Page 124 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 5 Paraneoplastic Syndromes 103

Non–immune mediated hemolytic anemia can arise sec- It is important to rule out other causes for erythrocytosis.
ondary to microangiopathy, tumor cell erythrophagocytosis, or Relative erythrocytosis results from dehydration. Absolute eryth-
rocytosis can be primary (polycythemia vera) or secondary to
oxidative damage to erythrocytes. Microangiopathic hemolytic
VetBooks.ir anemia (MAHA) is caused by endothelial cell injury and fibrin chronic respiratory disease, heart disease causing right-to-left
90
deposition, most commonly seen in patients with disseminated
shunting, or nonneoplastic renal disease. Classically, dogs and
intravascular coagulation (DIC), and by inherent abnormalities cats with paraneoplastic erythrocytosis will have elevated serum
in tumor vasculature, most notably with HSA. 83,104,105 These erythropoietin levels, but there is considerable overlap with
pathologic alterations cause shearing and destruction of eryth- dogs and cats that are normal and even those with polycythemia
rocytes, resulting in increased numbers of schistocytes in periph- vera. 90,126
eral blood. Clinically significant tumor cell erythrophagocytosis Paraneoplastic erythrocytosis typically resolves with removal of
is seen most commonly with HS, particularly the hemophago- the primary tumor. However, patients presenting with hypervis-
cytic variant. 106–108 In addition to a markedly regenerative ane- cosity syndrome might require emergency treatment before sur-
mia, common clinicopathologic abnormalities include a negative gery or chemotherapy induction (see Hyperviscosity Syndrome,
direct agglutination test, thrombocytopenia, hypoalbuminemia, earlier). 90,125
and hypocholesterolemia. Erythrophagocytosis, with or without
secondary anemia, has also been documented in dogs with lym- Leukocytosis
phoma, plasma cell tumors, and acute megakaryoblastic leuke-
83
mia, and in cats with lymphoma and mast cell tumor (MCT). Mild to moderate neutrophilic leukocytosis is common in dogs
Oxidative injury to erythrocytes is characterized by Heinz bodies and cats with cancer, and is usually attributable to inflammation
and/or eccentrocytes. In retrospective studies, 15% of dogs with or tissue necrosis associated with the cancer; however, extreme
eccentrocytosis, and 11% of cats with Heinz body anemia had neutrophilic leukocytosis (≥70,000 cells/μL), often with a left
underlying malignancies. 109,110 Lymphoma was the most com- shift, monocytosis, and eosinophilia, has been reported in dogs
mon cancer for both species. with pulmonary carcinoma, renal tumors, intestinal T-cell lym-
Nonregenerative anemias result from cancers directly or indi- phoma, metastatic fibrosarcoma, and adenomatous rectal polyps,
rectly affecting erythropoiesis. Cancer cells can infiltrate the mar- and in cats with pulmonary SCC and dermal tubular adenocar-
row and replace normal hematopoietic tissue, a condition called cinoma. 83,127–133 This is thought to arise because of tumor pro-
myelophthisis. This is seen most commonly with hematopoietic duction of granulocyte colony-stimulating factor (G-CSF) and/
cancers, such as acute leukemias, lymphoma, multiple myeloma, or granulocyte-macrophage colony-stimulating factor (GM-
mast cell neoplasia, and disseminated HS. 83,104,108,111–114 Aplas- CSF). 83,131,132 Extreme neutrophilic leukocytosis, also referred
tic anemia can result from paraneoplastic hyperestrogenism (see to as a leukemoid response, can be difficult to distinguish from
earlier). Decreased serum folate and cobalamin (vitamin B ) con- chronic myelogenous leukemia (CML), as the prevalence of the
12
centrations have been reported in cats with GI lymphoma. 115 One characteristic cytogenetic abnormalities identified in people with
of the most common causes of anemia in cancer patients is anemia CML, although identified in dogs, has not been determined. 134,134b
of inflammatory disease (AID, also called anemia of chronic dis- This PNS is generally thought to have minimal clinical signifi-
ease). This is characterized by a mild to moderate nonregenera- cance, although a retrospective study evaluating dogs with severe
tive, normocytic, normochromic anemia. Inflammatory cytokines leukocytosis (≥50,000 white blood cells [WBC]/μL, with >50%
such as TNF-α, interferon-gamma (IFN-γ), IL-1, IL-6, and IL-10 neutrophils) resulting from a variety or neoplastic and nonneo-
reduce the production of endogenous erythropoietin in the face plastic etiologies identified a high mortality rate. 135
of hypoxemia, and suppress the erythroid progenitor response to Eosinophilia is an uncommon PNS in veterinary cancer
erythropoietin. 102 IL-6 increases production of hepcidin by the patients, but is seen most frequently in dogs and cats with MCT
liver. Hepcidin is an acute phase protein that causes increased cel- and lymphoma, particularly T-cell lymphoma. 136–140 Mast cells
lular internalization and degradation of ferroportin, a membrane produce the eosinophilic cytokine IL-5 and other eosinophil
bound protein that exports iron from macrophages, hepatocytes, chemotactic factors, and in people T-cell lymphomas have been
and duodenal enterocytes into the peripheral blood. 83,102 The net documented to produce IL-5. 136,139 Eosinophilia also has been
effect is the sequestration of iron, resulting in hypoferremia and reported in dogs with oral fibrosarcoma, mammary carcinoma,
decreased availability of iron for erythropoiesis. and leiomyosarcoma, and in cats with oral SCC and bladder tran-
sitional cell carcinoma. 83,141–144 Eosinophilia is also frequently
Erythrocytosis (Polycythemia) seen as part of a leukemoid response.
Paraneoplastic erythrocytosis has been reported in dogs with Thrombocytopenia
a variety or renal tumors (carcinoma; adenocarcinoma; fibro-
sarcoma; and lymphoma, with or without other organ involve- Thirteen percent to 36% of dogs with cancer present with throm-
ment), nasal fibrosarcoma, cecal leiomyosarcoma, and spinal cord bocytopenia before any treatment, 145,146 and 39% of thrombocy-
schwannoma. 60,116–124 It also has been reported in cats with renal topenic cats are diagnosed with underlying neoplasia. 147 In both
adenocarcinoma. 125 Paraneoplastic erythrocytosis is associated species, thrombocytopenia is especially common with hematopoi-
with increased serum erythropoietin levels. The erythropoietin is etic and vascular cancers. 145–147 General mechanisms for thrombo-
most often produced by the tumor cells. 117,118,121,123 However, cytopenia include decreased platelet production, increased platelet
it also has been hypothesized that elevated erythropoietin levels destruction, increased platelet sequestration, and increased plate-
might result from impaired renal blood flow causing local tissue let consumption. However, in a series of 214 thrombocytopenic
hypoxia. 90,121 In people, paraneoplastic erythrocytosis can also dogs with cancer, 61% had no identifiable explanation for their
result from tumor cells producing androgenic hormones and pros- thrombocytopenia, although not all dogs had exhaustive diagnos-
taglandins that enhance the effects of erythropoietin. 1 tic evaluations. 146