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.

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.

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.
Cushings 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 ZollingerEllison syndrome.

Skeletal syndromes
In the skeletal syndromes, hypertrophic osteopathy and myelofibrosis are of importance in veterinary medicine.

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 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.

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.

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.

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 der-

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matofibrosis 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 (Cushings disease) can
occur in animals with pituitary or adrenal cortical tumors. In Cushings disease, the animals show alopecia, thin appearing skin and
often hyperpigmentation.

References:
1. McGavin and Zachary: Pathologic basis of veterinary
disease, 2007, 4th Edition, Mosby Elsevier
2. Kessler: Kleintieronkologie, 2005, 2nd Edition, 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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Systemic

Endocrine

Symptom

Associated tumors (if known)

Anorexia / cachexia

Numerous malignant neoplasms

Fever

Numerous neoplasms

Hypercalcemia

- Malignant lymphoma
- Multiple myeloma
- Anal sac carcinoma
- Tumors with bone metastases
- Tumors of the parathyroidea
- Other carcinomas

Hypoglycemia

Hypergastrinemia

- Gastrinoma
- Mast cell tumor

Cushings disease

- Pituitary tumors
- Adrenal cortical tumors

Insulinoma
Liver tumors
Malignant lymphoma
Leukemia

Thyrotoxicosis
Hyperhistaminosis
Hypercatecholaminemia
Hyperestrogenism
Hypertrophic osteoarthropathy

Skeletal

- Primary and metastatic lung tumors

- Space-occupying thoracic lesions

Myelofibrosis
Leukocytosis

- Numerous tumors

Thrombocytosis

Vascular /
hematopoietic

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
Thrombocytosis

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
(Cushings disease)

- Pituitary tumors
- Adrenal cortical tumors

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