Paraneoplastic Syndromes (Case 37: A Problem Set of Three Common Cases)

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Chapter 45
Paraneoplastic Syndromes (Case 37: A Problem Set of Three Common Cases)

Nishanth Sukumaran MD and Mary Denshaw-Burke MD

Case 1: A 70-year-old man presents to the ED with confusion and dehydration. Family members report a weight loss of 30 pounds over the last 6 months and increased forgetfulness over the last several weeks. He has a 50-pack-year smoking history. He has dry mucous membranes on examination. Laboratory values reveal a blood urea nitrogen (BUN) of 50 mg/dL, serum creatinine of 2.5 mg/dL, and serum calcium of 17 mg/dL. Chest radiograph shows a 5 cm × 4 cm mass in the right upper lobe.

Differential Diagnosis

Hypercalcemia and Abnormal Chest Radiograph

Tumor secretion of parathyroid hormone–related peptide (PTHrP)

Bone metastasis

Tumor secretion of calcitriol

Ectopic secretion of parathyroid hormone (PTH)

Case 2: A 65-year-old woman presents to the ED with progressive confusion. Laboratory values reveal serum sodium of 120 mEq/L, serum osmolality of 245 mOsm/kg water, urine osmolality of 600 mOsm/kg water, and urine sodium of 65 mmol/L. A CT scan of the chest shows a mass in the right middle lobe.

Differential Diagnosis

Hyponatremia in Malignancy

Poor dietary intake

Increasedt gastrointestinal losses from tumor or treatment

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

Renal failure or congestive heart failure secondary to chemotherapy

Adrenocortical insufficiency from tumor metastasis to adrenal glands

Case 3: A 68-year-old man presents to his family doctor with a 2-month history of dry cough. He also reports a 1-year history of difficulty in getting up from a chair and climbing stairs. He describes muscle aches and cramping, especially after long walks. Chest radiograph shows a left upper lobe mass.

Differential Diagnosis

Weakness in Malignancy

Asthenia

Brain metastasis

Lambert-Eaton myasthenic syndrome (LEMS)

Spinal metastasis with cord compression

 

Speaking Intelligently

Paraneoplastic syndromes are diseases or symptoms that are the consequence of the presence of cancer in the body, but they are not directly due to the local presence of cancer cells. These phenomena are mediated by humoral factors (hormones and cytokines) secreted by the tumor cells or an immune response directed against the tumor. Paraneoplastic syndromes may parallel the underlying malignancy, and successful treatment of the malignancy may lead to disappearance of the syndrome. However, many paraneoplastic syndromes, especially of immunologic or neurologic etiology, may not respond predictably to treatment of the underlying malignancy. Selected paraneoplastic syndromes are discussed in more detail in the Clinical Entities section.

PATIENT CARE

Clinical Thinking

• Paraneoplastic syndromes may be the presenting symptom in someone who has not yet been diagnosed with cancer or may develop during the course of treatment for cancer.

• The incidental finding of a possible paraneoplastic syndrome should lead to a prompt workup to rule out an underlying malignancy.

• The identification and treatment of the underlying malignancy not only improves symptoms from the paraneoplastic syndrome but also may improve survival if the malignancy is diagnosed at an earlier stage.

• In some patients with a known malignancy, the discovery of a paraneoplastic syndrome may indicate a worse outcome.

History

• Patients with paraneoplastic syndromes may be either acutely symptomatic needing emergent care or asymptomatic.

• Some patients present with mental status changes such as confusion and coma. The history can be obtained from the patient’s spouse or other family members in the event that the patient is too obtunded to provide any history.

• History of clinically significant weight loss, anorexia, and smoking should draw attention to malignancy as an underlying cause.

• Once a malignancy is suspected, it is imperative to elicit a focused history related to identifying the underlying malignancy.

• A history of drenching night sweats and pruritus could indicate a lymphoproliferative disorder.

• Symptoms such as hemoptysis, persistent cough, hoarseness, and shortness of breath could be indicative of a lung malignancy.

• History should always include questions regarding age-appropriate screening.

• A comprehensive social history including smoking, alcohol use, and occupational exposure to various chemicals should be obtained.

• Family history of malignancies, especially at a younger age, may indicate a genetic link.

Physical Examination

• Patients with hypercalcemia of malignancy have a very high serum calcium level and generally present with signs of volume depletion, such as hypotension, tachycardia, confusion, and dry mucous membranes.

• Patients with SIADH are euvolemic and may present with confusion.

• Patients with LEMS present with proximal muscle weakness.

• The presence of confluent macular erythema (heliotrope rash) and discrete erythematous papules overlying the metacarpophalangeal and interphalangeal joints (Gottron papules) suggests a diagnosis of dermatomyositis, which may be associated with an underlying malignancy.

• Brown to black velvety hyperpigmentation of skin, usually found in body folds, is termed acanthosis nigricans. When seen in individuals over 40 years of age, it is suggestive of an internal malignancy, especially of the gastrointestinal tract.

• Explosive onset of multiple seborrheic keratoses (sign of Leser-Trélat) is a sign of possible internal malignancy of the gastrointestinal tract, breast, or lung.

• Physical exam findings suggesting malignancy also include clubbing, lymphadenopathy, palpable breast mass, and hepatosplenomegaly.

Tests for Consideration

• Comprehensive metabolic profile: Used to diagnose hyponatremia, hypercalcemia, and renal failure either secondary to hypercalcemia or from volume depletion.
It may also provide a clue to diagnosis of underlying pancreatic and hepatobiliary malignancies.

$12

• CBC with differential count: Eosinophilia is commonly associated with Hodgkin lymphoma and mycosis fungoides.
Basophilia is associated with chronic myelogenous leukemia and other myeloproliferative disorders.

$11

IMAGING CONSIDERATIONS

→ Chest radiograph, CT scanning, and MRI can help identify the tumor. They are most often used along with bone scans or PET to stage tumors.

$45, $334, $534, $247, $1037

 

Clinical Entities Medical Knowledge

Hypercalcemia of Malignancy

Pφ

There are four subtypes of malignancy-associated hypercalcemia: (1) local osteolytic hypercalcemia due to bone metastases from solid tumors or marrow invasion by primary hematologic malignancies, typically in patients with lymphoma, myeloma, and breast cancer; (2) hypercalcemia due to production of calcitriol (1,25(OH)2D) by lymphomas; (3) ectopic secretion of authentic PTH by rare malignancies (ectopic hyperparathyroidism); and (4) humoral hypercalcemia of malignancy (HHM).

Paraneoplastic syndrome–related hypercalcemia includes all of the above except local osteolytic hypercalcemia. HHM is caused by systemic secretion of PTHrP by malignant tumors; it is commonly associated with squamous cell carcinoma of the lung. Some tumors also cause hypercalcemia by secretion of cytokines such as transforming growth factor-β, tumor necrosis factor-α, and interleukin-1.

TP

Patients with mild hypercalcemia (<12 mg/dL) may be asymptomatic or present with nonspecific symptoms such as fatigue, depression, and constipation. However, patients with hypercalcemia associated with malignancy present with much higher calcium levels and are frequently obtunded. They usually present with confusion and even coma. Although these patients usually have a known malignancy, hypercalcemia may be the presenting finding leading to diagnosis.

Dx

The following is the diagnostic approach to hypercalcemia:

• Serum calcium is bound to albumin, and the measured total calcium levels may be underestimated or overestimated depending on decreases or increases in albumin. A rough estimation of corrected calcium is determined by adding 0.8 mg/dL to total calcium for every 1 mg/dL of serum albumin below 3.5 mg/dL.

• Serum ionized calcium measurement should be considered when there is doubt about the validity of the total calcium measurement.

• Intact PTH should be routinely measured in all cases of hypercalcemia. Levels are elevated in primary hyperparathyroidism and some cases of HHM, where the tumor produces PTH. However, in most cases of HHM, the serum PTH is normal.

• Although most patients with HHM have elevated levels of PTHrP, the diagnosis is usually obvious on clinical grounds. Therefore, PTHrP measurement should be undertaken only in the few cases where the diagnosis is uncertain.

• Plasma 1,25(OH)2D should be measured when sarcoidosis, other granulomatous disorders, or the 1,25(OH)2D lymphoma syndrome is considered in the differential diagnosis

Tx

The following is the approach to management of hypercalcemia of malignancy:

• General measures include discontinuation of calcium from parenteral feeding solutions, discontinuation of medications that cause hypercalcemia (e.g., calcium and vitamin D supplements, thiazide diuretics, and lithium), increased weight bearing by the patient if possible, and discontinuation of sedative medications.

• Normal saline, at a rate of 200–500 mL/hr, should be administered depending on the degree of hypercalcemia, baseline level of volume depletion, renal impairment, and cardiovascular status.

• Loop diuretics are administered only after full hydration is achieved. Loop diuretics such as furosemide block the reabsorption of calcium in the loop of Henle, aiding in the excretion of calcium.

• Bisphosphonates work by blocking osteoclastic bone resorption. As oral bisphosphonates are poorly absorbed, only IV preparations are used for hypercalcemia. In the United States, the two drugs approved for use by the Food and Drug Administration (FDA) in mild to severe hypercalcemia are pamidronate and zoledronic acid.

• Serum phosphate and creatinine should be closely monitored to keep phosphate levels between 2.5 and 3.0 mg/dL, serum creatinine in the normal range, and the calcium × phosphate product in the range of 30–40.

• Agents such as glucocorticoids, calcitonin, and mithramycin are either infrequently used or are used when the use of bisphosphonates is ineffective or contraindicated.

• In selected patients who are likely to respond to treatment but have acute or chronic renal failure, and aggressive fluid infusion is not possible, dialysis may be a reasonable option. See Cecil Essentials 24, 58, 74.

 

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Pφ

ADH is secreted from the posterior pituitary gland to prevent water loss in the kidneys. When water is ingested, the resulting dilution of plasma and decrease in plasma osmolality is sensed by the osmoreceptors in the hypothalamus, and ADH secretion is switched off. In SIADH, the release of ADH is not inhibited by decreased plasma osmolality. The principal malignancy associated with SIADH is small cell lung cancer, accounting for 75% of the cases. Other less frequently associated malignancies include those of the duodenum, pancreas, and head and neck. The tumors cause ectopic secretion of ADH leading to symptoms and signs of SIADH.

TP

Most patients are asymptomatic or experience minimal symptoms, and hyponatremia is discovered incidentally on routine laboratory evaluation. When symptoms develop, they generally reflect central nervous system toxicity. In early stages patients complain of fatigue, headaches, anorexia, and mild altered mental status. As the syndrome progresses, patients may experience continued delirium, confusion, and seizures. Ultimately, patients may suffer refractory seizures or coma, and, in rare cases, death.

Dx

Patients with SIADH present with hyponatremia and are found to have a low serum osmolality and elevated urine osmolality. The urine sodium concentration is usually >40 mEq/L. The serum BUN and uric acid concentrations are low, with normal acid-base and potassium balance. Patients have normal renal, adrenal, and thyroid function.

Tx

Asymptomatic hyponatremia is treated with fluid restriction of 500 to 1000 mL/day. Severe, symptomatic, or resistant hyponatremia requires administration of 3% hypertonic saline, the effects of which can be enhanced if given with a loop diuretic. The rate of correction should not exceed 8–10 mEq/L on any day of treatment to prevent the development of central pontine myelinolysis. Demeclocycline can be used in resistant cases. Conivaptan, a vasopressin receptor antagonist, was approved by the FDA for treatment of hypervolemic hyponatremia. Treatment of small cell carcinoma of the lung with chemotherapy is generally associated with improvement of SIADH. See Cecil Essentials 28, 58.

 

Lambert-Eaton Myasthenic Syndrome

Pφ

LEMS is an autoimmune disorder associated with antibodies directed against the presynaptic voltage-gated calcium channels (VGCCs) of the neuromuscular junction. Blockade of calcium channels leads to inhibition of acetylcholine release from the presynaptic vesicles, thus affecting muscle contraction. Approximately 50% of LEMS cases are associated with small cell carcinoma of lung.

TP

Patients present with slowly progressive proximal muscle weakness. The typical presentation is that of alteration in gait, as well as difficulty rising from a chair or climbing stairs. Muscle aches and cramping are common. Autonomic dysfunction is often present and could be a clue to diagnosis. Dry mouth is the most common autonomic symptom, and erectile dysfunction is common in men. In contrast to myasthenia gravis, the symptoms of LEMS are worse in the morning and improve as the day progresses.

Dx

Maximal isometric contraction of the relevant muscles for 10–15 seconds can lead to temporary improvement of muscle weakness, a phenomenon known as post-exercise or post-activation facilitation. Radioimmunoassay is utilized to detect antibodies against the VGCCs. An incremental response to repetitive nerve stimulation on electrophysiologic studies is also observed.

Tx

Treatment of underlying malignancy is essential in the treatment of paraneoplastic LEMS. Often, this may be the only treatment needed. For mild symptomatic disease, pyridostigmine, either alone or in combination with 3,4-diaminopyridine or guanidine, can be used. Immunosuppressive agents such as corticosteroids and azathioprine have been used with limited success. More significant or refractory weakness may require treatment with IV immunoglobulin or plasmapheresis. See Cecil Essentials 24, 58, 132.

 

 

Practice-Based Learning and Improvement: Evidence-Based Medicine

Title
Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials

Authors
Major P, Lortholary A

Institution
Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada

Reference
J Clin Oncol 2001;19:558–567

Problem
Is zoledronic acid superior to pamidronate in the treatment of hypercalcemia of malignancy?

Intervention
Patients were randomized to treatment with either a single dose of zoledronic acid (4 or 8 mg) via a 5-minute IV infusion or pamidronate (90 mg) via a 2-hour IV infusion.

Comparison/control
Two identical, concurrent, parallel, multicenter, randomized, double-blind trials were conducted at centers in the United States/Canada and Europe/Australia. A total of 287 patients were randomized in the two trials.

Quality of evidence
Level I

Outcome/effect
Zoledronic acid was found to be superior to pamidronate. Zoledronic acid at a dose of 4 mg is the dose recommended for initial treatment of hypercalcemia of malignancy and 8 mg for relapsed or refractory hypercalcemia. The safety profile of zoledronic acid was similar to that of pamidronate. However, renal adverse events were reported somewhat more frequently in the zoledronic acid groups compared to the pamidronate groups.

Historical significance/comments
Before this study, pamidronate was the standard of care for hypercalcemia of malignancy. This study proved that zoledronic acid provides a more effective and more convenient treatment for hypercalcemia of malignancy.

 

Interpersonal and Communication Skills

Deliver News of Worsening Prognosis in a Sensitive Manner

The diagnosis of a paraneoplastic syndrome may lead to discovery of a new cancer or may suggest a poorer prognosis in a patient known to have a malignancy. Breaking news about an underlying cancer is the most critical conversation you will have with your patient. Be prepared that patients will respond in various ways including denial, anger, intellectualization, and feelings of guilt. It is important to recognize these various responses, and it is vital to approach the subject as sensitively and empathetically as possible. When possible, and at the discretion of the patient, family members and other supportive persons should be present during these conversations, which may help to comfort the patient when first hearing about the diagnosis of cancer. When concluding initial discussions, it is important to assure both the patient and family that you will be available to answer follow-up questions as they arise.

 

Professionalism

Telephone Challenges: Maintain Patient Confidentiality

When you give a diagnosis of cancer to a patient, it is necessary to state the facts honestly and sensitively, and the patient’s confidentiality must be respected at all times. You must ask the patient specifically with which family members and/or friends you may discuss medical issues. Especially when a patient is in the intensive care unit, it is not uncommon that the physician will end up fielding phone calls from those inquiring about the patient’s condition. While it may seem difficult or unfair, unless you have specific permission to discuss the matter with the caller, the correct answer is to state that you are unable to discuss the patient’s medical issues with anyone without the patient’s permission.

 

Systems-Based Practice

Consider Costs and Benefits When Prescribing Medications

In the United States there are two drugs that are approved for use in hypercalcemia of malignancy and considered agents of choice in mild to severe hypercalcemia: pamidronate (Aredia) and zoledronic acid (Zometa). Although a relative superiority of zoledronic acid over pamidronate has been demonstrated, these differences may be of minor clinical significance for the individual patient. The choice of one agent over the other is currently based on convenience and cost. The standard dose of zoledronic acid is 4 mg given over a 15-minute period, whereas pamidronate is given at a dose of 60–90 mg over a 2-hour period. Pamidronate is currently less expensive; however, zoledronic acid is more convenient to use. Both agents have been associated with impairment of renal function, and monitoring of renal function should be a routine practice.

Suggested Readings

AAEM Quality Assurance Committee. American Association of Electrodiagnostic Medicine. Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome. Muscle Nerve 2001;24:1239–1247.

Burtis WJ, Wu TL, Insogna KL, Stewart AF. Humoral hypercalcemia of malignancy. Ann Intern Med 1988;108:454–457.

Dau PC, Denys EH. Plasmapheresis and immunosuppressive drug therapy in the Eaton-Lambert syndrome. Ann Neurol 1982;11:570–575.

Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 2007;356:2064–2072.

Fleisch H. Bisphosphonates: mechanisms of action (review). Endocr Rev 1998;19:80–100.

Johnson BE, Chute JP, Rushin J, et al. A prospective study of patients with lung cancer and hyponatremia of malignancy. Am J Respir Crit Care Med 1997;156:1669–1678.

Lang B, Newsom-Davis J, Wray D, et al. Autoimmune etiology for myasthenic (Eaton-Lambert) syndrome. Lancet 1981;2:224–226.

Major P, Lortholary A. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19:558–567.

Motomura M, Johnston I, Lang B, et al. An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. Neurol Neurosurg Psychiatr 1995;58:85–87.

Ralston SH, Gallagher SJ, Patel U, et al. Cancer-associated hypercalcemia: morbidity and mortality: clinical experience in 126 treated patients. Ann Intern Med 1990;112:499–504.

Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG. Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia. Lancet 1992;339:164–167.

Robertson GL. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. Am J Med 2006;119(7 Suppl 1):S36-S42.

Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol 2009;29:282–299.

Stewart AF. Hypercalcemia associated with cancer. N Engl J Med 2005;352:373–379.

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