Anna R. Hollis
Paraneoplastic Syndromes
A paraneoplastic syndrome is a disease or clinical sign that arises consequent to neoplasia, but is not caused by the local presence of neoplastic cells. The pathophysiology is complex. These signs are mediated by hormones or cytokines produced by the tumor cells, depletion of essential substances such as iron, or an immune response to the tumor. In many cases, it is not possible to elucidate a definitive pathophysiologic cause. The reported frequency of paraneoplastic syndromes in humans with neoplasia ranges from 2% to 20%, and the syndromes may be seen with any type of neoplasia. However, they are most commonly found with cancer of the lung, breast, ovaries, and lymphatic system (lymphoma). Paraneoplastic syndromes often precede the detection of an active malignancy, and thorough investigation is therefore warranted to determine the cause of any clinical sign for which the cause is not immediately apparent. Recognition of paraneoplastic syndromes is particularly important because they can occur early in the course of neoplastic disease, facilitating early tumor discovery. The severity of the paraneoplastic abnormality may reflect the tumor burden. This means that improvement or resolution of the paraneoplastic syndrome indicates a reduction of tumor burden, which can be useful for monitoring purposes. In addition, treatment of the metabolic abnormalities associated with some paraneoplastic syndromes may be required to ensure effective management of the neoplasia. In some instances, the clinical signs of paraneoplastic disease may be more significant than those directly caused by the initiating tumor.
Paraneoplastic syndromes are broadly classified into the following categories: miscellaneous (nonspecific), rheumatologic, renal, gastrointestinal, hematologic, cutaneous, endocrine, and neuromuscular. This diversity of paraneoplastic syndromes highlights the need for a thorough clinical workup of any unexplained clinical sign or hematologic or biochemical abnormality. Paraneoplastic syndromes are a growing area of interest in equine internal medicine. Most of the clinical presentations described in this chapter have more common nonneoplastic causes, but paraneoplastic syndromes can produce a complex and challenging clinical problem for the equine clinician.
Paraneoplastic Syndromes with Miscellaneous Manifestations
Cancer cachexia is extremely debilitating and can be life threatening. It is one of the most common paraneoplastic syndromes associated with neoplasia in humans, and it is associated with a poor prognosis. The etiology of cancer cachexia is complex, and contributing factors include anorexia, impaired digestion, increased muscle breakdown with impaired muscle synthesis, increased nutritional demand caused by neoplastic tissue demands, nutrient losses in effusions or exudates, inflammation, and a variety of metabolic and endocrine derangements. Many humoral factors contribute to the development of cancer cachexia. The syndrome is recognized clinically as severe weight loss from wasting of muscle and fat, often accompanied by muscle weakness and fatigue. This negatively affects the quality of life. An increase in the plane of nutrition alone will not reverse the process, and a great deal of interest exists at present in the development of pharmaceutical agents to antagonize the peripheral melanocortin actions believed to be important in the pathogenesis of cancer cachexia. No such agents are commercially available at present.
Pyrexia is a well-recognized paraneoplastic syndrome that is particularly common in lymphoma. Nonspecific intermittent or remittent fevers are observed, the pathogenesis of which is not completely understood. Interleukin-1 (IL-1), IL-6, and tumor necrosis factor are pyrogenic and are produced in cell culture by some tumor cell lines. They cause pyrexia by inducing synthesis of prostaglandin E2 in vascular endothelial cells in the hypothalamus, affecting the function of temperature-regulating neurons.
Tumor lysis syndrome is an oncologic emergency characterized by severe metabolic derangements. It is most commonly seen in human patients with lymphoproliferative tumors who are undergoing tumor treatment, but occasionally occurs in the absence of therapy. Tumor lysis syndrome is caused by rapid tumor cell turnover or extensive destruction of tumor cells, resulting in the release of intracellular ions and metabolic byproducts into the systemic circulation. The most common abnormalities are hyperkalemia, hyperuricemia, and hyperphosphatemia. Although rare in veterinary patients, acute renal failure is a common sequela, and tumor lysis syndrome should be considered in any equine patient presenting with signs of both renal failure and neoplasia.
Amyloidosis is a paraneoplastic manifestation of plasma cell tumors, especially multiple myelomas. Systemic light-chain amyloidosis in the nasal cavity and cutaneous amyloidosis have been reported in horses with multiple myeloma, plasmacytoma, lymphoma, and adenomas. Any case of unexplained reactive amyloidosis should prompt a full malignancy investigation, although the primary neoplasia can be difficult to identify.