Paraneoplastic Syndromes      Paraneoplastic Syndromes   PDF  (106 KB)

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. 
 
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. 
      

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. 
           

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 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

   

 

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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