Page 122 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 5 Paraneoplastic Syndromes 101

calciuresis. Once rehydrated, the loop diuretic furosemide can be clinical consequences, diagnosis, and therapy of tumor-induced
used with continued saline diuresis to further promote urinary hypoglycemia.
calcium loss. More refractory cases can be treated with bisphos-
VetBooks.ir phonates, which inhibit osteoclast-mediated bone resorption. Hyperestrogenism
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Pamidronate (1.0–2.0 mg/kg IV) is effective for treating HM in
dogs induced by various cancers, and it also has been shown to be The tumor most commonly associated with hyperestrogenism is
an effective treatment in both dogs and cats with hypercalcemia the Sertoli cell tumor. Overall, 25% to 50% of dogs with Sertoli
secondary to nonneoplastic conditions. In humans, zoledronate cell tumors will display clinical signs of hyperestrogenism. 62–64
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is more effective at inducing normocalcemia and maintains nor- Approximately half of canine Sertoli cell tumors develop in crypt-
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mocalcemia for a longer duration. It also is less nephrotoxic than orchid testes, and clinical hyperestrogenism occurs more com-
pamidronate. 44,47 Zoledronate has not been evaluated for HM monly when Sertoli cell tumors develop in cryptorchid testes. 63–65
in veterinary patients, but it has been used safely in dogs with Therefore a Sertoli cell tumor must remain a differential diagno-
malignant osteolysis (dose 0.1–0.25 mg/kg IV). In those rare sis when a dog presents with clinical signs of hyperestrogenism,
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situations in which marked hypercalcemia with life-threatening even if a testicular mass is not palpated on physical examination.
consequences (e.g., coma) require immediate correction, the use Ultrasound is then indicated to screen for an inguinal or intraab-
of salmon calcitonin (4-8 IU/kg, S.C., q8–12 hours) will more dominal tumor. Paraneoplastic hyperestrogenism also can occur
rapidly lower blood calcium than bisphosphonates; however, rarely in dogs with seminomas, interstitial cell tumors, and ovar-
its use is limited by expense, availability, and the propensity for ian granulosa cell tumors. 66–68 This PNS has not been reported
tachyphylaxis (rapid resistance to effects) to occur within days. 37 in cats.
Glucocorticoid steroids can quickly induce a rapid reduction in Dogs with Sertoli cell tumors have significantly higher plasma
serum calcium level. However, it is essential that a definitive cause estradiol-17β levels compared with healthy controls. Sertoli cell
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for hypercalcemia be identified before any steroid therapy is initiated. tumors also have lower expression of 5α-reductase type 1 than
If lymphoma or another hematopoietic tumor is the underlying normal testes, and plasma testosterone levels were lower in affected
cause of HM, the premature use of steroids can interfere with the dogs. 69,70 Clinical signs of feminization secondary to Sertoli cell
ability to confirm a diagnosis, necessitating additional diagnostics tumors correlated best with reductions in the testosterone/estra-
and/or discontinuation of the steroids and waiting for the can- diol ratio rather than absolute increases in estradiol-17β. 69
cer to become clinically evident again. In addition, steroids can Clinical signs of hyperestrogenism include bilaterally symmet-
induce resistance to other chemotherapy agents, decreasing the ric alopecia, cutaneous hyperpigmentation, epidermal thinning,
ability to attain a complete remission and shortening the length gynecomastia, galactorrhea, pendulous prepuce, penile atrophy,
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of survival. atrophy of the contralateral testicle, either prostatic atrophy or
prostatomegaly (the latter secondary to squamous metaplasia), and
Hypoglycemia attraction of other males. 62,63 Estrogen also can have myelotoxic
effects. Bone marrow toxicosis is characterized initially by a tran-
The most common cause of paraneoplastic hypoglycemia in the sient increase in granulocytopoiesis and neutrophilic leukocytosis,
dog is insulinoma (pancreatic beta-cell tumor). 49,50 Functional followed by progressive bone marrow hypoplasia or aplasia leading
pancreatic beta-cell tumors typically produce excess amounts of to aplastic anemia (nonregenerative anemia, thrombocytopenia,
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insulin, but rarely they can also release IGF-1 or IGF-2. 51,52 The and leukopenia). Severely pancytopenic dogs can present with
reader is directed to Chapter 26 for a discussion of insulinomas. additional clinical signs associated with anemia (weakness, leth-
The non–islet cell tumors most commonly associated with argy, pale mucous membranes, tachycardia), thrombocytopenia
paraneoplastic hypoglycemia are primary liver tumors (hepa- (petechia, ecchymoses, epistaxis, GI bleeding) and/or leukope-
tocellular adenocarcinoma and adenoma) and smooth muscle nia (infection, sepsis). The clinical signs of hyperestrogenism will
tumors (leiomyosarcoma and leiomyoma, with tumors arising resolve with surgical removal of the Sertoli cell tumor, but this
from liver, stomach, duodenum, and jejunum). 53–57 Case reports can take several months. Consequently, the mortality rate for dogs
also exist for paraneoplastic hypoglycemia associated with a vari- with severe myelotoxicosis and pancytopenia is high. 62,63
ety of other tumors, including hemangiosarcoma (HSA), lym-
phoma, lymphocytic leukemia, mammary carcinoma, melanoma, Acromegaly (Hypersomatropism)
plasma cell tumor, renal adenocarcinoma, and salivary adenocar-
cinoma. 53,58–60 Tumor cell production of IGF-2 is the most com- In cats, acromegaly is caused by hypersomatropism—excessive
mon mechanism for paraneoplastic hypoglycemia in non–islet cell GH secretion by a functional pituitary adenoma arising from
tumors. 1,53,54,61 Other mechanisms include production of IGF-1 somatotroph cells. 71–73 In contrast, canine acromegaly most com-
or somatomedins, hypermetabolism of glucose, production of monly results from progestin-induced GH secretion by mammary
substances stimulating insulin release, production of hepatic glu- ductal epithelium. However, there are case reports of two GH-
cose inhibitor, insulin binding by a monoclonal immunoglobulin producing mammary tumors and one GH-producing pituitary
(plasma cell tumors), insulin receptor proliferation, or rarely, ecto- tumor in dogs. 74,75
pic insulin production. 1 GH antagonizes insulin by reducing insulin receptors and
Insulinomas usually are small, and visualization on abdominal interfering with a wide range of postreceptor processes. 71–73
ultrasound is inconsistent. 49,50 The diagnosis is most often made The vast majority of cats initially present with diabetes mel-
by documenting hypoglycemia along with an inappropriately litus, and insulin resistance is common. Over time, the chronic
elevated serum insulin level. In contrast, most intraabdominal exposure to excess GH results in overgrowth of connective tis-
non–islet cell tumors causing hypoglycemia are large and read- sue, bone, and viscera. Cats can develop broad facial features,
ily identifiable on abdominal palpation or ultrasound. 53–56 The prognathica inferior, diffuse thickening of the oropharyngeal
reader is directed to Chapter 26 for an extensive discussion of the tissues, hepatomegaly, renomegaly, adrenomegaly, hypertrophic