increases (leading to a higher level of spontaneous resistance), and areas of poor vascular perfusion increase.

Answer 4

Treatment used before localized treatment modalities such as surgery or radiation therapy, with the objective of reducing the size of the primary tumor and reducing the scope and side effects of other definitive treatment.

Answer 5

The use of chemotherapy drugs primarily as radiation sensitizers rather than for their direct antitumor effect.

Answer 6

Cisplatin and carboplatin can be delivered to dogs as an intracavitary infusion into the pleural, pericardial, or peritoneal cavities to successfully control malignant effusions or intravesicularly (into the urinary bladder) for bladder tumors. Cisplatin has also been injected intralesionally, in a collagen or oil-based vehicle, to control localized tumors. (Encapsulation in liposomes can reduce or alter the toxicity of some chemotherapy drugs)

Answer 7

Mesna and dexrazoxane. -Mesna reduces the risk of cystitis associated with ifosfamide and cyclophosphamide by binding toxic metabolites in the urine. -Dexrazoxane protects against doxorubicin-associated chronic cardiotoxicity and reduces severity of doxorubicin-associated extravasation injury when used quickly thereafter.

Answer 8

Implies thats smaller animals have a higher metabolic rate and therefore should receive a higher dose on a body weight basis. For other drugs (e.g., doxorubicin) dose based on BSA is imperfect, and small dogs and cats should be dosed at lower rate than larger dogs. (Until further guidelines are available, veterinarians should check the dosing basis for any drug to be used, become familiar with the individual drugs that require lower dose for small pets, and use a BSA conversion table when metabolic dosing is indicated).

Answer 9

For example, in dosing of myelosuppressive drugs, because there will be variation in individual metabolism of drugs and in the sensitivity of normal tissues, the aim should be to deliver doses that produce a neutrophil nadir of between .............. and ......... cells/µL.

Answer 10

Because most chemotherapy drugs are effective in the active phases of the cell cycle, toxicity from chemotherapy is most common in tissues that are renewing and is usually related to drug dose. Although most tumor cells are in active phases of the cell cycle, most normal tissues have a relatively low growth fraction.

Answer 11

Normal tissues can be classified as static (nerve, striated muscle), in which the capacity for mitosis is limited; expanding (organs, glands), in which mitosis can be induced; and renewing (hematopoietic cells, mucosa, epidermis, gametes, fetal tissues), in which the growth fraction approaches that of tumor tissue. The major toxicities of chemotherapy affect the latter group.

Answer 12

Myelosuppression is a general term applied to the toxic effects of chemotherapy on the bone marrow. In general, the prognosis after uncomplicated myelosuppression is good, and most dogs and cats recover within a few days.

Answer 13

The proliferating hematopoietic progenitors and precursors, which are starting to commit to a particular lineage but are still immature. The more differentiated cells form a nonproliferating pool of maturing hematopoietic cells that will be unaffected by chemotherapy and will provide mature cells for 5 to 10 days. This means that the nadir (or low point) of peripheral cell counts occurs after this pool is exhausted. The time at which the nadir occurs also depends on the life span of the hematopoietic cell.

Answer 14

Neutrophils live only hours in both dogs and cats, and their nadir occurs first 5 to 10 days after chemotherapy.

Answer 15

Platelets live for approximately 10 days and their nadir occurs 1 to 2 weeks after chemotherapy.

Answer 16

Erythrocytes live for 120 days in the dog and 70 days in the cat; although anemia may occur over a prolonged course of chemotherapy, it rarely requires intervention such as transfusion support.

Answer 17

Like the maturing cells, hematopoietic stem cells are largely nonproliferating and so are relatively resistant to chemotherapy toxicity. However, they are stimulated to divide by the loss of proliferating precursor cells and rapidly replace the lost cells so that nadirs after chemotherapy rarely last more than several days. This also has implications for the interval between administrations of myelosuppressive drugs. If these drugs are given when the stem cell pool is dividing (i.e., soon after the previous administration), then severe prolonged myelosuppression caused by stem cell destruction may occur. The usual timing for myelosuppressive drug administration is every 2 to 3 weeks. Some drugs (such as lomustine and carboplatin) may have delayed or prolonged nadirs, and dosing intervals are longer for these drugs.

Answer 18

Doxorubicin Vinblastine Cyclophosphamide Carboplatin Mitoxantrone Lomustine (CCNU) Vinorelbine

Answer 19

Melphalan Vincristine (0.75 mg/m2)* Methotrexate Cisplatin Chlorambucil Hydroxyurea 5-Fluorouracil However, the combination of vincristine and L-asparaginase can be highly myelosuppressive.

Answer 20

L-asparaginase* Vincristine (0.5 mg/m2)* Corticosteroids Bleomycin Streptozotocin However, the combination of vincristine and L-asparaginase can be highly myelosuppressive.

Answer 21

A complete blood count (CBC), including a platelet count, should be collected at the expected neutrophil nadir, usually 1 week after administration. The absolute neutrophil count (not the total leukocyte count) should be evaluated. Although many animals have a low neutrophil count without clinical signs, a count of less than 1000 cells per µL is sufficient reason to reduce all subsequent doses of that myelosuppressive drug.

Answer 22

Thrombocytopenia rarely causes clinical signs; however, at counts less than 50,000, the risk of bleeding increases and clinicians should be alert to petechiation, ecchymoses, or mucosal bleeding.

Answer 23

Inappetence, anorexia, nausea, vomiting, or diarrhea. Management of such toxicity depends on severity of signs. Again, most GI toxicity is mild, self-limiting, and carries a good prognosis. Oral metoclopramide may reduce severity of vomiting. Subsalicylate may be helpful for diarrhea in dogs. For severe GI signs, IV fluid support and antiemetic treatment should be considered. More effective antiemetics include metoclopramide infused at a constant rate, the serotonin antagonists ondansetron and dolasetron, and maropitant. Cisplatin is a powerful emetogen, and prophylactic administration of butorphanol immediately after cisplatin administration should reduce both incidence and severity of vomiting.

Answer 24

IV fluids should be administered, because dehydration may exacerbate the nephrotoxic effects of cisplatin.

Answer 25

Antibiotics should be administered to these animals in addition to supportive and symptomatic care.

Answer 26

In veterinary oncology, cardiotoxicity is only clinically a problem with doxorubicin chemotherapy. Acute cardiotoxicity is related to peak plasma levels and occurs when administration is too rapid. Although the arrhythmias are self-limiting, they can cause collapse. Acute cardiotoxicity is related to peak plasma levels and occurs when administration is too rapid. Although the arrhythmias are self-limiting, they can cause collapse. The end result resembles dilated cardiomyopathy and may progress to congestive heart failure (CHF). Although cardiotoxicity in dogs can occur at any cumulative dose, it is most frequent above 180 mg/m2, and doxorubicin should not be given above this level without echocardiographic monitoring

Answer 27

By delivering the drug as a continuous infusion over several hours, by using liposome-encapsulated doxorubicin, or by pretreatment with the cardioprotectant drug, dexrazoxane. The latter two options are yet to be fully evaluated in clinical veterinary practice.

Answer 28

Nephrotoxicity is the primary dose-limiting toxicity of cisplatin and streptozotocin, and depends on both the individual and cumulative dose. This toxicity also carries a poor prognosis. Cisplatin should not be administered to dogs with preexisting renal disease and should be used with caution in dogs with urinary tract tumors. It is important to check the serum creatinine level before each cisplatin treatment. Cisplatin should not be administered if the serum creatinine is above normal range. In addition, cisplatin should always be delivered with appropriate saline diuresis. Doxorubicin has been associated with nephrotoxicity in cats.

Answer 29

Liver enzyme serum activities (ALT) should be assessed prior to lomustine (CCNU) administration. Irreversible hepatic toxicity can result if lomustine therapy is continued in the face of serum ALT elevations.

Answer 30

Urothelial toxicity (sterile hemorrhagic cystitis) is associated with cyclophosphamide and ifosfamide administration. Although this toxicity is uncommon after cyclophosphamide administration, it will commonly occur after ifosfamide treatment in humans unless the urothelial protectant, mesna, is given concurrently. Concurrent administration of furosemide substantially reduces the risk of its occurrence. When it occurs, it is usually self-limiting and carries a fair to good prognosis; however, clinical signs of stranguria, dysuria, and hematuria can be severe as well as persisting for weeks. This toxicity should be distinguished from infectious cystitis by bacterial culture; however, even if bacteria are isolated and signs resolve with antibiotic administration, the drug should not be administered again because infectious cystitis could have been secondary to chemical cystitis.

Answer 31

Chlorambucil is usually substituted for cyclophosphamide if urothelial toxicity occurs in lymphoma patients. If urothelial toxicity occurs, steroidal or nonsteroidal antiinflammatory drugs (NSAIDs) may reduce the severity of signs. In persistent cases, intravesicular instillation of 25% dimethyl sulfoxide (DMSO) for 20 minutes may help reduce signs and may be repeated weekly.

Answer 32

Hypersensitivity reactions may occur during doxorubicin administration because of histamine release from mast cells. This effect only occurs with rapid administration and is not a problem if the drug is given as a slow infusion A similar but more severe reaction occurs after IV administration of etoposide and paclitaxel because of “carrier” solutions in these formulations. Both carriers cause massive histamine release, the effects of which are only partly prevented by pretreatment with antihistamines and corticosteroids.

Answer 33

True anaphylaxis may occur after L-asparaginase administration, particularly by the IV or intraperitoneal route. This toxicity occurs rarely if L-asparaginase is administered IM or SQ.

Answer 34

Cisplatin causes fatal, acute pulmonary edema in cats and should not be administered systemically. Topical and systemic administration of 5-fluorouracil causes acute fatal neurotoxicity in cats, and products containing this drug should not be used.

Answer 35

Myelosuppression

Answer 36

Tumor cells may develop drug resistance spontaneously through mutation. The mutation rate is higher in tumors than in normal tissue because of the genetic instability characteristic of malignancy. With each cell division comes the risk of a resistance mutation; therefore the larger a tumor is (i.e., the more cell divisions it has undergone), the higher the likelihood that this has occurred Tumor cells can also develop drug resistance specifically. Exposure to sublethal drug concentrations can result in gene amplification of detoxifying proteins.

Answer 37

Between anthracyclines, mitotic inhibitors, and others. However, alkylating agents are not substrates for the mdr pump, and so they become the mainstay of treatment in patients that appear to have this type of drug resistance.

Answer 38

An asymptomatic, middle-aged dog with stage 3, B-cell lymphoma, for which the prognosis is guardedly optimistic. The owners of such a dog may even elect to try more aggressive combination chemotherapy to improve the chance of long remission.

Answer 39

1. The induction phase encompasses the often intensely scheduled initial treatments. During this phase, a dog or cat has a relatively higher risk of toxicity but usually also the greatest chance of response 2. Consolidation is sometimes used at the end of induction. Unrelated, effective drugs are administered to further reduce the proportion of surviving cancer cells 3. Maintenance is a less intense phase (usually involving decreased frequency of administration) during which the drugs previously used for induction are administered. Maintenance therapy probably has little influence on whether an animal is cured, but it may prolong survival by increasing the time to relapse. 4. Rescue is therapy given when the drugs used during the other three phases no longer result in remission. Unrelated drugs (often alkylating agents because they are less likely to show cross-resistance) are used for rescue

Answer 40

In veterinary oncology, primary chemotherapy usually is reserved for hematopoietic tumors (lymphoma, leukemias, multiple myeloma). Chemotherapy for dogs with metastatic solid tumors (carcinomas and sarcomas) is rarely curative and is better considered to be palliative.

Answer 41

After surgery, adjuvant chemotherapy may be given to slow the progress of metastatic disease or possibly to provide a cure.

Answer 42

Neutropenia is a toxicity of many chemotherapy agents, and the nadir (lowest point) generally occurs 5 to 10 days after administration. A complete blood count (CBC) should be obtained 7 days after most treatments. Monocytosis on a CBC often predicts imminent neutrophil recovery, because monocytes have one fewer maturation step than granulocytes and therefore are released from the bone marrow earlier

Answer 43

Neutrophil recovery is usually rapid; however, a nadir of less than 1000/µL should prompt a 25% dosage reduction for all subsequent administrations of the drug associated with that episode of neutropenia. It is not necessary to reduce the dosage of other myelosuppressive drugs, because they may not cause the same degree of suppression. Each drug should be assessed individually. If a dosage reduction is made, the nadir should again be assessed.

Answer 44

Neutropenia at the time of the next chemotherapy treatment is a reason to delay administration of a myelosuppressive drug (but not of a nonmyelosuppressive drug, such as L-asparaginase or prednisone). In general, a neutrophil count of less than 3000/µL requires a delay in chemotherapy, usually of 1 week, before the CBC is rechecked. If the pet takes a long time to recover (as occurs for many cats and some dogs after receiving carboplatin), it may be necessary to reduce the dosage so that the optimal intertreatment interval and dose intensity can be maintained.

Answer 45

Thrombocytopenia may be dose limiting for some chemotherapy agents (carboplatin, cumulative for CCNU and occasionally chlorambucil), but is rarely clinically significant for other drugs. Platelet nadirs occur later than neutrophil nadirs, but are rarely as severe and recovery is slower but complete. Thrombocytopenia in a pet about to receive CCNU should prompt a dose reduction or discontinuation.

Answer 46

Renal function should be assessed by serum creatinine and urine specific gravity determinations before administration of nephrotoxic drugs (cisplatin in dogs; doxorubicin in cats) or renally excreted drugs (carboplatin).

Answer 47

Serum liver enzyme activity (alanine aminotransferase [ALT]) should be assessed prior to administration of lomustine. Irreversible hepatic toxicity can result if lomustine therapy is continued despite increases in serum ALT activity. Increases in serum bilirubin should prompt dose reductions in hepatically metabolized drugs.

Answer 48

Metoclopramide The recent introduction of serotonin antagonists such as ondansetron and dolasetron and the neurokinin 1(NK1) antagonist, maropitant (Cerenia) have markedly altered toxicity patterns for animals treated with many drugs.

Answer 49

The pet's diet should remain as stable as possible during chemotherapy to avoid exacerbation of gastrointestinal damage. Prophylactic absorbents (e.g., Kaopectate) may reduce the risk of diarrhea. If diarrhea occurs, a bland diet should be offered; if the diarrhea persists, and causes such as parasitism in these often immunosuppressed patients have been eliminated, sulfasalazine or metronidazole may reduce the severity. Prophylactic trimethoprim-sulpha (TMPS) antibiotics should be considered

Answer 50

Cyclophosphamide and ifosfamide are hepatically metabolized to their active forms and also to compounds that can cause bladder wall damage (acrolein). Prolonged contact time between the bladder wall and acrolein results in hemorrhagic cystitis. Furosemide, given as a single dosage (2 mg/kg either IV or PO) at the time of cyclophosphamide administration, almost completely abrogates this toxicity. Mesna is a thiol drug that is active only in urine; it binds to acrolein, preventing the toxicity of urothelial damage. Because mesna is expensive, its use usually is limited to dogs receiving ifosfamide or that have a high risk of urothelial damage.

Answer 51

Treatment of hemorrhagic cystitis includes the use of antiinflammatory drugs (e.g., piroxicam, 0.3 mg/kg given orally once a day); with prolonged cases, intravesicular dimethyl sulfoxide (DMSO) may accelerate recovery.

Answer 52

Neutropenia is a common side effect of many chemotherapeutics and may occasionally be severe (e.g., neutrophil count less than 500/µL at the nadir). The risk of sepsis is low in animals receiving antibiotics concurrently, because the nadir rarely persists longer than a couple of days. Many oncologists recommend prophylactic use of a broad-spectrum, oral antibiotic (e.g., TMPS) in animals receiving a myelosuppressive agent for the first time. If the nadir is greater than 1000/µL, subsequent administrations may be given without prophylactic antibiotics. (Neutropenic dogs have high endogenous G-CSF and are unlikely to benefit from exogenous administration)

Answer 53

Cyclophosphamide (Cytoxan) is used primarily for the treatment of lymphoma in dogs and cats. Chlorambucil (Leukeran) is used primarily for the treatment of chronic lymphocytic leukemia or low-grade lymphoma in dogs and cats and as a substitute for cyclophosphamide if hemorrhagic cystitis occurs. Melphalan (Alkeran) is used primarily in combination with prednisone for the treatment of multiple myeloma in dogs and cats. Lomustine (CCNU, Ceenu) is used for the treatment of lymphoma, mast cell tumors, brain tumors (response in gliomas and meningiomas) and histiocytosis. Ifosfamide (Ifex) is active against lymphoma and soft tissue sarcomas, particularly in cats.

Answer 54

Antitumor drugs act by deoxyribonucleic acid (DNA) intercalation, interfering with topoisomerases, and other mechanisms. These drugs usually exhibit cross-resistance with others in their class and with drugs in other classes, such as vincristine, paclitaxel, and etoposide. This resistance is mediated by the MDR glycoprotein.

Answer 55

Doxorubicin (Adriamycin; generic form) Mitoxantrone (Novantrone) Dactinomycin is a low-cost alternative to doxorubicin Bleomycin

Answer 56

Cisplatin: canine osteosarcoma and many carcinomas. It is not for use in cats Carboplatin has efficacy similar to cisplatin, with no apparent renal toxicity, and is safe in cats

Answer 57

The enzyme L-asparaginase is used primarily for lymphoma in dogs

Answer 58

vinca alkaloids paclitaxel (rarely used in veterinary medicine) Vincristine (Oncovin) Vinblastin (Velban)

Answer 59

Mitotic inhibitors act to inhibit assembly (vinca alkaloids) or disassembly (paclitaxel) of the mitotic spindle. The commonly used mitotic inhibitor vincristine is curative for canine transmissible venereal tumor. It also is very effective in combination chemotherapy for lymphoma in dogs and cats. It is included in some combinations for the treatment of sarcomas. Vinblastine is effective in combination chemotherapy against lymphoma in dogs and cats; however, it is seldom used because of its myelosuppressive effect, which makes it more problematic than vincristine to include with other drugs. Vinblastine also appears to have efficacy for mast cell tumors in dogs.

Answer 60

The immune system is generally divided into two primary components: the innate immune response, and the highly specific, but more slowly developing adaptive or acquired immune response. Immune responses can be further separated by whether they are induced by exposure to a foreign antigen (an “active” response) or if they are transferred through serum or lymphocytes from an immunized individual (a “passive” response). The ideal cancer immunotherapy agent should be able to discriminate between cancer and normal cells (i.e., specificity), be potent enough to kill small or large numbers of tumor cells (i.e., sensitivity), and last be able to prevent recurrence of the tumor (i.e., durability).

Answer 61

Innate immunity is rapidly acting but typically not specific and includes physicochemical barriers (e.g., skin and mucosa); blood proteins such as complement, phagocytic cells (macrophages, neutrophils, dendritic cells [DCs], and natural killer [NK] cells); and cytokines, which coordinate and regulate the cells involved in innate immunity.

Answer 62

Adaptive immunity is thought of as the acquired arm of immunity, which allows for exquisite specificity, an ability to remember previous existence of a pathogen (i.e., “memory”), differentiate self from non-self, and have the ability to respond more vigorously upon repeat exposure to a pathogen. Adaptive immunity consists of T and B lymphocytes.

Answer 63

The T cells are further divided by CD (cluster of differentiation) and MHC (major histocompatibility complex) into helper T cells (CD4 and MHC class II) and cytotoxic T cells (CD8 and MHC class I), NK cells, and regulatory T cells (Treg).

Answer 64

B lymphocytes produce antibodies (humoral system) that may activate complement, enhance phagocytosis of opsonized target cells, and induce antibody dependent cellular cytotoxicity (ADCC). B-cell responses to tumors are believed to be less important than the development of T-cell–mediated immunity, but there is little evidence to fully support this notion

Answer 65

The innate and adaptive arms of immunity are not mutually exclusive

Answer 66

Immune responses can be further separated by whether they are induced by exposure to a foreign antigen (an “active” response) or if they are transferred through serum or lymphocytes from an immunized individual (a “passive” response). Although both approaches have the ability to be extremely specific for an antigen of interest, one important difference is the inability of passive approaches to confer memory.

Answer 67

The principal components of the active/adaptive immune system are lymphocytes, antigen-presenting cells, and effector cells. Furthermore, responses can be subdivided by whether they are specific for a certain antigen, or a nonspecific response whereby immunity is attempted to be conferred by upregulating the immune system without a specific target.

Answer 68

Mice that lack IFN-γ and B/T cells develop tumors, especially at a young age.

Answer 69

BRMs are molecules that can modify the biologic response of cells to changes in their external environment, which in the context of cancer immunotherapy could easily span nonspecific and specific immunotherapies. (“immunopotentiators” which are often related to bacteria and/or viruses)

Answer 70

Elicitation of an antitumor immune response that results in clinical regression of a tumor and/or its metastases.

Answer 71

The immune system detects tumors through specific tumor-associated antigens (TAAs) that are recognized by both CTLs and antibodies.

Answer 72

ras, p53, p21, and/or others.

Answer 73

Eradication of a tumor with preservation of normal tissue structure and function. The increase in the use of radiation therapy has led to a progressive decrease in the need for radical surgery as the sole treatment for many common cancers.

Answer 74

The radiation used in radiation therapy is called ionizing radiation because it is sufficiently energetic to cause ionization and excitation of atoms and molecules in cells, resulting in a variety of short-lived ions and chemically unstable free radicals that cause molecular damage.

Answer 75

Genomic deoxyribonucleic acid (DNA). Most of the damage to DNA results indirectly from interaction of DNA with free radicals derived from the ionization of cellular water molecules, the most common molecule in cells.

Answer 76

Single-strand breaks (SSB), double-strand breaks (DSB), base damage, and DNA-DNA or DNA-protein crosslinks.

Answer 77

Radiation repair is usually more efficient in normal cells than in tumor cells. Although the majority of DNA damage can be repaired, heterologous DNA DSB are most often irreparable. Irreversible damage to the DNA results in chromosomal aberrations, gene mutations, cell degeneration, and cell death.

Answer 78

Proliferative cell death (mitotic cell death) and programmed cell death (apoptosis)

Answer 79

Cells engaged in the mitotic cycle. This form of cell death is particularly relevant to radiotherapy of tumors, because one of the most important characteristics of a tumor is its ability to divide indefinitely.

Answer 80

This mechanism of cell death leads to cell necrosis and results in local inflammation.

Answer 81

Susceptibility to radiation-induced apoptosis is cell-type specific and is most prominent in hematopoietic or lymphoid cells, but not in stromal- or epithelial-derived tissues.

Answer 82

Apoptosis requires intact cellular mechanisms that are often compromised in tumor cells. The tumor suppressor gene protein p53 plays a pivotal role in radiation-induced apoptosis. Its mutation, which is common in some cancers, results in a decreased contribution from apoptosis to the overall cell death in different cell types. While mitotic cell death and apoptosis kill and eliminate cancer cells, radiation-induced terminal growth arrest irreversibly prevents further tumor evolution.

Answer 83

Terminal growth arrest is a process similar to senescence, in which the cells remain physiologically active but have lost their ability to proliferate. This cytostatic effect on tumor cells results in a delayed tumor response to irradiation.

Answer 84

The degree and speed of tumor regression after therapeutic irradiation is determined by several factors, including the susceptibility to ionizing radiation related to tumor type and the contribution of inhibition of cell proliferation and cell death; tumor cell kinetics (i.e., the rate of cellular proliferation, cell death, and cell loss); the proportion of clonogenic cells; and the amount of vasculoconnective tissue in or around the tumor.[4]

Answer 85

Tumors that regress quickly and completely (e.g., high-grade mast cell tumors in dogs and oral squamous cell carcinomas in cats) may also recur quickly. Incomplete tumor regression at the completion of treatment does not necessarily indicate treatment failure. Some soft tissue sarcomas, meningiomas, and pituitary adenomas may remain detectable for weeks or even months after the course of radiotherapy is finished and yet ultimately disappear and never recur.

Answer 86

Chronologically, the clinical effects of irradiation are subdivided into acute effects, which occur during or immediately after treatment (during the first 3 months) and late effects, which occur months to years after completion of treatment. The rate of appearance of injury depends not only on the proliferative activity of the stem cells but also on the lifetime of the differentiating progeny of these cells. Acute effects result primarily from radiation-induced stem cell depletion. The most common acute radiation reactions involve the skin and mucous membranes. These reactions result from stem cell proliferation inadequate to maintain the epithelial surface. The acute effects of radiation therapy always accompany curative radiotherapy because to some extent they mirror the damage done to tumor tissue. , they are not complications but normal tissue reactions that are usually self-limited and resolve naturally after treatment.

Answer 87

Late effects are considered complications of radiation therapy. They are caused primarily by damage to the vasculoconnective stroma and slowly proliferating parenchymal tissues, such as the kidneys, cartilage, bone, or lungs. Clinically, radiation complications appear to be less severe in cats than in dogs.

Answer 88

Normal tissue. Maximal doses are therefore limited even for tumors with high local failure rates. Thus a radiocurable tumor is one that can be eradicated by a dose of radiation that is well tolerated by the surrounding normal tissues. A practical implication of this information is that a tumor curable in one anatomic site may not be curable in another.

Answer 89

A curative dose of radiation is a dose that will potentially cure or control the disease and result in a probability of serious complications of less than 5% for bone or soft tissue necrosis and less than 1% for spinal cord injury.

Answer 90

Teletherapy, Brachytherapy, Systemic Radiation Therapy

Answer 91

The projection of radiation through space (also called external beam therapy) from the source of radiation to the patient; Teletherapy is administered with external radiation sources called megavoltage units such as a cobalt-60 unit or a linear accelerator. Cobalt-60 units produce high-energy gamma radiation. Linear accelerators are becoming more widely available in veterinary medicine. They are capable of producing high-energy x-rays and also electrons. High-energy x- or γ-rays allow uniform treatment of large- and deep-seated tumor volumes and allow sparing of superficial structures (skin and subcutaneous tissues). Electron beams are useful in the treatment of superficially located tumors or those overlying radiosensitive normal tissues (spinal cord, brain, lung, and gastrointestinal tract)..

Answer 92

A radiation technique in which sealed radioactive sources are applied directly to the area to be treated. The short distance between the source of irradiation and the tumor results in a significant dose decrease as distance from the radiation source increases. It is used for small lesions close to radiosensitive normal tissues that cannot be completely excised and for operable cutaneous tumors with indistinct margins for which there is a high probability of recurrence. Because brachytherapy is used to treat smaller target volumes and the volume irradiated outside the target volume is minimized, the potential for complications is lower than with teletherapy. As a result, large doses (>60 Gy) of radiation may be used without increasing risk of serious complications. When radioactive sources (usually strontium-90) are applied to the tumor's surface (see Figure 323-1, D), the technique is called surface brachytherapy or plesiotherapy. Treatment is curative for superficial lesions of the skin, including carcinoma in situ and early squamous cell carcinoma (SCC) lesions less than 2 mm thick . (Treatment doses of 120 to 150 Gy commonly given)

Answer 93

Systemic radionuclide therapy is achieved by use of organ-seeking radiopharmaceuticals that are administered systemically. Irradiation is selective to the tissue that concentrates the radioisotope. Clinical applications of systemic radiotherapy include radioactive iodine-131 for the treatment of feline hyperthyroidism and functional thyroid cancer in dogs and cats; phosphorus-32 for myeloproliferative and lymphoproliferative diseases, such as polycythemia vera and essential thrombocythemia[11]; and samarium-153 or strontium-89 for metastatic bone tumors

Answer 94

The inability to tolerate the multiple episodes of anesthesia necessary for positioning and immobilization during treatment. Concurrent disease, particularly of the heart and liver, may be more limiting to survival than the cancer being treated.

Answer 95

When there is no evidence of widespread metastases. Animals are treated with curative intent when it is expected that a finite probability exists that the tumor will be destroyed after adequate therapy, even if that chance is low. Radiation therapy given with curative intent is called “definitive therapy” if it is used for a localized, primary tumor that has been biopsied or incompletely resected.

Answer 96

When it is applied to a primary tumor or to sites of potential spread when the malignant cell burden is microscopic or below the level detectable by current imaging methods.

Answer 97

The goals of palliation are to relieve pain or other complications resulting from an incurable tumor and to improve quality of life. Palliation is acceptable for animals with a short life expectancy because the probability of developing late complications is limited.

Answer 98

Radiation therapy plays an important role in the curative treatment of small malignant solid tumors. It is also used in the management of benign tumors, including adenomas of the pituitary and perianal glands and oral epulides in dogs and thyroid adenomas in cats. Surgery is a local treatment. Radiotherapy, by contrast, offers locoregional treatment covering a wider area. Treatment is less constrained by anatomic boundaries and surgical techniques. Local control rates for radiation therapy are equivalent to those for surgery for small, localized tumors (2 to 4 cm) in many sites, and irradiation has the advantage of controlling the disease in situ, thus avoiding disruption of anatomic structure and preserving function. In practice, radiation therapy is used for lesions that are technically difficult to completely resect without excessive functional and cosmetic mutilation. Less frequently, primary radiotherapy is used for tumors that are highly radiocurable or that are technically unresectable. . Radiation therapy is the mainstay of treatment for central nervous system (CNS) and intranasal tumors because most such lesions are inoperable. The main combinations of surgery and radiation therapy include preoperative and postoperative radiation therapy. The optimal sequencing depends on the tumor's size, location, and histologic characteristics.Radiation therapy may be used postoperatively as an adjuvant treatment for control of postoperative microscopic disease or as definitive treatment for control of residual gross disease. The advantages of postoperative irradiation are that the entire surgical specimen is available for review for exact histopathologic classification; the extent of microscopic tumor can be assessed directly; and a high dose of radiation can be given without increasing surgical morbidity. Advantages of preoperative radiation are that it can eradicate subclinical or microscopic disease beyond the margins of the surgical resection; it may theoretically diminish tumor implantation within the operative field; and it can decrease the potential for dissemination of tumor cells that might produce distant metastases. In some cases it may convert a nonresectable tumor into one that can be resected. The optimal interval between irradiation and surgery is usually 3 to 4 weeks. Preoperative irradiation is more “dose effective” than postoperative radiotherapy; that is, a lower dose is needed preoperatively to reduce rates of local recurrence to the same extent as postoperative radiation. A subset of animals with advanced, incompletely resectable cancer may be treated with definitive irradiation followed by surgery if the tumor undergoes significant regression and becomes resectable. In this setting the timing between irradiation and surgery is longer (8 to 10 weeks) to allow tumor shrinkage and normal tissue recovery than in planned preoperative irradiation.

Answer 99

Adjuvant chemotherapy is used for treatment of subclinical disease after effective local treatment (surgery and/or irradiation) has been completed. The initial decision to use local treatment alone or both a local and systemic approach depends on the risk of occult distant disease and the availability of effective chemotherapy.

Answer 100

For the treatment of locally advanced, unresectable disease, concomitant chemoradiotherapy is the most promising approach.

Answer 101

Lymphoma (lymphosarcoma)

Answer 102

It is defined as a proliferation of malignant lymphoid cells affecting primarily the lymph nodes or solid visceral organs, such as the liver or spleen.

Answer 103

I Single lymph node II Multiple lymph nodes in a regional area III Generalized lymphadenopathy IV Liver and/or spleen involvement (with or without stage III) V Bone marrow or blood involvement and/or any nonlymphoid organ (with or without stages I to IV)

Answer 104

Substage a Without clinical signs of disease Substage b With clinical signs of disease

Answer 105

In the dog, 80% to 85% of cases are of the multicentric anatomic type and present as WHO stage III or IV Alimentary (≈7%), cutaneous (≈6%), mediastinal (≈3%) and miscellaneous extranodal sites (central nervous system [CNS], bone, heart, nasal cavity, and primary ocular locations) are less frequently encountered.

Answer 106

Most canine lymphoma is of the B-cell immunophenotype, with approximately 25% to 30% being of T-cell derivation.

Answer 107

Studies prior to this era reported that the mediastinal and multicentric forms of lymphoma predominated and that these represented younger, FeLV-positive cats. Contemporary reports document that lymphoma primarily affects older, FeLV-negative cats and that the alimentary form predominates. Only 10% to 20% of cases are now associated with FeLV antigenemia, compared with the 60% to 70% figure published before FeLV testing and vaccination became available. The median age of 9 to 10 years now reported is considerably higher than the 4- to 6-year medians reported prior to this era. The median age of cats within various anatomic tumor groupings has not changed, however, and sites traditionally associated with FeLV (i.e., mediastinal and multicentric locations) still occur primarily in younger, FeLV-antigenemic cats. Similarly, the alimentary form occurs most often in older, FeLV-negative cats.

Answer 108

Large granular lymphocyte lymphoma, a granulated, round cell tumor, usually involves the intestinal tract and abdominal viscera, with systemic involvement being the norm. Affected cats are generally FeLV/FIV negative, and a preponderance of CD3/CD8 T-cell immunophenotype suggests a small intestinal intraepithelial origin. A second distinct class of lymphoma in cats resembling human Hodgkin's disease also has been characterized. This appears to be a more indolent form of lymphoma, often arising in older FeLV negative cats as a single mandibular or cervical lymph node which is effaced by an immunophenotypically mixed population of lymphocytes (“T-cell-rich B-cell lymphoma”) admixed with a population of bizarre giant or multinucleate cells.

Answer 109

Affected cats are generally FeLV/FIV negative, and a preponderance of CD3/CD8 T-cell immunophenotype suggests a small intestinal intraepithelial origin.

Answer 110

In stage V disease, if bone marrow involvement is marked, peripheral cytopenias may result in presentations reflecting neutropenic sepsis, thrombocytopenic hemorrhage, or anemia.

Answer 111

Precaval syndrome is characterized by pitting edema of the head, neck, and forelimbs secondary to tumor compression of the cranial vena cava. Nearly half of cases with mediastinal lymphoma are associated with paraneoplastic hypercalcemia, therefore polydipsia and polyuria are common presenting complaints for this anatomic form.

Answer 112

Cats with alimentary lymphoma or large granular lymphocyte lymphoma present with varying degrees of weight loss, unkempt hair coat, inappetence, chronic diarrhea, and vomiting. Cats with mediastinal disease are often in severe respiratory distress because of the effects of an intrathoracic mass or the presence of significant pleural effusion. Cats with renal lymphoma may present with polyuria/polydipsia secondary to renal failure. In the case of nasal lymphoma, sneezing, chronic serosanguineous nasal discharge, exophthalmos, and facial deformity are common presentations. Cats with FeLV-associated lymphoma are more likely to present with pale mucous membranes as a result of anemia. Cats with Hodgkin's-like disease often present with a solitary enlarged mandibular or cervical node and are otherwise clinically healthy (substage a).

Answer 113

Anemia, when present, is usually normocytic, normochromic, and nonregenerative, reflecting anemia of chronic disease. Regenerative anemias may reflect concomitant blood loss or hemolysis. Cats with FeLV-associated disease may have a macrocytic anemia. If significant myelophthisis is present, the anemia may be accompanied by thrombocytopenia and leukopenia.

Answer 114

Circulating atypical lymphocytes may be indicative of bone marrow involvement and leukemia. It is important to differentiate multicentric lymphoma with bone marrow involvement (i.e., stage V disease) from primary lymphoblastic leukemia (discussed later in this chapter), as prognoses differs significantly between the two. Hypoproteinemia is more commonly observed in animals with alimentary lymphoma.

Answer 115

For staging due to the prognostic significance of marked marrow involvement; it is also recommended for cases in which lymphoma is suspected but is not documented by assessment of peripheral nodes

Answer 116

Often owing to the ectopic production of parathyroid hormone-related peptide.

Answer 117

B-cell-derived lymphoma

Answer 118

The predominance of a homogenous population of immature lymphoid cells is suggestive of lymphoma, although several small cell and indolent nodular varients exist and histological/immunophenotypic assessment of these less common forms is recommended. Avoidance of nodes draining reactive areas (e.g., submandibular nodes in the presence of periodontal disease) is recommended, because reactive hyperplasia may mask (or mimic) the true neoplastic condition.

Answer 119

In the cat, FNA assessment alone is not sufficient in most cases because of the difficulties encountered in distinguishing lymphoma from benign hyperplastic lymph node syndromes unique to the species, and whole lymph node excision is often necessary for diagnosis.

Answer 120

Thoracocentesis followed by cytologic/flow-cytometric evaluation of pleural fluid is often diagnostic in cats with mediastinal lymphoma, but is less likely to be of value in dogs with effusions secondary to mediastinal involvement. Conversely, cerebrospinal fluid (CSF) analysis is more commonly helpful in dogs than cats with CNS lymphoma because the more common spinal form in cats is generally extradural.

Answer 121

Most complex combination protocols are modifications of “CHOP” protocols initially designed for human oncologic use. The CHOP protocol represents combinations of cyclophosphamide (C), doxorubicin (hydroxydaunorubicin [H]), vincristine (Oncovin [O]), and prednisone (P). Regardless of which CHOP-based protocol is used, the overall median remission and survival times are approximately 8 and 12 months, respectively. . More current treatment protocols have abandoned the use of a maintenance phase, as most data now show no benefit from their inclusion

Answer 122

Furosemide is given concurrently with cyclophosphamide to decrease the incidence of sterile hemorrhagic cystitis

Answer 123

Doxorubicin remains the most effective and commonly used single agent chemotherapy protocol available for dogs with lymphoma

Answer 124

If a situation arises where clients choose to use only oral medications, lomustine (CCNU; 70 mg/m2, PO, q 3 weeks) and prednisone therapy can be used,

Answer 125

Ancillary therapy for hypercalcemia is usually unnecessary because initiation of chemotherapy results in normalization of serum calcium within a few days. If the animal is ill, azotemic, or showing significant signs attributable to hypercalcemia, therapy directed specifically at hypercalcemia concurrent with the initiation of systemic chemotherapy is warranted.

Answer 126

In general, cats do not enjoy as high a response rate or as long remission and survival durations as dogs with intermediate or high-grade lymphoma

Answer 127

Cats with this form of lymphoma responds favorably and enjoy comparably long remission and median survival times of approximately 2 years using a protocol of oral chlorambucil and prednisone Cats with large granular lymphoma tend to respond more poorly to chemotherapy, although durable responses have been reported. (Ultimately, most dogs and cats with lymphoma successfully treated with induction chemotherapy relapse with a more drug-resistant form. At the first recurrence, it is recommended that reinduction first be attempted by repeating the induction protocol that was initially successful. While the likelihood of a response is high at reinduction, the length of the response is generally half that seen with the initial therapy; however, a subset of animals will enjoy long-term reinductions. If reinduction fails or if the patient does not respond to the initial induction, so-called rescue agents or rescue protocols can be utilize) using such as lomustine (CCNU), L-asparaginase, actinomycin-D, mitoxantrone, decarbazine, temozolomide, doxorubicin

Answer 128

The immunophenotype and the WHO substage. Dogs with T-cell lymphoma generally have significantly shorter remission and survival durations. Similarly, dogs presenting with substage b disease (i.e., clinically ill) do poorly compared with dogs with substage a disease.

Answer 129

Unlike in the dog, the T-cell immunophenotype has not been established as a negative prognostic factor in the cat. Factors most strongly associated with a more positive prognosis in cats appear to be presence of low-grade lymphoma, complete response to therapy (which unfortunately cannot be determined prior to treatment), negative FeLV status, early clinical stage, substage a disease, and the addition of doxorubicin to the treatment protocol. Cats with alimentary small cell lymphoma have the best overall prognosis as median survivals are generally 2 years or longer with therapy

Answer 130

ALL is characterized by proliferations of morphologically immature lymphoblasts in the bone marrow or peripheral blood. ALL may be confused with multicentric lymphoma in dogs that also have advanced stage V disease (i.e., secondary bone marrow infiltration). However, the primary component of ALL is leukemia.

Answer 131

Middle-aged to older dogs are typically affected. Cats with ALL are usually younger and are often FeLV antigenemic. Presentations are nonspecific and commonly include lethargy, weight loss, intermittent pyrexia, hepatosplenomegaly, and nonspecific abdominal pain. Neurologic signs, both central and peripheral, have been reported. The majority of affected animals are anemic, and varying degrees of thrombocytopenia and leukopenia are commonly present.

Answer 132

The diagnosis is suggested by documentation of marked lymphoblast proliferation in the bone marrow or peripheral blood. Bone marrow aspirate or core biopsy and a CBC are usually all that are required for diagnosis of acute leukemia; however, immature forms can be difficult to classify beyond a blast form and flow-cytometric analysis of immunophenotype is the standard method for confirming lymphoid lineage and subcatagorization. The presence of 30% or more lymphoblasts in the bone marrow is considered diagnostic. Aspiration cytology of lymph node and involved organs and conformation of retroviral status in cats may be contributory.

Answer 133

Because bone marrow infiltration is present but peripherally circulating lymphoblasts are absent.

Answer 134

By its more rapid progression, lack of significant lymphadenopathy in approximately 50% of cases, poor chemoresponsiveness, short survival times, and conformation of the CD34 immunophenotype. The prognosis is generally poor for dogs and cats with ALL In the dog, cell size, cell number and immunophenotype can predict prognosis; large cells with CD21 expression, counts >30,000/µL and expression of CD34 have been associated with a more negative prognosis.

Answer 135

CLL is characterized by the proliferation of phenotypically mature lymphocytes rather than lymphoblasts. Interestingly, immunophenotypic and clonotypic analysis has shown that the majority of CLL cases in dogs arise from CD8+ T cells, many of which show a large granular lymphocytic morphology.

Answer 136

CLL is characterized by the proliferation of phenotypically mature lymphocytes rather than lymphoblasts. Interestingly, immunophenotypic and clonotypic analysis has shown that the majority of CLL cases in dogs arise from CD8+ T cells, many of which show a large granular lymphocytic morphology. CLL is reported primarily in older dogs and cats. The clinical presentation is nonspecific and may include lethargy, organomegaly, pyrexia, polyuria/polydipsia, hemorrhage (from thrombocytopenia), intermittent lameness, and collapse. Most dogs present with mild to moderate lymphadenopathy, splenomegaly, and pale mucous membranes. However, asymptomatic lymphocytosis may be detected on routine geriatric or preanesthetic screening in some animals. A normocytic, normochromic, nonregenerative anemia usually accompanies a marked mature peripheral lymphocytosis, which may range from 10,000 to 300,000/µL or more. Thrombocytopenia and neutropenia may be present as a result of myelophthisis. Although a minority of cases present with hyperglobulinemia, approximately half have evidence of a monoclonal gammopathy, often with Bence Jones proteinuri

Answer 137

CLL is characterized by the proliferation of phenotypically mature lymphocytes rather than lymphoblasts. Interestingly, immunophenotypic and clonotypic analysis has shown that the majority of CLL cases in dogs arise from CD8+ T cells, many of which show a large granular lymphocytic morphology. CLL is reported primarily in older dogs and cats. The clinical presentation is nonspecific and may include lethargy, organomegaly, pyrexia, polyuria/polydipsia, hemorrhage (from thrombocytopenia), intermittent lameness, and collapse. Most dogs present with mild to moderate lymphadenopathy, splenomegaly, and pale mucous membranes. However, asymptomatic lymphocytosis may be detected on routine geriatric or preanesthetic screening in some animals. A normocytic, normochromic, nonregenerative anemia usually accompanies a marked mature peripheral lymphocytosis, which may range from 10,000 to 300,000/µL or more. Thrombocytopenia and neutropenia may be present as a result of myelophthisis. Although a minority of cases present with hyperglobulinemia, approximately half have evidence of a monoclonal gammopathy, often with Bence Jones proteinuri. No association with FeLV infection has been documented in the cat.

Answer 138

Unlike ALL, CLL can have a protracted clinical course and is usually initially responsive to chemotherapy. Although the prognosis is good in the short term, eventually CLL becomes resistant to therapy or progresses to ALL. When this happens, lymphoblasts replace mature lymphocytes as the abnormally proliferating population, and survival is short.

Answer 139

A group of nonlymphoid bone marrow cell disorders in which proliferation of one, several, or all of the marrow cell lines occurs. In general, MPDs are classified first on the basis of the derivation of the cell in question and second on the degree of cellular differentiation. The disorders may represent preneoplastic or neoplastic conditions that may have a benign or malignant course. These are rare conditions in companion animals. With few exceptions (e.g., see Polycythemia Vera), the veterinary literature on MPDs is sparse at best and is composed almost entirely of single case reports. Animals with a chronic MPD may have no clinical signs until organ involvement or bone marrow myelophthisis results in systemic disease. Most MPDs have been associated with FeLV infection in cats. The diagnosis of MPD is based on demonstration of the proliferating cell line in the absence of nonneoplastic diseases associated with bone marrow hyperplasia or hypoplasia. The acute MPDs are generally poorly responsive to single agent or combination chemotherapy protocols, therefore their prognosis is grave.

Answer 140

Polycythemia vera (PV) is defined as an abnormal proliferation of erythroid precursors in the bone marrow; this occurs independent of erythropoietin (EP), and the cells follow a normal, orderly pattern of maturation. The result is an abnormally elevated packed cell volume, erythroid count, and blood hemoglobin level. PV must be differentiated from so-called relative polycythemia or secondary polycythemia.

Answer 141

Relative polycythemia is a result of hemoconcentration secondary to severe dehydration, body fluid shifts, or acute splenic contraction in dogs. It is readily corrected with fluid-based therapies.

Answer 142

Secondary polycythemia is defined as EP-mediated erythrocytosis. Conditions associated with secondary polycythemia include right-to-left cardiac shunts, congestive heart failure, severe chronic pulmonary disease, some forms of renal disease, and neoplasms that secrete EP or EP-like substances.

Answer 143

Middle-aged dogs and cats are typically affected. Clinical signs and physical findings associated with PV include hyperemic mucous membranes, injected scleral and retinal vessels, weakness, exercise intolerance, frank hemorrhage (epistaxis, hematuria, melena), neurologic signs (dementia, seizures, paralysis, ataxia), and occasional splenomegaly. Cardiac or renal compromise may also be present. The majority of signs reported occur secondary to hyperviscosity syndrome, discussed in the plasma cell tumor portion of this chapter.

Answer 144

Erythroid hyperplasia with relatively normal patterns of maturation is found on bone marrow cytology.

Answer 145

Therapy for PV involves reduction of the red blood cell mass and suppression of erythroid production in the bone marrow. Reduction of the red blood cell mass can be achieved by phlebotomy and reinfusion of the patient's plasma after removal of the red blood cells. Several techniques can be used to suppress erythrocyte production, including the use of radioactive phosphorous (P) or, more commonly available, chemotherapy. The most commonly used antineoplastic drug of choice is hydroxyurea.

Answer 146

Neoplastic proliferations of cells of the B-lymphocyte plasma cell lineage. This population is believed in most instances to be monoclonal (i.e., derived from a single cell), because it typically produces homogenous immunoglobulin.

Answer 147

Multiple myeloma (MM), IgM (Waldenstrom's) macroglobulinemia, and solitary plasmacytoma (including solitary osseous plasmacytoma and extramedullary plasmacytoma). Multiple myeloma is the most important plasma cell neoplasm based on incidence and severity.

Answer 148

In MM, malignant plasma cells produce an overabundance of a single type, or component, of immunoglobulin, which is referred to as the M-component. Less commonly, biclonal immunoglobulin production has been reported. The M-component may represent any class of immunoglobulin or only a portion of the molecule, such as the light-chain (Bence Jones protein) or heavy chain (heavy chain disease) of the molecule.

Answer 149

extra medullary sites.

Answer 150

Hyperviscosity syndrome (HVS) represents one of a constellation of clinicopathologic abnormalities resulting from greatly increased serum viscosity. The magnitude of HVS is related to the type, size, shape, and concentration of the M-component in the blood. It is more common with IgM macroglobulinemias because of their high molecular weight; however, IgA- and IgG-associated HVS can occur, albeit less frequently

Answer 151

A result of sludging of blood in small vessels, ineffective delivery of oxygen and nutrients, and coagulation abnormalities.

Answer 152

Renal disease is present in 30% to 50% of dogs with MM. This can occur as a result of Bence Jones (light chain) proteinuria, tumor infiltration into renal tissue, hypercalcemia, amyloidosis, diminished perfusion secondary to HVS, dehydration, or ascending urinary tract infection. Bence Jones proteinuria (BJP) occurs in approximately 25% to 40% of dogs with MM; the true incidence of BJP in cats is not well established.

Answer 153

The production of osteoclast-activating factor, other cytokines, or circulating N-terminal parathyroid hormone-related protein by neoplastic cells. Hypercalcemia may be exacerbated by associated renal disease. Hypercalcemia is rare in cats with MM

Answer 154

Variable cytopenias may be observed in association with MM. A normocytic, normochromic, nonregenerative anemia is encountered in approximately two thirds of dogs. This can result from myelophthisis, blood loss from coagulation disorders, anemia of chronic disease, or increased erythrocyte destruction secondary to high serum viscosity. Similar factors lead to thrombocytopenia and leukopenia in 25% to 30% of affected dogs.

Answer 155

M-components may interfere with coagulation in a number of ways, including inhibition of platelet aggregation and the release of platelet factor-3, adsorption of minor clotting proteins, generation of abnormal fibrin polymerization, production of heparin-like anticoagulants, and a functional decrease in calcium.

Answer 156

MM: Cardiac disease, if present, is usually a result of excessive cardiac workload and myocardial hypoxia secondary to hyperviscosity. Myocardial infiltration with amyloid and anemia may be complicating factors.

Answer 157

Bone marrow plasmacytosis and serum or urine myeloma proteins (M-component), as well as detection of osteolytic bone lesions and/or other sites of visceral organ involvement. In the absence of osteolytic bone lesions or overt visceral organ involvement, a diagnosis can be made if marrow plasmacytosis is associated with a progressive increase in the M-component. Definitive diagnosis usually requires a bone marrow aspirate or core biopsy. Normal marrow contains less than 5% plasma cells, whereas myelomatous marrow often greatly exceeds this level. Malignant plasma cells can have a varied microscopic appearance, ranging from that of normal plasma cells to early stages of differentiation. Serum electrophoresis and immunoelectrophoresis are performed to detect a monoclonal gamopathy, and to categorize the isotype of immunoglobulin involved. Historically, the M-component was usually of the IgG or IgA class in nearly equal incidence in dogs, however in the author's experience involving clinical investigations of novel agents, the vast majority of dogs present with IgA disease. If IgM constitutes the M-component, the term macroglobulinemia (i.e., Waldenstrom's macroglobulinemia) is used. As previously stated, biclonal gammopathy may also be encountered. In the cat, MM is usually associated with IgG elevations. If Bence Jones proteinuria is suspected, heat precipitation and electrophoresis of urine are necessary, because commercial urine dipstick methods are not capable of this determination. Approximately 25% to 30% of dogs with MM have evidence of bony lysis or diffuse osteoporosis

Answer 158

The prognosis for dogs with MM is good for initial control of the tumor and a return to good quality of life. In a group of 60 dogs with MM, 43% achieved complete remission (i.e., serum immunoglobulins normalized) and 49% achieved partial remission (i.e., immunoglobulins less than 50% of pretreatment values). The prognosis for MM in the cat is generally not as favorable as in the dog; however, occasional long-term survival has been reported,

Answer 159

Cutaneous EMP Gastrointestinal EMPs The natural behavior of noncutaneous EMP appears to be much more aggressive The diagnosis of SOP and EMP requires tissue biopsy. Dogs with cutaneous plasmacytomas are usually cured by means of surgical excision. Dogs with SOP or EMP of the alimentary tract treated by surgical excision (in combination with systemic chemotherapy once systemic disease is documented) enjoy long-term survival in the majority of cases.

Answer 160

Both viral and nonviral forms exist. The papillomaviruses are DNA viruses and are species specific. Cutaneous papillomas: They most commonly occur on the head, eyelids, and feet and are not associated with papillomavirus. Canine oral papillomatosis is a contagious disease of viral origin that often affects young or immunocompromised dogs. In cats, most solitary cutaneous papillomas are not caused by papillomavirus. In contrast, papillomas that occur on the ventral tongue in cats are generally viral in origin, as are multiple cutaneous papillomas. These viral papillomas might be precursors to feline multicentric squamous cell carcinoma, or Bowen disease (see Feline Squamous Cell Carcinoma, below).

Answer 161

Intracutaneous cornifying epitheliomas (keratoacanthomas) arise from the outer portion of the hair follicle. They usually occur in relatively young, purebred dogs.

Answer 162

Squamous cell carcinoma (SCC) is a common malignant neoplasm in the dog. The etiology usually is not known. Tumors that develop in unpigmented or lightly pigmented skin, such as the abdomen and inguinal areas, are believed to be induced by ultraviolet radiation (sun damage). Occasionally SCC might be caused by burns, chronic infectious or immune-mediated diseases, or progression from viral papillomas

Answer 163

Canine Cutaneous Squamous Cell Carcinoma Canine Nasal Planum Squamous Cell Carcinoma Canine Digital Squamous Cell Carcinoma (the most common digital tumor in dogs)

Answer 164

In one study, 24% of cats infected with feline immunodeficiency virus (FIV) developed SCC

Answer 165

Feline Cutaneous Squamous Cell Carcinoma Feline Digital Squamous Cell Carcinoma (the most common digital tumor in cats) Feline Multicentric Squamous Cell Carcinoma in Situ (Bowen Disease). Bowen disease is a condition of small, plaquelike, crusted SCC lesions that histologically do not invade the basement membrane. Unlike solar-induced SCC, multicentric SCC in situ is found in haired, pigmented areas and might be caused by infection with a papillomavirus

Answer 166

Basal cell tumors (basal cell epitheliomas) are benign neoplasms that arise from the basal cells of the epidermis.

Answer 167

Sebaceous gland tumors are derived from sebocytes and are among the most common skin tumors in dogs.

Answer 168

Perianal gland tumors arise from canine circumanal glands, which are nonsecretory, modified sebaceous glands. They are referred to as hepatoid glands because the cells morphologically resemble hepatocytes. Circumanal glands contain receptors for androgens, both testosterone and estrogen, and intact males are at increased risk for tumor development. The vast majority of perianal gland tumors are benign and histologically might include hyperplastic lesions, adenomas, or epitheliomas. Rarely, hepatoid gland carcinomas occur. Most perianal gland tumors occur adjacent to the anus, but they can also occur on the ventral aspect of the tail and perineum

Answer 169

malignant carcinomas, and more than 20% might have evidence of lymphatic or vascular invasion

Answer 170

Modified apocrine sweat glands found in the external ear canal. Chronic otitis might be a predisposing factor

Answer 171

parathyroid hormone–related protein (PTHrP), leading to hypercalcemia of malignancy. Metastases generally arise in the iliac lymph nodes, although distant metastases might also be seen in the liver, spleen, lungs, bones, and other sites. Occasionally, extension from the iliac lymph nodes into the lumbar vertebrae may occur

Answer 172

Hypercalcemia generally resolves quickly after resection of the primary tumor. Supportive therapies such as intravenous fluids, corticosteroids, and/or bisphosphonates might be needed in some cases until surgery can be done or in which hypercalcemia cannot be controlled with surgery alone

Answer 173

Lymphoma, mast cell tumors, plasmacytomas, histiocytomas, and transmissible venereal tumors. Occasionally, melanomas and basal cell tumors might mimic round cell patterns.

Answer 174

The digits, lips, pinnae, oral cavity, and rectum. The majority of cutaneous plasmacytomas in the dog are benign and are unrelated to multiple myeloma. The majority of plasma cell tumors reported in cats are systemic in nature (myeloma-related disease), so testing as described for multiple myeloma

Answer 175

As a general rule, tumors arising from the haired skin are benign. Those arising from mucocutaneous junctions are malignant, the only exception being those arising on the eyelids. Melanomas of the digit might be highly malignant, and malignant melanomas commonly spread via lymphatics to draining lymph nodes and the lungs

Answer 176

Mesenchymal origin

Answer 177

Dogs: On the limbs or head. Cat: The trunk, either in the interscapular region, dorsal lumbar, or flank region.

Answer 178

Occur sporadically. It is well established that exposure to radiation, viral infection (feline sarcoma virus), trauma, or chronic inflammatory conditions are associated with development of sarcomas in dogs and cats. Conventional irradiation schedules for management of a primary cancer carries a risk of a second cancer developing. This occurs in less than 5%, with radiation-induced tumors occurring 3 to 5 years or more after radiation therapy

Answer 179

In a large study of risk factors associated with development of vaccine-associated sarcomas in cats, no specific brands or types of vaccine within antigen class or vaccine practice altered the risk of development of vaccine-associated sarcomas. Furthermore it was recognized that some long-acting injectable medications (long-acting penicillin, methyl prednisolone acetate) may also be associated with sarcoma formation. It is likely that a combination of injection-site local inflammatory reactions and genetic factors come into play. Similarly, the development of ocular sarcomas in cats are Vaccine-associated sarcomas have commonly occurred in the interscapular space, which has proven to be a difficult location for surgery, requiring removal of dorsal spinous processes and the surrounding musculature. For this reason, the Vaccine-Associated Feline Sarcoma Task Force (VAFSTF) has made the recommendation to vaccinate with rabies and feline leukemia virus (FeLV) in the distal hind limb (right and left hindlimb, respectively), such that amputation is possible to effect local tumor control. Even with amputation or hemipelvectomy, it may not be possible to completely excise a vaccine-associated sarcoma

Answer 180

P53 abnormalities have been reported in feline vaccine-associated sarcomas. Abnormalities in p53 and MDM2, a gene whose product suppresses p53 expression, have been reported in canine sarcomas

Answer 181

The most common route of metastasis is via the hematogenous route, and the most common sites of metastasis are the lung and liver. In cats with vaccine-associated fibrosarcomas, sites of metastasis that have been reported include lung, skin or subcutaneous sites, regional lymph nodes, mediastinum, liver, and pelvis.

Answer 182

In the intestinal tract. More recently there has been reclassification of canine gastrointestinal smooth-muscle tumors, with identification of gastrointestinal stromal tumors (GISTs) as a distinct entity from leiomyomas and leiomyosarcomas. GISTs appear to develop more frequently in the cecum and large intestine. GISTs express c-kit as detected by immunohistochemistry, and many have activating mutations that are thought to drive oncogenesis.

Answer 183

Leiomyosarcomas are most often located in the stomach, small intestine, spleen, or urogenital tract. Feline leiomyosarcomas are uncommon but occur in the intestinal tract more often than other sites.

Answer 184

Currently, a multimodal approach that includes surgery, radiation therapy, and chemotherapy seems reasonable to optimize the chance of tumor control in dogs with high-grade soft-tissue sarcomas and cats with injection-site sarcomas.

Answer 185

Hemangiosarcoma is a malignant cancer derived from multipotential bone marrow stem cells with differentiation arrest at the angioblast or hemangioblast stage

Answer 186

Virtually any anatomic site can have HSA as a primary or secondary (metastatic) tumor diagnosis. HSA occurs most frequently in dogs (approximately 2% of all tumors), and the most common site of origin is the spleen; however, additional sites include right atrium, pericardium, liver, muscle, lung, skin and subcutis, bone, kidney, central nervous system, peritoneum, retroperitoneum, oral cavity, nasal cavity, eye, and many others

Answer 187

Approximately two thirds of dogs with a splenic mass have a malignancy, therefore one third are not malignant, and two thirds of the malignant tumors of the spleen are HSA

Answer 188

lymphoma, leiomyosarcoma, fibrosarcoma, osteosarcoma, malignant fibrous histiocytoma, and other sarcomas (undifferentiated, liposarcoma, mesenchymoma), as well as nonneoplastic entities such as nodular hyperplasia, splenic hematoma, and hemangioma

Answer 189

Twenty-five percent of dogs with splenic HSA have been reported to also have right-atrial HSA. It is not known whether the splenic lesion or that in the right atrium is primary, secondary, or multiple primaries.

Answer 190

HSA (29%), followed by pituitary tumors (25%), lymphoma (12%), and metastatic carcinoma (12%).[27]

Answer 191

Via hematogenous routes—such as the lungs, liver, and/or brain—or by direct extension due to transabdominal implantation (omentum and/or mesentery) via tumor rupture.

Answer 192

The most common hematologic finding in dogs with HSA is anemia, generally a regenerative normocytic-normochromic anemia with polychromasia, reticulocytosis, nucleated red blood cells (RBCs), and anisocytosis. The anemia associated with HSA is generally felt to be due to microangiopathic hemolysis and possibly intracavitary hemorrhage with subsequent autotransfusion, which results in RBC fragmentation/schistocytosis in canine and human HSA, but not in cats.

Answer 193

Other common hematologic abnormalities in dogs and cats with HSA include neutrophilic leukocytosis, band neutrophilia, and thrombocytopenia. Significant thrombocytopenia can be seen in approximately half of dogs with HSA. In addition, spontaneous hemorrhage and disseminated intravascular coagulation (DIC) may occur and, therefore, a coagulogram is strongly recommended prior to the use of invasive diagnostics and/or surgery. Fifty-three percent of cats with visceral HSA have increased aspartate transaminase (AST) levels

Answer 194

osteosarcoma (OSA), chondrosarcoma (CSA), fibrosarcoma (FSA), and hemangiosarcoma (HSA). OSA can also occur primarily in the axial skeleton and extraskeletal tissues, including visceral organs, skin, and mammary glands. Repetitive injury to the physis has been proposed due to the high incidence of OSA in the metaphyseal region of large-breed dogs with late-closing phases. Appendicular OSA is a highly aggressive tumor. More than 60% of dogs will eventually die because of metastatic disease; however, less than 15% of dogs have clinically detectable metastasis at the time of initial diagnosis

Answer 195

Radiation reduces local inflammation, minimizes pain, slows progression of metastatic lesions, and improves quality of life in dogs with primary and metastatic lesions

Answer 196

the local bone tumor and micrometastatic disease. The efficacy of chemotherapy in other types of primary bone tumors is less clear. Surgery, unless combined with chemotherapy, is considered palliative

Answer 197

Pulmonary and skeletal sites are most frequently involved, although other metastatic sites include subcutaneous tissue, mediastinum, myocardium, diaphragm, kidneys, spleen, small intestine, spinal cord and brain, and lymph nodes

Answer 198

Generalized malaise is the most common sign in dogs with pulmonary metastasis. Respiratory signs are usually a late development. Occasionally, hypertrophic osteopathy may be the first indication of pulmonary metastasis.

Answer 199

Bisphosphonates block osteoclast activity, thereby minimizing the risk of pathologic fracture

Answer 200

The combination of pamidronate and an NSAID can also effectively palliate dogs with tumor-related bone pain, with up to 28% of dogs experiencing an analgesic effect for more than 4 months (median: 231 days).[21] Limb-sparing

Answer 201

OSA of the axial skeleton accounts for 25% of all OSA and 59% of OSA in dogs weighing less than 15 kg

Answer 202

Signs include a visible external mass and neurologic signs due to extradural compression of the brain. Axial OSA may also involve the maxilla and mandible; however, it is less common than the other tumors affecting these bones.

Answer 203

The most common canine oral tumors are malignant melanoma, squamous cell carcinoma, FSA, OSA, and benign epulides. The most common cause of death in dogs with axial OSA is local tumor recurrence rather than metastasis.

Answer 204

OSA is the most common extradural tumor of the nervous system and accounts for up to 16% of axial OSA. Other vertebral tumors include CSA, FSA, HSA, MCE, lymphoma, liposarcoma, giant cell tumor, plasma cell tumors—either as solitary plasmacytoma or multiple myeloma—and metastatic carcinomas and sarcomas. A thorough physical examination should be performed to identify possible occult primary tumors. Carcinomas of the mammary and thyroid glands, bladder and prostate, and visceral HSAs are known to metastasize to the vertebrae. Thoracic and lumbar vertebrae are most commonly involved

Answer 205

Pain and neurologic deficits are the two most common signs in dogs with vertebral tumors. Neurologic deficits are caused by compression of the nerve roots or spinal cord

Answer 206

Primary bone tumors are uncommon in cats. Unlike dogs, 10% to 33% of primary bone tumors in cats are benign. OSA is the most common tumor, accounting for 70% to 80% of all feline bone tumors, whereas FSA, CSA, HSA, and rhabdomyosarcoma have also been reported. Due to the infrequency of metastatic disease, limb amputation without chemotherapy is recommended for the treatment of cats with appendicular OSA.

Answer 207

OSA is the most common tumor of the feline axial skeleton. FSA and CSA are also reported to involve the axial skeleton

Answer 208

Metastasis usually occurs via the hematogenous route. In dogs, urogenital carcinomas, particularly bladder and prostate, are the most common primary tumors to metastasize to bone. Skeletal metastasis is also reported in dogs with OSA, mammary carcinoma, thyroid carcinoma, pulmonary carcinoma, nasal carcinoma, apocrine gland anal sac adenocarcinoma, and renal tumors. Metastatic lesions represent 24% of all bone tumors

Answer 209

Joint tumors are usually primary and malignant. Previously, synovial cell sarcoma (arising from mesenchymal cells) was considered the most common tumor of the canine joint. However, recent evidence suggests that other soft-tissue sarcomas of periarticular tissue are more prevalent. Synovial cell sarcoma is rarely diagnosed in cats.

Answer 210

The incidence of cutaneous mast cell disease is higher in dogs than in cats and constitutes the most important form in this species; primary noncutaneous forms are uncommon. The biologic behavior of mast cell disease in the dog is also more variable and unpredictable, with a greater risk of systemic spread. Like dogs, cats develop cutaneous mast cell disease, but primary visceral mastocytosis appears to be an equally important disease process. A primary gastrointestinal form is infrequently reported in both species.

Answer 211

Mast cells are a heterogenous cell population that originates in the bone marrow from a CD34+ pluripotent hematopoietic stem cell that is promoted to mast cell differentiation by a hemopoietin called stem cell factor or c-kit ligand. Undoubtedly, the development of MCTs involves many factors, including genetic propensity, but altered expression of the c-kit receptor for stem cell factor in a proportion of canine MCTs suggests that loss of normal regulation may be important in tumor development. The gastrointestinal tract and lungs are rich in normal mast cells, but development of tumors at these sites is rare.

Answer 212

Normal mast cells play an important role in mediating inflammatory responses. Mast cell activation stimulates release of a variety of substances from the variably sized intracytoplasmic granules. These substances include vasoactive amines (histamine, seratonin), enzymes (acid hydrolases, cathepsin G, phospholipase A, chymase, tryptase, carboxypeptidase), and proteoglycans (heparin, chondroitin sulfate).[4] Mast cells can also synthesize and release lipid mediators and cytokines. The ability to release these active substances and mediators and their ability to recruit other cytokines and inflammatory cells helps explain many of the clinical manifestations of these tumors. Unique local clinical signs related to these cellular products range from nonpainful swelling to pruritus, ulceration, erythema, bruising, or prolonged hemorrhage

Answer 213

Unique local clinical signs related to the cellular products from the mast cell range from nonpainful swelling to pruritus, ulceration, erythema, bruising, or prolonged hemorrhage. Poor wound healing may be attributed to proteolytic enzymes and vasoactive amines. Systemic effects can also occur as part of a paraneoplastic syndrome, because plasma histamine concentrations in dogs with MCTs are significantly higher than in normal dogs. Elevated levels of circulating histamine can be associated with gastric hyperacidity and gastrointestinal ulceration, because binding of histamine to H2 receptors of gastric mucosal parietal cells stimulates gastric acid secretion and hyperacidity.

Answer 214

Histamine also increases gastrointestinal motility and capillary permeability, promoting intravascular thrombosis and subsequent mucosal ulceration. With marked systemic histamine release, there is also potential for arrhythmias, systemic hypotension, and shock due to H1 and H2 receptor binding on blood vessels, cardiac muscle, and smooth muscle.

Answer 215

Cutaneous MCTs are likely to arise from tissue mast cells in the dermis. The clinical course of mast cell disease is somewhat unpredictable, but all tumors are considered potentially malignan

Answer 216

The typical metastatic pattern is through the reticuloendothelial system. The first and most common site of metastasis is regional lymph nodes, followed by the spleen, liver, and bone marrow. One of the unique features of MCT behavior is the development of multiple dermal or subcutaneous tumors in the same patient. Histologically, canine MCTs have been graded I through III, with tumor grade having substantial impact on overall prognosis. .

Answer 217

If mast cell disease is known or suspected, premedication with H1 and H2 receptor blockers should be given, and there should be planning for wide surgical margins.

Answer 218

MCTs are categorized as round cell tumors, because they typically have round cytoplasmic borders, do not cluster, and exfoliate well.

Answer 219

Because metastasis is typically to the reticuloendothelial system, the regional lymph nodes, liver, spleen, and bone marrow are usually targeted for evaluation. It is quite common for a peripheral lymph node to contain a small population of normal mast cells, particularly if there is allergic or parasitic skin disease, making definitive diagnosis of nodal metastasis problematic. When few mast cells are present in potential metastatic sites, it is difficult or impossible to determine whether the mast cell infiltrate represents metastatic neoplasia, mast cell hyperplasia, or a non pathologic state. Because the lymph node is the first site of metastasis, nodal assessment with cytology or histology is the single most important diagnostic step in staging. Pulmonary metastasis is rare, so thoracic radiographs are only indicated for assessing intrathoracic lymphadenopathy for MCTs located on the cranial portion of the body.

Answer 220

As is true with most types of neoplasia, the conventional choices for therapy are surgery, radiation, and chemotherapy. Each of these modalities has a role in the treatment of mast cell disease. Supportive management of patients with MCTs may include H1 and H2 receptor antagonists, omeprazole, misoprostol, sucralfate, metoclopramide, and prednisone in an antiinflammatory dosage.

Answer 221

The three principal forms of mast cell disease in the cat are cutaneous, visceral (systemic, splenic), and gastrointestinal. Metastasis is less common in cats, but when it occurs, it is primarily to the regional lymph nodes.

Answer 222

Basal cell tumor, squamous cell carcinoma, and fibrosarcoma. Visceral MCT and lymphoma are the two most common hematopoietic tumors of the spleen, and MCT is the third most common intestinal tumor in the cat, after lymphoma and adenocarcinoma.

Answer 223

Visceral or systemic mastocytosis is a disease that is relatively unique to the cat. This form of disease has been reported to comprise up to 50% of all feline mast cell disease and typically involves the spleen, liver, and abdominal lymph nodes. Clinical signs include a palpable or visible intraabdominal mass, vomiting with or without hemorrhage, weight loss, anorexia, abdominal discomfort, ascites, and lethargy. Gastrointestinal signs are due to either the space-occupying large mass or histamine release with resultant gastric ulceration. An acute abdominal crisis can occur with intestinal perforation secondary to ulceration or with splenic rupture.

Answer 224

Laboratory abnormalities may include anemia and mastocytemia, with circulating mast cells noted in up to 50% of cats and mast cells within body cavity effusions. Neoplastic cells frequently spread from spleen to liver, abdominal lymph nodes, and bone marrow.

Answer 225

Prior to splenectomy, cats should be medicated with H1 and H2 receptor blockers and cyproheptadine to mitigate the adverse effects of intraoperative mast cell degranulation

Answer 226

At first, only rabies and feline leukemia virus (FeLV) vaccines were identified as risk factors[5-7]; but other vaccines, including those for panleukopenia and viral respiratory diseases, were also found to be associated with the development of sarcomas.[5,7-9] It was shown that vaccines containing aluminum as an adjuvant, vaccines with no adjuvant, and vaccines with nonaluminum adjuvants may all be associated with injection-site sarcomas. However, there was significantly less inflammation in biopsy sites where nonadjuvanted vaccine had been administered

Answer 227

In addition to vaccines, injections of long-acting medications—such as corticosteroids, penicillin, or lufenuron—have also been associated with sarcoma formation. Thus, the cause is thought to be an inflammatory or immunologic reaction, leading to chronic inflammation that can result in uncontrolled proliferation of fibroblasts and myofibroblasts. In susceptible cats, this can lead to malignant transformation and tumorigenesis. Although most FISSs are fibrosarcomas,[2] other tumors—such as osteosarcomas,[36] chondrosarcomas,[37] rhabdomyosarcomas,[37] malignant fibrous histiocytomas,[36],[37] and myofibroblastic sarcomas[38]—have been identified via differentiation of the malignant mesenchymal stem cells

Answer 228

Growth factors promote proliferation and can induce malignant transformation. This, in turn, can be involved in the regulation of angiogenesis. The overexpression of growth factors is considered to be one of the causes of carcinogenesis. Overexpression of basic fibroblast growth factor (FGF-β), transforming growth factor-α (TGF-α), and platelet-derived growth factor (PDGF) have been detected in FISS. These factors are assumed to play a role in tumor development. Mutations in the tumor-suppressor gene p53, implicated in cancer initiation and progression, have been identified in numerous feline sarcomas but not in nonneoplastic tissue of these cats Furthermore, high rates of proliferation-marker expression and suppressor genes, such as p53, c-kit, and mdm-2 have been identified.

Answer 229

Electrochemotherapy uses local electric pulses that increase cell membrane permeability, allowing bleomycin, an antitumor antibiotic, to reach its intracellular DNA target.

Answer 230

1. Canine cutaneous histiocytoma usually occurs as a single lesion in young dogs and spontaneously regresses. Metastatic histiocytoma is a rare example of aggressive behavior of this tumor. 2. Langerhans cell histiocytosis (LCH) covers a spectrum of disease from multiple cutaneous histiocytomas only to multiple cutaneous histiocytomas with lymph node and internal organ involvement. The lesions are characterized by extensive regional cutaneous infiltration by histiocytes, which otherwise resemble those in histiocytoma. Cutaneous histiocytosis (CH) presents with single or multiple lesions, which tend to wax and wane and may even spontaneously regress. Few cases respond to corticosteroids. The remainder persist and may require more aggressive immunosuppressive therapy. 3. Systemic histiocytosis (SH) is a familial disease of Bernese Mountain Dogs and also occurs sporadically in other breeds. SH presents with prominent skin manifestations identical to those seen in CH, but mucous membranes (ocular and nasal) and a variety of other organ systems including lymphoid organs, lung, and bone marrow may also be involved. Although the lesions may wax and wane, SH is a progressive disease that often requires continuous immunosuppressive therapy. 4 & 5. Histiocytic sarcoma (HS) and malignant histiocytosis (MH) occur with high incidence in Bernese Mountain Dogs, Rottweilers, Flat-Coated Retrievers, and Golden Retrievers and sporadically in many other breeds. HSs occur as localized lesions in the spleen, lymph nodes, lungs, bone marrow, skin and subcutis, brain, and periarticular tissue of large appendicular joints. HSs can also occur as multiple lesions in single organs (especially spleen), and they disseminate rapidly to involve multiple organs. Hence disseminated HS is difficult to distinguish from MH, which is a multisystem, rapidly progressive disease in which there is simultaneous involvement of multiple organs such as the spleen, lymph nodes, lungs, bone marrow, and skin and subcutis. Response of HS and MH to chemotherapy is at best brief.

Answer 231

The development of canine-specific monoclonal antibodies for many of the functionally important molecules of macrophages and dendritic antigen-presenting cells (APCs) has enabled the identification of the cell lineages involved in canine histiocytic disorders. Despite the large variation of clinical and pathologic features of canine histiocytic diseases, the majority represent proliferations of cells of various dendritic cell (DC) lineages. Histiocytes differentiate from CD34+ committed stem cell precursors into macrophages and several DC lineages,

Answer 232

Cytokines influencing DC development include granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-alpha. Macrophage development from CD34+ precursors is influenced by GM-CSF and M-CSF. Blood monocytes can differentiate into either macrophages under influence of M-CSF or into DCs under influence of GM-CSF and interleukin (IL)-4

Answer 233

DCs are the most potent APCs for induction of immune responses in naïve T cells. Canine DCs have been best defined in canine skin Canine DCs abundantly express CD1 molecules which, together with major histocompatibility complex (MHC) class I and MHC class II molecules, are responsible for presentation of peptides, lipids and glycolipids to T cells. Hence DCs are best defined by their abundant expression of molecules essential to their function as APCs. Of these, the family of CD1 proteins is largely restricted in expression to dendritic APCs in skin, whereas MHC classes I and II are more broadly expressed.

Answer 234

It is important to realize that dendritic APCs arise in bone marrow and migrate through blood to a variety of epithelial sites (cutaneous and mucosal), where they take up residence either within epithelia or in dermis and lamina propria. In these sites they function as antigen-processing and ultimately antigen-presenting cells, which interact with T cells. Migration of DC (as veiled cells) beyond the skin to the paracortex of lymph nodes occurs following contact with antigen. Defective interaction of dendritic APCs and T cells appears to contribute to the development of reactive cutaneous histiocytic proliferative diseases (CH and SH), which are related DC disorders arising out of disordered immune regulation

Answer 235

Histiocytoma is a common, benign, cutaneous neoplasm of the dog. Histiocytomas usually occur as solitary lesions, which undergo spontaneous regression. The age-specific incidence rate for histiocytomas drops precipitously after 3 years, although histiocytomas do occur in dogs of all ages. Multiple histiocytomas are also readily confused with CH on clinical appearance, although morphologically, histiocytomas are consistently epidermotropic and commonly epidermally invasive; these are not features of CH. The rare cases of multiple histiocytoma with metastasis to local lymph nodes, as well as the cases in which confluent histiocytic lesions occur in many cutaneous sites with rapid systemic spread, represent a spectrum of diverse clinical behavior and are best characterized as LCH.

Answer 236

The presence of multiple histiocytomas is now a well-recognized syndrome. There is a spectrum of clinical disease ranging from skin involvement only to skin, lymph node, and internal organ involvement. This spectrum of disease best fits under the umbrella of LCH (Langerhans Cell Histiocytosis). In about 50% of instances, dogs with multiple histiocytomas are euthanized due to lack of regression of lesions and complications in management of the extensive ulcerated lesions that are often present. Multiple histiocytomas with lymph node metastasis have a poor prognosis because spontaneous regression has not been encountered, and all of these dogs have been euthanized.

Answer 237

Histiocytoma is readily distinguished from other histiocytic disorders and cutaneous lymphoma with the aid of IHC. Histiocytomas have the phenotype of epidermal LCs.[ They express CD1a, CD1b, CD1c, MHC class II, CD11c, and E-cadherin. Among skin leukocytes, E-cadherin expression is unique to LCs. LCs use E-cadherin to localize in the epidermis via homotypic interaction with E-cadherin expressed by keratinocytes. Histiocytomas lack expression of CD4 and Thy-1, which are consistently expressed by histiocytes in CH and SH. Hence cutaneous histiocytoma is a localized epidermal LC tumor.

Answer 238

Because massive CD8+ T-cell infiltration is observed in all instances of histiocytoma regression, therapeutic intervention with the aim of immunosuppression should be avoided once a definitive diagnosis of histiocytoma has been reached to allow unfettered cytotoxic T-cell function.

Answer 239

When spread to distant sites beyond the local lymph node occurs, the disease is then termed .......... HS; this is more likely to occur unnoticed when primary lesions occur in cryptic sites (eg spleen, lung, and bone marrow). This latter form of HS is most like MH. MH is an aggressive, histiocytic neoplasm, which arises in multiple sites simultaneously. Most lesions previously defined as MH are probably more correctly termed disseminated HS. The occurrence of true MH is difficult to establish because the lesions often occur in cryptic sites, and the existence of histiocytic neoplasia is only recognized after clinical signs have appeared and disease progression is advanced. HS and MH are capable of widespread metastasis, hence in time the two syndromes merge clinically and it is not always possible to differentiate true multicentric origin (MH) from widespread metastasis of disseminated HS.

Answer 240

The HS complex of diseases is best recognized in the Bernese Mountain Dog, in which a familial association is apparent. Other breeds are predisposed to HS complex diseases and include Rottweilers, Golden Retrievers, and Flat-Coated Retrievers

Answer 241

Primary lesions of HS occur in spleen, lymph node, lung, bone marrow, skin and subcutis especially of extremities, and in periarticular tissues of the limbs. Secondary sites are widespread, but consistently include liver and lung (with splenic primary), and hilar lymph node (with lung primary). Clinical signs include anorexia, weight loss, and lethargy. Other signs depend on the organs involved and are a consequence of destructive mass formation

Answer 242

Canine malignant histiocytosis (MH) is an aggressive neoplasm of macrophages and dendritic cells. It carries a poor prognosis because of the development of widespread metastasis and poor sensitivity to chemotherapy.

Answer 243

MH and HS lesions express leukocyte surface molecules characteristic of DC (CD1, CD11c and MHC II).

Answer 244

Multiple cutaneous nodules may be distributed over the entire body but are especially prevalent in the scrotum, nasal apex, nasal planum, and eyelids. Ulceration of the skin overlying the nodules is common. Peripheral lymph nodes are often palpably enlarged. The disease course may be punctuated by remissions and relapses, which may occur spontaneously, especially early in the disease course. In severe disease, lesions become persistent and do not respond to immunosuppressive doses of corticosteroids. SH has proven to be a difficult and frustrating condition to treat. Intractable cases are best treated with immunosuppressive doses of cyclosporine A or leflunomide Cost of treatment can be substantially reduced by coadministration of cyclosporine A and ketoconazole.

Answer 245

Cutaneous Histiocytosis: CH is a histiocytic proliferative disorder that primarily involves skin and subcutis and does not extend beyond the local draining lymph nodes. CH occurs in a number of breeds. Evidence of spread beyond the skin would invoke the diagnosis of SH, a closely related disorder. Lymphadenopathy has not been emphasized in published reports and has only been documented in a small number of our cases. The lesions occur as multiple cutaneous and subcutaneous nodules up to 4 cm in diameter Lesions may disappear spontaneously or regress and appear at new sites simultaneously.

Answer 246

The clinical behavior and consistent clinical response to immunosuppressive therapy with agents capable of profoundly inhibiting T-cell activation has reinforced the concept that SH and CH occur in the context of disordered immune regulation arising from defective interaction of DCs and T cells. The end result of this dysregulated immune interaction is chronic proliferation of DCs and T cells. The initiation of the process is probably antigen driven, although studies to identify the nature of the antigens involved have been unrewarding. Hence it is important to perform tests to rule out infectious agents in the initial workup of a reactive histiocytosis case

Answer 247

We believe that the continued distinction of SH and CH as separate entities, in the light of our research, is probably no longer justifiable. It would be preferable to consider them within the spectrum of reactive histiocytoses of interstitial DC origin, in which clinical outcome is predictable more by the distant migratory potential of the proliferating histiocytes beyond the skin. In this view, CH and SH would be regarded as skin limited and systemic interstitial DC proliferations, respectively. A wide range of clinical behavior is to be expected within each grouping, with SH usually exhibiting more aggressive disease. CH and SH should not be confused with malignant DC disorders (HS and MH), which can occur in the same topographic locations. Cytologic and immunophenotypic differences can distinguish these diseases in most instances.

Answer 248

True histiocytic proliferative diseases in cats have not been extensively documented in the veterinary literature. The lesion referred to as “malignant fibrous histiocytoma” is most likely a soft tissue sarcoma with giant cells; the neoplastic population does not express histiocytic markers. At least three different histiocytic proliferative diseases have been recognized in cats: progressive histiocytosis, pulmonary LCH, and HS/MH.

Answer 249

Feline progressive histiocytosis (FPH) behaves as a low-grade HS, which originates in skin from resident DC. The initial clinical course is indolent and morphologically the histiocytes are cytologically bland. However, in time the lesions are more troublesome and morphologically there is a higher frequency of cytologic atypia more consistent with HS.

Answer 250

The lesions have been considered an analogue of canine histiocytoma, although spontaneous regression is not observed unlike canine histiocytoma. Canine histiocytoma is an LC proliferation, but the cell of origin in FPH has features in common with dermal DCs, which are interstitial DCs. Lesions consist of diffuse dermal histiocytic infiltrates, which may extend into the subcutis. The initial presentation of FPH may be a solitary skin nodule, although usually multiple papules, nodules, or plaques develop. Some cats develop lesions in lymph nodes and internal organs including the lungs, kidneys, spleen, and liver. Histiocytes of FPH consistently express CD18, CD1a, CD1c, and MHC II. This immunophenotype is consistent with a DC origin. However, both the epitheliotropic and nonepitheliotropic lesions mostly lack expression of E-cadherin. These features indicate that FPH is not composed of LCs, despite the existence of epitheliotropic infiltrates.

Answer 251

Pulmonary Langerhans cell histiocytosis is a disease of aged cats (10 to 15 years), which causes progressive respiratory failure leading to euthanasia. Pulmonary lesions are characterized by histiocytic infiltrates within terminal and respiratory bronchioles. The lesional histiocytes expressed CD18 and E-cadherin. E-cadherin is expressed by LCs.

Answer 252

Localized HS has been observed in cats. The poorly demarcated tumor masses were located in the subcutis of the ventral abdomen or the extremities. Metastasis to draining lymph nodes occurs. Alternatively, primary HS may occur in the spleen. The round and spindle-shaped tumor cells express CD18, CD1, and MHC II. This immunophenotype is consistent with a DC origin, although the precise sublineage of DCs has yet to be determined. The tumor cells lack expression of E-cadherin and hence are not of LC origin Feline HS shares morphologic features with canine HS, including variable cytology encompassing mononuclear and multinucleated round cells, and discrete to aggregated spindle cells

Answer 253

Renal tumors are usually malignant but uncommon in cats and dogs. The most common renal tumor in cats is lymphoma; up to 50% of these cats are FeLV positive.

Answer 254

In dogs the most common primary renal tumors are epithelial in origin (carcinoma or adenocarcinoma), although primary sarcomas and nephroblastomas are also reported. Bilateral involvement is common for lymphoma but occurs rarely in patients with carcinoma

Answer 255

A rare finding in dogs is palpable thickening and warmth in the distal long bones secondary to the paraneoplastic syndrome of hypertrophic osteopathy

Answer 256

Animals with renal tumors may have either anemia or polycythemia secondary to decreased or increased erythropoietin production, respectively. Another rare paraneoplastic syndrome of uncertain etiology in dogs with renal adenocarcinoma is neutrophilic leukocytosis.

Answer 257

Tumors of the urinary bladder are uncommon in dogs and rare in cats. Transitional cell carcinoma (TCC) is the most common primary tumor of the urinary bladder in both species. Transitional cell carcinoma (TCC) is the most common cancer of the urinary tract in dogs. Other differentials include squamous cell carcinoma, leiomyosarcoma, leiomyoma, and rhabdomyosarcoma. The bladder may also be invaded by prostatic neoplasia or metastatic disease (hemangiosarcoma, lymphoma).

Answer 258

TCC often involves the apex of the bladder in cats.[6] As this tumor is uncommon, the disease may go undiagnosed until it is diffusely invasive. However, even in cases of extreme local invasion, metastatic disease is not common. In dogs, TCC typically involves the trigone.TCC in dogs is metastatic; up to 40% of dogs have spread at the time of diagnosis, 17% involve the lungs Obstruction of the ureters and urethra, as well as invasion and disruption of the normal function of the urethral sphincter, are common.

Answer 259

Medical management of TCC with piroxicam may have efficacy. Combination therapy of piroxicam and mitoxantrone might be used

Answer 260

Prostatic adenocarcinomas and TCC, with many tumors having features of both

Answer 261

Mast cell tumor, squamous cell carcinoma.

Answer 262

Transmissible venereal tumor (TVT).

Answer 263

Interstitial cell tumor, seminoma, and Sertoli cell tumor.

Answer 264

Roughly 25% to 50% of Sertoli cell tumors are functional and can cause hyperestrogenemia. The Sertoli cell tumor is also the type most likely to metastasize. Although most testicular tumors are incidental findings on physical examination, clinical signs may include decreased libido, signs of prostatomegaly (stranguria, tenesmus), and inappetance and/or weakness secondary to anemia. Asymmetric testicles, scrotal or inguinal swellings, prostatomegaly, or signs of hyperestrogenism including alopecia, gynecomastia, a pendulous prepuce, and a poor haircoat may be seen on physical examination

Answer 265

Bone marrow suppression is a rare but well-documented complication of hyperestrogenism. This syndrome is characterized initially by thrombocytopenia and neutrophilic leukocytosis, which ultimately progresses into pancytopenia

Answer 266

Histologic terminology used for these benign tumors includes leiomyoma, fibroleiomyoma, fibroma, or polyp. Lipomas may also occur in this area, and hemangiomas can be seen. Malignant tumors are rare, with leiomyosarcoma the most likely. TVTs may also occur. Tumors may be intraluminal or extraluminal. Intraluminal tumors are often associated with stranguria

Answer 267

In dogs the majority of uterine tumors are mesenchymal; 85% to 90% are leiomyomas, and 10% are leiomyosarcomas. German Shepherd Dogs may be overrepresented in the literature due to the syndrome of renal cystadenocarcinomas and associated uterine leiomyomas. In cats, uterine adenocarcinoma is the most common primary tumor of the uterus

Answer 268

In dogs, roughly one half of ovarian tumors are epithelial and include the histologic diagnoses of papillary adenoma, cystadenoma, papillary adenocarcinoma, and undifferentiated adenocarcinoma. Epithelial tumors are rare in cats. Germ cell tumors make up roughly 10% of ovarian neoplasms in dogs. Sex-cord stromal tumors make up 35% to 50% of ovarian tumors

Answer 269

Estrogen and progesterone receptors have been identified in dog and cat MGT; for dogs the less well differentiated the tumor, the more likely the tumor is to be hormone-receptor negative.

Answer 270

The most common types of malignancies in dogs are solid carcinomas, followed by tubular adenocarcinomas; only about 3% are sarcomas, and 1% are inflammatory carcinomas. Of the 50% that are malignant, 50% will recur or metastasize following the first surgical resection

Answer 271

The majority (80% to 90%) of feline MGTs are malignant, most often adenocarcinomas, and they exhibit highly metastatic behavior.

Answer 272

Desmopressin (DDAVP) is a vasopressin peptide analog with hemostatic properties that has been successfully used during surgery in patients with bleeding disorders. Recently published experimental and clinical data indicate that perioperative administration of DDAVP can minimize spread and survival of residual mammary cancer cells.

Answer 273

Paraneoplastic syndromes (PNSs) are the signs and symptoms that result from indirect effects of tumors due to their production and release of biologically active substances such as hormones, growth factors, and cytokines. Many oncologists apply the term paraneoplastic syndrome only to those instances when the compound released from the tumor is one not normally produced by the tumor cell of origin. By this definition, many commonly cited PNSs, including hypoglycemia secondary to a pancreatic insulinoma, are not considered to be true PNSs. They are, however considered with PNSs here due to the fact that they result in effects at sites remote to the underlying malignancy.

Answer 274

The most common cause of hypercalcemia in dogs is underlying malignancy, whereas nonneoplastic causes predominate in cats.[

Answer 275

The primary mechanism of hypercalcemia of malignancy (HM) is the promotion of bone resorption by osteoclasts and subsequent release of calcium into the bloodstream. In primary hyperparathyroidism, bone resorption is promoted via increased parathyroid hormone (PTH) concentrations. However, many tumors originating outside of the parathyroid glands can cause increased serum calcium concentrations by elaborating substances other than PTH, the most common of which is parathyroid hormone–related peptide (PTHrP)

Answer 276

PTHrP is a 16kDa protein that shares structural homology with PTH in the first 13 amino acids of its N-terminal portion. PTH binds to the PTH receptor with an affinity equal to that of PTH, resulting in similar biologic effects

Answer 277

Other substances elaborated by tumor cells that can cause HM include interleukin-1β (IL-1β, previously called osteoclast activating factor), transforming growth factor-β (TGF-β), and the receptor activator of nuclear factor κ-B ligand (RANκL). The latter is a membrane-associated protein that stimulates osteoclast activity by binding to a receptor on the surface.

Answer 278

In dogs, HM is most commonly associated with lymphoma, apocrine gland anal sac adenocarcinoma (AGASAC), multiple myeloma, and thymoma, but many other tumor types may cause hypercalcemia

Answer 279

In AGASAC, there is a linear correlation between serum calcium and PTHrP concentration, thus suggesting that PTHrP is central to the etiology of HM in this disease. A similar correlation has not been demonstrated for dogs with lymphoma, which would imply that PTHrP production is not the only mechanism of HM in this neoplasia

Answer 280

Dogs with T cell lymphoma and those with cranial mediastinal lymphoma are more likely to develop HM than dogs with other anatomical or immunophenotypic forms of the disease. The HM associated with canine multiple myeloma is believed to be due to increased bone resorption in the immediate proximity of neoplastic foci. HM is less common in cats but has been associated with lymphoma and a variety of carcinomas.

Answer 281

HM can have significant effects on the kidneys. In HM, the distal tubules become less responsive to antidiuretic hormone (ADH), leading to polyuria and polydipsia. As hypercalcemia becomes more marked, renal blood flow and glomerular filtration rates decrease, thus decreasing renal function.

Answer 282

Deposition of calcium in the renal parenchyma leads to mineralization of the basement membrane, exacerbating renal effects. Dogs with HM are more frequently azotemic than those with parathyroid-dependent hypercalcemia. In animals with hypercalcemia and renal failure, it may be difficult to ascertain whether hypercalcemia is a result of the renal failure or vice versa.

Answer 283

Clinical signs of hypercalcemia include inappetence or anorexia and weight loss, polyuria and polydipsia, weakness, vomiting, bradycardia, obtundation, twitching, and shaking. Cats experience less polyuria, polydipsia, and gastrointestinal (GI) signs than do dogs. Approximately 25% of cats with hypercalcemia show signs of lower urinary tract disease, often associated with calcium oxalate urolithiasis.

Answer 284

Diagnostic evaluation should include assaying serum ionized calcium concentrations, as this is the biologically active fraction. If the ionized calcium is increased, serum should be submitted for measurement of phosphorus, PTH, and PTHrP concentrations. Typically, dogs and cats with HM have increased serum ionized calcium, normal or low serum phosphorus, low PTH, and increased PTHrP concentrations. If HM is suspected, identification of the underlying neoplasia is key to diagnosis and therapy.

Answer 285

Furosemide may be used to promote calciuresis once hydration is reestablished. Prednisone will decrease serum calcium and should be reserved for cases in which the diagnosis has been established. The premature use of corticosteroids in animals with myeloma or lymphoma may both obscure diagnosis and induce resistance to later use of other chemotherapeutic agents. Additional pharmacologic options for decreasing calcium are described in Chapter 79 but are rarely needed in the treatment of HM, especially if the underlying malignancy can be addressed. Hypercalcemia refractory to saline diuresis and furosemide therapy may be treated with pamidronate (1 mg/kg given over 2 hours in 250 mL 0.9% saline). Ultimately, effective treatment of the underlying malignancy is essential for sustained resolution of HM.

Answer 286

Hypoglycemia, defined as a blood glucose concentration

Answer 287

Nonneoplastic causes of hypoglycemia—including hypoadrenocorticism, hepatic dysfunction, breed-related causes (hunting dog hypoglycemia or hypoglycemia of young toy or miniature breeds), sepsis, and artifactual hypoglycemia due to prolonged storage of blood samples before processing

Answer 288

A variety of mechanisms may contribute to the PNS of hypoglycemia. Tumor production of insulin, insulin-like growth factors I and II (IGFI and IGFII), and somatomedins have all been associated with paraneoplastic hypoglycemia. In addition, upregulation of insulin receptors, decreased glycogenolysis or gluconeogenesis within the liver, excess tumor utilization of glucose, and binding of insulin by M proteins in multiple myeloma may contribute to paraneoplastic hypoglycemia. Because parenteral administration of dextrose can result in rebound release of insulin and worsening clinical signs, dogs and cats should be treated to effect only

Answer 289

The syndrome of inappropriate ADH secretion (SIADH) is characterized by hyponatremia, serum hypoosmolality, and urine hyperosmolality in the absence of renal or adrenal dysfunction. Although widely recognized as a PNS in human oncology, SIADH has not been reported in animals.

Answer 290

Tumor-related SIADH must be differentiated from drug-related SIADH. Vincristine, cylophosphamide, cisplatin, and morphine are among the drugs commonly used in veterinary oncology that are known to produce this syndrome in people

Answer 291

The most common neoplastic cause of hyperestrogenism is Sertoli cell tumor, usually of a cryptorchid testicle. Associated clinical signs include nonpruritic symmetrical alopecia, hyperpigmentation, gynecomastia, pendulous prepuce, and a symmetrically enlarged prostate. Signs of feminization such as attraction of intact male dogs and squatting to urinate are typical observations made by owners of affected dogs. The more clinically relevant effect of hyperestrogenism is bone marrow suppression that results in pancytopenia and attendant lethargy, bleeding secondary to thrombocytopenia, petechiae, vomiting, anorexia, fever, and pale mucous membranes.

Answer 292

Anemia is one of the most common PNSs in dogs and cats, occurring in association with a wide variety of tumors. Several different mechanisms may contribute to paraneoplastic anemia, including blood loss, bone marrow infiltration, anemia of chronic disease, immune-mediated hemolytic anemia, hyperestrogenism, and microangiopathic hemolytic anemia. In addition to paraneoplastic anemia, direct mechanisms of anemia including blood loss secondary to erosion of underlying tissue and vasculature, as with nasal carcinoma and hemangiosarcoma, and erythrophagocytosis by tumor cells, as with malignant histiocytosis that may contribute to anemia in cancer. Thus direct and indirect mechanisms of anemia must be considered and treated to resolve this complication.

Answer 293

....at a site distant from the primary tumor, rather than occurring at the tumor site, secondary to direct infiltration of surrounding tissues and vasculature by the mass.

Answer 294

Examples include blood loss due to GI ulceration that occurs with mast cell tumors (due to histamine) and gastrinomas (due to gastrin). This type of anemia is usually regenerative early in the course of the disease but later becomes nonregenerative, microcytic, and hypochromic, accompanied by decreased serum iron concentration and increased iron-binding capacity.

Answer 295

In such animals, therapy must entail a careful balance between tumor eradication from the marrow and preservation of the remaining erythrocyte precursors. L-asparaginase is one chemotherapy drug that can be used to treat stage V lymphoma and lymphocytic leukemias without adversely affecting the normal precursors within the marrow. This is not the case with most other chemotherapy agents-

Answer 296

Low serum iron, decreased serum transferrin, decreased transferrin saturation, increased serum ferritin, and increased reticuloendothelial iron stores. Iron absorption is reduced, as well. Because this type of anemia progresses slowly and has a mild effect on the erythron, supportive care is rarely necessary. Resolution of ACD can be anticipated once the primary tumor is addressed.

Answer 297

Immune-mediated hemolytic anemia (IMHA) can occur as a PNS associated with hematopoietic malignancies and, less commonly, with solid tumors. The IMHA associated with malignancy is a secondary IMHA, in which antibodies directed against tumor cell-membrane antigens cross-react with erythrocytes. The anemia can be acute or chronic, mild or severe, and it is nonregenerative in many cases.

Answer 298

The direct Coombs test that detects erythrocyte-bound immunoglobulin (IgG and IgM) and/or complement (C3) may have false-positive test results in dogs and cats with neoplastic disease. However, in cancer-bearing dogs and cats, a positive Coombs test and other clinical and hematologic findings consistent with IMHA warrant a tentative diagnosis of this PNS. Elimination of the underlying malignancy is the most important factor for resolving secondary paraneoplastic IMHA.

Answer 299

Microangiopathic hemolytic anemia is most often associated with microvascular tumors, such as hemangiosarcoma (HSA), but it can occur with any tumor that leads to disseminated intravascular coagulation (DIC). Erythrocyte fragmentation can result from intravascular fibrin formed in DIC, or it may be caused by abnormal vascularity within the tumor, pulmonary intraluminal tumor emboli, or by narrowing of pulmonary arterioles secondary to intimal proliferation. Resolution of the underlying malignancy is considered the only effective therapy for paraneoplastic microangiopathic hemolytic anemia.

Answer 300

Erythrocytosis, or polycythemia, is an uncommon PNS that is most often associated with primary or secondary tumors of the kidney. Other neoplasms that have been reported to cause erythrocytosis include lymphoma, schwannoma, nasal fibrosarcoma, transmissible venereal tumor, bronchioloalveolar carcinoma, and intestinal (cecal) leiomyosarcoma

Answer 301

Paraneoplastic erythrocytosis is a form of secondary erythrocytosis in which the underlying mechanism is an increased level of erythropoietin (EPO), rather than a direct effect on the bone marrow. EPO may be produced ectopically by a tumor, or it may be produced in excess by the kidney, either in direct response to renal hypoxia caused by tumor compression or through the action of hypoxia-inducible transcription factors, which stimulate EPO production

Answer 302

Clinical findings with polycythemia include erythema of the mucous membranes, polydipsia, and neurologic signs such as disorientation, ataxia, and seizures secondary to hyperviscosity or hypervolemia.

Answer 303

Paraneoplastic neutrophilic leukocytosis is characterized by an increase in the number of mature neutrophils in the absence of infection or leukemia. This PNS is associated with renal carcinomas (transitional cell and tubular), lymphoma, metastatic fibrosarcoma, pulmonary carcinoma, and rectal adenomatous polyps. The underlying etiology is tumor production of colony-stimulating factors (CSFs) such as granulocyte (G)-CSF in cats and both G-CSF and granulocyte-monocyte (GM)-CSF in dogs. The PNS of neutrophilic leukocytosis is usually an incidental finding independent of clinical signs, which resolves with successful treatment of the underlying tumor.

Answer 304

Paraneoplastic eosinophilia is a rare manifestation of cancer that has been reported in dogs with pericardial leiomyosarcoma, intestinal T cell lymphoma, rectal polyps, mammary carcinoma, and oral fibrosarcoma and in cats with mast cell tumors (MCTs), intestinal T cell lymphoma, and transitional cell carcinoma of the bladder. Eosinophilia as a PNS is generally an asymptomatic incidental finding, although it may occur with disseminated MCT, in which case prognosis is poor.

Answer 305

Lymphoma, melanoma, HSA, OSA, MCT, and various carcinomas

Answer 306

Increased platelet utilization, destruction, or decreased production. Increased utilization occurs with tumors that induce hemorrhage (HSAs and MCTs) or coagulopathies such as disseminated intravascular coagulation seen with metastatic tumors and HSA. As with anemia, immune-mediated destruction of platelets can be seen with lymphoma or multiple myeloma. Decreased platelet production can occur secondary to myelophthisis induced by marrow-infiltrating malignancies.

Answer 307

Clinical signs of thrombocytopenia are generally not evident until the platelet count decreases below 30,000/μL. When this occurs, or when thrombocytopenia is accompanied by DIC, clinical findings may include petechiation and hemorrhage. Treatment varies depending upon the severity of thrombocytopenia and the underlying cause, although resolution of the primary tumor is the ideal. Fresh whole blood may be indicated prior to tumor resection. Therapy for anemia and DIC are described elsewhere. In the case of immune-mediated thrombocytopenia (ITP) secondary to hematological malignancies, the thrombocytopenia is managed with immunosuppressive dosages of corticosteroids, along with chemotherapy to treat the tumor.

Answer 308

Thrombocytosis (platelet counts above 500,000/μL) may be an incidental finding in dogs and cats with neoplastic disease but is rarely of clinical concern. It has been described in animals with OSA, gingival carcinoma, chronic myeloid leukemia, bronchoalveolar carcinoma, metastatic SCC, and in those undergoing chemotherapy

Answer 309

(1) an increase in serum factors that induce platelet aggregation, (2) a change in the lipid composition of plasma membranes, and (3) an increase in number of newer platelets, which have a higher activity. Platelet hyperaggregability and hypercoagulability is of clinical relevance in that it may predispose animals to thromboembolism and aid metastasis

Answer 310

The cancers most often associated with DIC were HSA, mammary carcinoma, and lung carcinoma. Others include thyroid carcinoma, nasal carcinoma, SCC, OSA, granulosa cell tumor, gastric carcinoma, and adrenocortical tumors.

Answer 311

Along with the underlying mechanisms of DIC common to other diseases, TF is expressed on cancer cells and complexes with factor VIIa to stimulate thrombin formation, as well as activating factor IX of the intrinsic pathway and factor X of the common pathway

Answer 312

Hyperglobulinemia is a PNS that occurs most commonly in association with multiple myeloma, although other neoplastic diseases—including lymphoma, chronic lymphocytic leukemia, and plasmacytoma—are also reported causes

Answer 313

The mechanism of hyperglobulinemia is excess production of monoclonal (or rarely, biclonal) immunoglobulins by plasma cells or lymphocytes.[98],[100] Most animals with multiple myeloma have an IgG or IgA monoclonal gammopathy, and clinical signs relate to the effects of excess globulins in the circulation.

Answer 314

Production of normal immunoglobulins may be inhibited, leading to infections. Other significant clinical sequelae may include hyperviscosity syndrome and associated hypertension and tissue hypoxia. Bleeding tendencies are also common with hyperglobulinemia and relate to decreased adhesion of platelets to damaged endothelial surfaces, coating of platelets with immunoglobulins, and release of platelet factor III. Confirmation of hyperglobulinemia is via serum or urine electrophoresis

Answer 315

pancreatic and biliary carcinoma

Answer 316

Superficial necrolytic dermatitis (SND) is a rare PNS associated with glucagon-secreting tumors in dogs and pancreatic carcinoma in one cat. Far more common than the paraneoplastic glucagon-associated form of SND is that associated with hepatopathy; hence, the other name for this disorder, hepatocutaneous syndrome. Hypoaminoacidemia is a characteristic feature and may be central to the etiology of this disorder.

Answer 317

Nodular dermatofibrosis is a rare but well-recognized cutaneous PNS, affecting dogs that have bilateral renal cystadenocarcinoma. The disorder is most often seen in middle-aged to older German Shepherd Dogs, in which renal cystadenocarcinomas are heritable in an autosomal dominant fashion.

Answer 318

Metabolic alterations associated with this PNS are complex and result from a competition between the host (patient) and the tumor for nutrients that favors anaerobic metabolism, along with altered cytokine profiles, hyperlactatemia, and changes in insulin responsiveness. Clinical signs include weight loss, reduced fat mass, and muscle wasting, often despite a good appetite. In addition to treatment of the underlying malignancy, aggressive nutritional support is necessary. Appetite stimulants (mirtazapine, cyproheptadine, diazepam, oxazepam) and antinausea medications (maropitant, ondansetron) may be helpful, along with dietary changes

Answer 319

Examples include release of histamine from an MCT and gastrin from a gastrinoma. Both substances bind to receptors on the parietal cells and cause gastric acid secretion and subsequent GI ulceration.

Answer 320

Diagnosis is via identification of the primary tumor, along with visual (endoscopic) or laboratory evidence (anemia, elevated BUN unaccompanied by increased creatinine) of GI ulceration. Increased serum gastrin levels provide further evidence of gastrinoma. Therapy is aimed at resolution of the primary tumor, usually by surgical excision, and treatment for GI ulceration with proton-pump inhibitors, H2 receptor blockers, and sucralfate.

Answer 321

Myasthenia gravis (MG) is an uncommon PNS that most often occurs with thymoma but is a condition also reported with cholangiocellular carcinoma, lymphoma, and OSA. The cause of paraneoplastic MG is production of antibodies to the nicotinic acetylcholine (ACh) receptors by the tumor. A rare disorder of MG development after thymectomy for thymoma has also been described

Answer 322

Clinical signs include muscle weakness, dysphagia, regurgitation, and aspiration pneumonia secondary to megaesophagus. Diagnosis is aided by detection of circulating autoantibodies against the acetylcholine receptor (AchR) or by the edrophonium (tensilon) test and electromyography with repetitive nerve stimulation.

Answer 323

Myasthenia gravis (MG): Anticholinesterase agents such as pyridostigmine bromide or neostigmine prolong the interaction of ACh with available receptors and may improve signs of muscle weakness. Resection of the primary tumor is recommended when feasible and may eliminate clinical signs. However, owners must be forewarned that anti-AchR titers do not always decrease significantly after tumor resection, and MG may not resolve.

Answer 324

The likely etiology is production of antibodies targeting antigens that are shared between the tumor and the peripheral nerves. This PNS is characterized by focal or whole body weakness. Tumor extirpation is the only effective therapy for this condition.

Answer 325

As such, neoplasia should be considered in the differential diagnosis list for dogs and cats that have protein-losing renal disease. Nephropathy may also occur in dogs and cats with paraneoplastic hypercalcemia, which may cause mineralization of the basement membrane.

Answer 326

This PNS is most often associated with primary intrathoracic masses, although renal, adrenal, and metastatic Sertoli cell tumors and urinary bladder tumors have also been reported. Alternatively, nonneoplastic space-occupying lesions within the thoracic or abdominal cavities—including abscesses, granulomas, foreign bodies, and parasites—may induce HO.

Answer 327

The disorder is characterized by progressive periosteal proliferation along the shafts of long bones of distal extremities and occasionally along other bones of the appendicular skeleton. The etiology is not completely understood, but one mechanism is thought to involve stimulation of the vagus nerve, resulting in increased blood flow to the distal extremities. Presenting complaints include shifting leg lameness or reluctance to move, and affected limbs are typically warm and edematous. The periosteal proliferation may be palpable in some cases.

Answer 328

True paraneoplastic fever occurs secondary to elaboration of pyrogenic cytokines by either the tumor or by the host immune response to the tumor. These pyrogens include IL-1, IL-6, interferons, and tumor necrosis factor-α, which act as endogenous pyrogens on the thermoregulatory center of the anterior hypothalamus. In addition to infection-related and pyrogen-induced fever, neoplastic infiltration into the hypothalamus may result in fever. Therapy is dependent upon the underlying cause of the fever, although symptomatic therapy with NSAIDs may provide some palliation if the underlying cancer cannot be eliminated

Cancer Flashcards

(354 cards)