The cancer cells, also called neoplastic cells, are cells that have all the chemical constituents of normal cells but have not differentiated properly or totally so that they can contribute to the normal function of the organ system in which it has developed. Also sometimes it releases some chemical constituents in the bloodstream that can elicit unnecessary responses in the body. These responses are a result of the stimulation of hormonal, hematologic, dermatologic, rheumatologic, renal and neurologic factors. The term paraneoplastic syndromes refer to the disorders that accompany benign and malignant tumors but are not directly related to mass effects or invasion. Tumors of neuroendocrine origin, such as small-cell lung carcinoma (SCLC) and carcinoids are common causes of paraneoplastic syndromes, and produce a wide variety of peptide hormones and antibodies. This doesn’t mean that the hormones are produced by only these tumors; potentially every tumor has the ability to produce hormones or to induce cytokine and immunologic responses. 

Paraneoplastic syndromes are more prevalent than anticipated. The signs, symptoms and metabolic alterations associated with paraneoplastic disorders may be overlooked in the context of a malignancy and its treatment. If any atypical clinical manifestations are observed in a cancer patient, the presence of a paraneoplastic syndrome should be considered.

Endocrine paraneoplastic syndromes:

The endocrine responses are elicited by chemical substances in our body called hormones. The normal source from where the hormone is produced is called the eutopic source whereas the source other than the original from where the hormone is produced is called the ectopic source. For example, ACTH (Adrenocorticotropic hormone) is produced eutopicallyfrom the cells situated in the anterior pituitary gland, but it can be expressed ectopically in SCLC. This unnecessary production of hormone can elicit unwanted responses. 

The ectopic expression of hormones might be considered just as an epiphenomenon associated with cancer if it doesn’t result in clinical manifestations. But the excessive production of some hormones like ACTH, PTHrP (Parathyroid hormone related protein) and vasopressin can lead to significant morbidity and complicate the cancer treatment plan. Moreover the presence of paraneoplastic endocrinopathies may be suggestive of underlying malignancy and prompt the search for an unrecognized tumor.

Hematologic paraneoplastic syndromes:

The hematologic paraneoplastic syndromes are not as well characterized as the endocrine ones because in the latter the ectopic hormones responsible are identified. 

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Endocrine paraneoplastic syndromes:
A large number of paraneoplastic endocrine syndromes have been described, linking overproduction of particular hormones with specific types of tumors. However, certain syndromes are recurring. The most common paraneoplastic syndromes include hypercalcemia (excess calcium) from overproduction of PTHrP and other factors, hyponatremia (low sodium) from excess vasopressin, and Cushing’s syndrome from ectopic ACTH.

The common paraneoplastic syndromes are:

  • Hypercalcemia of malignancy
  • It is caused by the overproduction of ectopic hormones PTHrP (Parathyroid hormone-related protein, 1,25-dihydroxyvitamin D, and rarely by parathyroid hormone and prostaglandin E2 (PGE2)
  • Typical tumor types that secrete these ectopic hormones include squamous cell carcinomas of head and neck, and breast cancer that secrete PTHrP; lymphomas that secrete 1,25-dihydroxyvitamin D; lung and ovary that secrete parathyroid hormone; and renal and lung that secrete prostaglandin E2 (PGE2)
  • Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
  • The ectopic hormone responsible is vasopressin which is secreted by lung (squamous and small cell), gastrointestinal, genitourinary and ovarian cancers
  • Cushing’s syndrome
  • It is caused by the overproduction of ACTH (Adrenocorticotropic hormone) which is secreted by lung cancer (small cell, bronchial carcinoid, adenocarcinoma, squamous), thymictumor, pancreatic islet tumor, medullary thyroid carcinoma and pheochromocytoma
  • The rare expression of hormone is CRH (Corticotropin releasing hormone) which is secreted by pancreatic islet tumor, carcinoid, lung cancer and prostate cancer
  • The other hormones responsible are ectopic expression of gastric inhibitory peptide (GIP), luteinizing hormone (LH)/human chorionic gonadotropin (hCG), and very rarely GPCRs (G-protein coupled receptors). These rare ectopic expression is usually caused by macronodular adrenal hyperplasia

The less common paraneoplastic syndromes are:

  • Non-islet cell hypoglycaemia (low blood sugar)
  • Male feminization
  • Diarrhea or intestinal hypermotility

The rare paraneoplastic syndromes are:

  • Oncogenic osteomalacia (softening of the bones)
  • Acromegaly (caused by overproduction of growth hormone)
  • Hyperthyroidism
  • Hypertension
  • Consumptive hypothyroidism


The treatment approaches for different types of paraneoplastic syndromes are as follows:

Hypercalcemia treatment focusses on the removal of excess calcium. In severe cases, calcitonin administration should be done.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) causes hyponatremia in patients and so treatment focusses on inhibiting vasopressin secretion by administering drugs like demeclocycline and the vaptan class of drugs. 

Cushing’s syndrome is caused by the overproduction of ACTH and causes significant morbidity. Extreme cortisol excess that accompanies may cause depression or personality changes in patients. Metabolic derangements like diabetes mellitus and hypokalemia (low potassium) can worsen fatigue. Surgical management of tumors may be complicated because of poor wound healing and predisposition to infections. Opportunistic infections caused by organisms such as Pneumocystis cariniiand mycoses are often the cause of death in patients with ectopic ACTH production. These patients likely have increased risk of venous thromboembolism reflecting the combination of malignancy and altered coagulation factor profiles. Cortisol levels reduction is usually indicated depending on prognosis and treatment plans for the underlying malignancy. The treatment may bring down ACTH to acceptable levels but is rarely sufficient to reduce cortisol levels to normal. Drugs administered are ketoconazole, metyrapone, mitotane or other agents that block steroid production for treating hypercortisolism associated with ectopic ACTH production. Glucocorticoid replacement should be provided to prevent adrenal insufficiency.

The other paraneoplastic syndromes are either less common or rare and involves ameliorating the symptoms and reduce the hormone that are causing them.

Hematologic paraneoplastic syndromes:

The usual hematologic problems that are encountered as paraneoplastic syndromes are:

Erythrocytosis caused by the ectopic production of erythropoietin by cancer cells. Treatment involves successful resection of the tumor. If surgery, chemotherapy or other conventional therapies are not possible then phlebotomy may control many of the symptoms.

Granulocytosis is present in approximately 30% of the patients with solid tumors. 50% of these have identifiable nonparaneoplastic etiology like tumor necrosis, infection, glucocorticoid administration, etc. The other patients have proteins in urine and serum that stimulate growth of bone marrow cells. Patients with granulocytosis are usually asymptomatic and require no treatment.

Thrombocytosis is present in 40% of patients with lung and gastrointestinal cancers; 20% of patients with breast, endometrial and ovarian cancers; and 10% of patients with lymphoma. Patients with thrombocytosis are more likely to have advanced-stage disease and have a poorer prognosis than do patients without thrombocytosis. Paraneoplastic thrombocytosis does not require treatment other than the treatment of the tumor.

Eosinophilia is present in approximately 1% of patients with cancer. These patients are usually asymptomatic. It is present in 10% of patients with lymphoma, 3% of patients with lung cancer, and occasional patients with cervical, gastrointestinal, renal, and breast cancer. Some of these patients who have marked elevated eosinophil counts develop shortness of breath and wheezing. The treatment is to treat the underlying tumor.

Thrombophlebitis and deep venous thrombosis is are often present with deep venous thrombosis and pulmonary embolism being the most common thrombotic conditions present in cancer patients. The coexistence of peripheral venous thrombosis with visceral carcinoma, particularly pancreatic cancer, is called Trousseau’s syndrome. The most common treatment approach used is administration of unfractionated heparin or low-molecular weight heparin followed with warfarin

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