 Paraneoplastic Syndromes 
| Definition and importance | | | | | Paraneoplastic disorders are indirect and usually remote effects that are caused by tumor cell products rather than by the primary tumor or its metastases. The incidence of paraneoplastic syndromes in animals is not known. Best descriptions of paraneoplastic syndromes exist for the dog. Recognition of paraneoplastic syndromes is important for a number of causes:
• Paraneoplastic syndromes can occur early in the cause of a tumorous disease, therefore,
a recognition of a specific paraneoplastic syndrome can facilitate early tumor diagnosis.
• Treatment of the metabolic abnormalities associated with paraneoplastic syndromes may be
required to assure effective cancer management.
• The severity of the paraneoplastic abnormalities reflects the tumor burden. Monitoring these
abnormalities may be therefore useful in determining tumor response to therapy and identifying
tumor recurrence or spread.
• Paraneoplastic syndromes itself can lead to severe clinical signs and may lead to emergency
cases.
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| Cachexia | | | | | Many animals with tumorous diseases show marked weight loss. In cancer cachexia, both muscle and fat are lost, whereas in simple starvation fat is lost preferentially. The etiology in cancer cachexia is complex. Contributing factors include anorexia, impaired digestion, nutritional demands of tumor tissue, nutritient loss in cancer- related effusions or exudates and a variety of metabolic or endocrine derangements. Many humoral factors, including cytokines and hormones, contribute to the development of cancer cachexia. Extra calories do not reverse cancer cachexia.
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| Endocrinopathies | | | | | Neoplasms of endocrine tissues produce the normal hormone products of the tissue of origin. Due to the fact that the organism is able to regulate this hormone production only to a very limited extent, the result is an overproduction of hormones. In endocrine tissues with more than one cell type (pancreas, pituitary gland, adrenal gland, thyroid), generally only a single cell type becomes neoplastic.
Several clinically significant endocrinopathies are seen fairly commonly in veterinary medicine. Frequent paraneoplastic endocrinopathies include: • Hyperthyroidism due to thyroid neoplasia in the cat.
• Cushing’s disease (hyperadrenocorticism) due to pituitary or adrenal cortical tumors in a variety
of species.
• Hypercalcemia due to tumors of the parathyroid glands.
• Hypercalcemia due to ectopic production of parathyroid hormone and parathyroid-hormone-
related protein by neoplastic tissue. In dogs, hypercalcemia is seen most frequently with
adenocarcinoma of the anal sac, lymphoma and multiple myeloma. In cats, hypercalcemia can
be associated to melanoma. In horses, hypercalcemia can be associated to squamous cell
carcinoma. Hypercalcemia presents clinically as muscle weakness, cardiac arrhytmia, anorexia,
vomiting and renal failure with polyuria and polydipsia.
• Hypoglycemia primarily due to insulinomas and in rare cases due to other neoplasms
(e.g. hepatic tumors). Hypoglycemia presents clinically mostly as neurologic signs, due to the
dependence of the nervous system on glucose.
• Hypergastrinemia and hyperhistaminosis due to mast cell tumors, especially mastocytosis
(cutaneous mast cell tumors rarely produce systemic signs). Hypergastrinemia can cause
gastroduodenal ulceration, abdominal pain, vomiting and weight loss. It is also known as
Zollinger- Ellison syndrome.
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| Skeletal syndromes | | | | | In the skeletal syndromes, hypertrophic osteopathy and myelofibrosis are of importance in veterinary medicine. • Hypertrophic osteopathy occurs in cats and dogs. Clinically, it presents as a symmetric
lameness and radiographically, extensive periosteal new bone growth is evident. Hypertrophic
osteopathy occurs with a variety of tumor types, although there is a strong association with
space-occupying neoplastic and non-neoplastic thoracic lesions. Etiologically, an abnormality
of growth hormone production is suspected, but nothing specific is known so far. • Myelofibrosis results from overgrowth of nonneoplastic fibroblasts in the bone marrow.
It may be associated with myeloproliferative disease or with distant tumors.
The cause for this condition is unknown.
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| Vascular and hematologic syndromes | | | | | Cancer of nonhematopoietic tissue can lead to a variety of vascular and hematologic syndromes, including eosinophilia and neutrophilic leukocytosis. The etiology of these conditions is unclear, but circulating cytokines are likely to be involved.
• Anemia is commonly seen in animals with neoplastic disease. The causes for anemia are
multiple and include chronic disease, bone marrow invasion, blood loss and hemolysis.
• Polycythemia has been reported and is associated with ectopic production of Erythropoietin,
especially by renal carcino mas.
• Leukocytosis was seen in dogs with pulmonary or renal carcinomas.
• Hypergammaglobulinemia occurs especially in dogs and cats with multiple myeloma, primary
macroglobulinemia and lymphoproliferative tumors.
• Thrombocytopenia is shown in approximately one third of dogs with cancer. The pathogenesis
of this paraneoplastic syndrome is manifold. Especially hemangiosarcomas, lymphomas and
melanomas bear the risk of thrombocytopenia. Thrombocytopenia is often associated with
neutropenia and anemia.
• Disseminated intravascular coagulation (DIC) can occur secondary to any large tumor and
especially in association with hematopoietic tumors or hemangiosarcomas.
• Anemia and DIC are frequently seen in dogs with hemangiosarcoma.
• Hyperviscosity syndrome can be the result of excessive production of immunoglobulins,
e.g. due to multiple myeloma. Hyperviscosity syndrome leads to altered neurologic function,
congestive heart failure or bleeding disorders.
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| Neurologic syndromes | | | | | Paraneoplastic neurologic syndromes in animals are usually related to hypercalcemia, hypoglycemia or hyperviscosity syndrome. The neurologic disorders often manifest as seizure activity. Primary peripheral nervous system disease has also been reported. • Myasthenia gravis can occur occasionally, usually in association with mediastinal tumors such
as thymoma. The underlying effect in Myasthenia gravis is a failure of nerve impulse
transmission at neuromuscular junctions.
• Peripheral neuropathy can be seen microscopically in many dogs with cancer, whereas clinical
symptoms are much less common.
• Polyneuropathy can occur rarely in dogs with insulinomas. In human medicine, many neurologic
syndromes are immune mediated. This is likely to be the case in animals as well.
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| Cutaneous syndromes | | | | | There are only few reports of cutaneous manifestations of paraneoplastic syndromes in dogs and cats. Unspecific symptoms like flushing, alopecia, amyloidosis, pruritus, exfoliative dermatitis, vasculitis, dermatomyositis or necrolytic dermatitis have been associated with a variety of tumor types.
The most important cutaneous paraneoplastic syndromes are:
• Feline paraneoplastic alopecia manifests as symmetrical, bilateral alopecia. The symmetrical
hair loss progresses from the ventrum to the head and to primarily the medial aspect of the
extremities. Often, the affected animals show concurrent signs of systemic illness. This
dermatosis has been reported in association with pancreatic carcinoma and biliary carcinoma.
• Feline thymoma-associated exfoliative dermatitis had been reported in six cases of cats with
thymoma. The lesion is characterized by diffuse erythema of the skin and exfoliation or scaling.
The lesions begin on the head and pinnae and then become generally distributed.
The underlying mechanism is unknown.
• Nodular dermatofibrosis is a paraneoplastic syndrome that has been described in Alsatians
and especially in German Shepards. It is suspected, that the disease is inherited in an
autosomal dominant pattern. The lesions consist of multiple, cutaneous nodules of collagenous
origin. Nodular dermatofibrosis is associated with renal cystade noma or cystadenocarcinoma.
The mechanism of the association between nodular der matofibrosis and renal cystic changes
is unclear.
• Feminization syndrome associated with testicular neoplasia is reported to occur in 24 - 57%
of dogs bearing sertoli cell tumors. Occasional reports describe the syndrome in association
with interstitial tumor or seminoma as well. The feminization syndrome is characterized by
various combinations of gynecomastia, attraction to other male dogs, pendulous prepuce, penile
atrophy, prostatic squamous metaplasia and myelosuppression in addition to skin changes.
The most important dermatologic changes are bilateral symmetric alopecia and thinning of the
epidermis. In addition to this, coat colour change, macular melanosis and preputial dermatosis
can occur.
• Superficial necrolytic dermatitis is a necrotizing skin condition in dogs that occurs in
association with internal disease. Superficial necrolytic dermatitis in dogs occur commonly in
association with hepatopathy, leading to the familiar name „hepatocutaneous syndrome“.
In addition to this superficial necrolytic syndrome can be associated with glucagonsecreting
neoplasia. Major dermatological findings include erosions and ulcerations, alopecia, exudation,
crusts and hyperkeratosis and fissuring of foot pads.
• Paraneoplastic pemphigus has only been reported in one case of a dog with mediastinal
lymphoma. The dog showed erosive and ulcerative lesions and cutaneous vesicobullous
lesions on the head, the extremities and the trunk. Paraneoplastic pemphigus therefore
represents a very rare lesion in veterinary medicine.
• Atrophic dermatitis (Cushing’s disease) can occur in animals with pituitary or adrenal cortical
tumors. In Cushing’s disease, the animals show alopecia, thin appearing skin and often
hyperpigmentation.
References:
1. McGavin and Zachary: Pathologic basis of veterinary disease, 2007, 4. Auflage, Mosby Elsevier
2. Kessler: Kleintieronkologie, 2005, 2. Auflage, Parey
3. Turek: Cutaneous paraneoplastic syndromes in dogs and cats: a review of the literature,
Vet. Dermatol. 2003, Dec;14(6):279-96
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| Symptom | Associated tumors (if known) | Systemic | Anorexia / cachexia | Numerous malignant neoplasms | Fever | Numerous neoplasms | Endocrine | Hypercalcemia | - Malignant lymphoma - Multiple myeloma - Anal sac carcinoma - Tumors with bone metastases - Tumors of the parathyroidea - Other carcinomas | Hypoglycemia | - Insulinoma - Liver tumors - Malignant lymphoma - Leukemia | Hypergastrinemia | - Gastrinoma - Mast cell tumor | Cushing’s disease | - Pituitary tumors - Adrenal cortical tumors | Thyrotoxicosis | | Hyperhistaminosis | | Hypercatecholaminemia | | Hyperestrogenism | | Skeletal | Hypertrophic osteoarthropathy | - Primary and metastatic lung tumors - Space-occupying thoracic lesions | Myelofibrosis | | Vascular / hematopoietic | Leukocytosis | - Numerous tumors | Thrombocytosis | | Thrombocytopenia | - Numerous tumors | Erythrocytosis | - Primary/metastatic renal tumors | Anemia | - Numerous tumors | Monoclonal Gammopathies | - Multiple myeloma - Malignant lymphoma - Lymphatic leukemia | Disseminated intravascular coagulation | - Numerous tumors, especially
hematopoietic tumors or
hemangiosarcoma | Leukopenia | | Neurologic | Polyneuropathy | - Insulinoma | Myasthenia gravis | - Thymoma | Peripheral neuropathy | | Cutaneous | Feline paraneoplastic alopecia | - Pancreatic or biliary carcinoma | Feline exfoliative dermatitis | - Thymoma | Nodular dermatofibrosis | - Renal cystic tumors | Feminization syndrome | - Testicular neoplasia | Superficial necrolytic dermatitis | - Hepatopathy - Glucagon-secreting tumors | Paraneoplastic pemphigus | - Mediastinal lymphoma | Atrophic dermatitis
(Cushing’s disease) | - Pituitary tumors - Adrenal cortical tumors | | |
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