Continuing Education Activity

Paraneoplastic syndromes are rare disorders with complex systemic clinical manifestations due to underlying malignancy. In paraneoplastic syndromes, the malignant cells do not directly cause symptoms related to metastasis; rather, they generate autoantibodies, cytokines, hormones, or peptides that affect multiple organ systems. Symptoms can manifest before or after the diagnosis of cancer. Prompt recognition of these syndromes is critical as it may reveal hidden malignancy, affecting clinical outcomes. This activity illustrates the evaluation and need for early recognition of paraneoplastic syndromes and highlights the role of the interprofessional team in evaluating patients with this complex medical condition.

Objectives:

• Describe the etiologies of the paraneoplastic syndromes.
• Explain how to evaluate a patient for paraneoplastic syndrome.
• Review the treatment options available for paraneoplastic syndromes.
• Summarize the importance of interprofessional teams in improving care coordination and outcomes for patients with paraneoplastic syndromes.

Introduction

Paraneoplastic syndromes are rare disorders with complex systemic clinical manifestations from an occult malignancy causing an altered immune system. In other words, malignant cells do not directly manifest symptoms of metastasis. Instead, they generate autoantibodies, cytokines, hormones, or peptides that affect multiple organ systems such as neurological, dermatological, gastrointestinal, endocrine, hematologic, and cardiovascular systems.[1] Symptoms can manifest before or after the diagnosis of cancer. Therefore, clinicians must recognize these syndromes to promptly diagnose the occult malignancy and improve patient clinical outcomes.

Etiology

Paraneoplastic syndromes are secondary to an occult malignancy, but the exact mechanism remains unclear. These syndromes commonly manifest in patients with lung cancer, breast cancer, hematological malignancies, medullary thyroid cancer, gynecological malignancies, and prostate cancer.[2][3]

Epidemiology

The precise incidence and prevalence of paraneoplastic syndrome are unknown because of the rarity of the disease; however, it can occur with any malignancy. A literature review suggests that paraneoplastic syndrome occurs in up to 8% of cancer patients.[4] Neurological manifestations in the form of neuropathies are the most common presentation. Males and females are affected equally.

Pathophysiology

Tumor cells are immunogenic and lead to the activation of both cell-mediated and humoral immune systems. It is noted that cytotoxic T cells recognize antigens on tumor cells and attack those cells or generate antibodies against the tumor cells. [5] However, the body's immune system can attack normal tissue with a similar antigen presentation and lead to symptoms. Most cases exhibit paraneoplastic syndrome with immunologic mechanisms; however, there are non-immunologic mechanisms of paraneoplastic syndrome. Paraneoplastic syndrome has heterogeneous manifestations affecting multiple organ systems in the body. Clinical manifestation does not necessarily associate with the clinical or pathological stage of the underlying malignancy, nor is it a prognostic indicator.[6] Paraneoplastic syndromes may evolve from immunologic or non-immunologic mechanisms.

Immunologic Mechanisms

Cell-mediated immunity, T cells attack tumor cell antigens and similar antigens in normal cells. Paraneoplastic antibodies, also known as onconeural antibodies, develop against a target receptor antigen (onconeural antigen) such as type-1 antineuronal nuclear (ANNA-1) antibodies, type-2 antineuronal nuclear (ANNA-2) antibodies, collapsing response mediator protein-5 (CRMP-5) antibodies, Purkinje cell cytoplasmic antibody type-1 (PCA-1) antibodies, anti-amphiphysin antibodies, anti-recoverin antibodies, anti-bipolar cells of the retina antibodies, anti-N-methyl D-aspartate (NMDA) receptor antibodies, anti-acetylcholine (Ach) receptor antibodies, and anti-gamma-aminobutyric acid A (GABA-A) receptor antibodies.

Non-Immunologic Mechanisms

Tumor cells produce hormones or cytokines leading to metabolic abnormalities such as hyponatremia due to excessive secretion of antidiuretic hormone or hypercalcemia due to the excessive parathyroid hormone-related peptide. In addition, hematological malignancies produce immunoglobulins that affect the peripheral nervous system and manifest as peripheral neuropathy.

History and Physical

Paraneoplastic syndromes may involve multiple organ systems with heterogeneous and complex clinical manifestations in the setting of an occult malignancy.

Clinical presentations are categorized based on the organ system as follows.

Neurological

Paraneoplastic syndromes may affect the central nervous system, neuromuscular junction, or peripheral nervous system and present accordingly.[7]

When the central nervous system is involved, patients may present with:

• Paraneoplastic Encephalitis/encephalomyelitis: This syndrome may include cerebellar encephalitis, brainstem encephalitis, limbic encephalitis, and myelitis. Patients may present with cognitive dysfunction, depression, personality changes, hallucinations, seizures, somnolence, autonomic dysfunction, and less common endocrine dysfunction if the hypothalamus is involved.[8] 
• Subacute cerebellar degeneration: It is commonly associated with breast cancer, small cell lung cancer, Hodgkin lymphoma, and ovarian cancer and clinically manifested as ataxia, dysarthria, dysphagia, diplopia, dizziness, nausea, and vomiting. It is caused by Anti-Hu antibodies or anti-voltage gated calcium channel (anti-VGCC) antibodies that cross-react with cerebellar antigens.
• Opsoclonus-myoclonus syndrome: Clinically characterized by uncontrolled rapid eye movement, body jerks, ataxia, hypotonia, irritability, and commonly affects children less than four years. Opsoclonus is the common manifestation in children, whereas ataxia is more prominent in adults.

When the neuromuscular junction is involved, patients may present with:

• Myasthenia gravis: Most commonly seen in patients with thymoma and is clinically manifested as a weakness of voluntary muscles and diaphragmatic weakness. Anti-AchR (acetylcholine receptor) antibody is positive in those patients, and electromyography (EMG) shows a decremental response to repetitive nerve stimulation.[9]
• Lambert-Eaton myasthenic syndrome (LEMS): It is caused due to impairment of voltage-gated calcium channels (VGCC) due to autoantibodies on the presynaptic membrane at the neuromuscular junction, which leads to decreased acetylcholine release.[9]  LEMS is strongly associated with small cell lung cancer (SCLC), about 3% of patients develop LEMS, and it can occur at any stage of the disease. Clinically LEMS is characterized by weakness of the proximal muscles predominantly affecting thigh and pelvic muscles; patients generally have difficulty in strenuous activity; moreover, patients also have difficulties in basic activities such as climbing stairs, walking, and getting up from a chair. Symptoms are gradual in onset with slow progression. Patients also demonstrate autonomic symptoms such as dry mouth, decreased sweating, and constipation. Clinical examination is positive for diminished tendon reflexes. The blood anti-VGCC antibodies are positive in approximately 85% of patients with LEMS. EMG shows an improved response to repetitive nerve stimulation.

When the peripheral nervous system is involved, patients may present with:

• Autonomic neuropathy: Frequently associated with SCLC and thymoma. Autonomic neuropathy affects parasympathetic, sympathetic, and enteric nervous systems. It is characterized by dry mouth, dry eyes, altered pupillary reflexes, bladder or bowel dysfunction, and orthostatic hypotension. A patient may also manifest as chronic gastrointestinal (GI) pseudo-obstruction leading to constipation, nausea, vomiting, dysphagia, and abdominal distension.
• Subacute sensory neuropathy: is characterized by paresthesias, neuropathic pain, decreased sensation, and diminished deep tendon reflexes. It affects both the upper and the lower extremities; distribution can be either multifocal, asymmetric, or symmetric.

Endocrine

Mainly involved due to ectopic adrenocorticotropic hormone (ACTH), ectopic antidiuretic Hormone (ADH), and ectopic parathyroid hormone-related peptide (PTHrP) secretion by the tumor cells.

• Cushing syndrome: caused by elevated ectopic adrenocorticotropic hormone (ACTH) due to tumor cells. It is manifested as muscle weakness, weight gain, peripheral edema, centripetal fat distribution, and high blood pressure.[10] Blood workup is significant for hypokalemia and elevated cortisol levels.
• Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): It is more frequently seen in SCLC patients and caused due to ectopic anti-diuretic hormone (ADH) by tumor cells.[11] Clinical manifestations vary from mild symptoms such as nausea, anorexia, fatigue, and lethargy to severe symptoms like confusion, seizures, respiratory depression, and coma. Laboratory findings are positive for hyponatremia, hyperosmolality, and increased urine osmolality.
• Hypercalcemia is frequently associated with lung cancer, multiple myeloma, and renal cell carcinoma. Hypercalcemia is mediated by different mechanisms, such as the ectopic production of the parathyroid hormone-related peptide (PTHrP) by tumor cells. Due to excessive PTH-like activity, these patients also have co-existing hypophosphatemia. Patients present with generalized weakness, lethargy, nausea, vomiting, altered mental status, bradycardia, acute renal failure, hypertonia, and hypertension. They have diminished deep tendon reflexes and a short QT interval on an electrocardiogram.
• Non-islet tumor hypoglycemia: It is also called "Doege-Potter syndrome" caused due to secretion of insulin-like substance or big IGF-II in fibrosarcoma, other mesenchymal sarcomas, and hepatocellular carcinoma.[12]
• Carcinoid syndrome: Carcinoid syndrome: is due to ectopic secretion of serotonin or bradykinin. It is mainly seen in carcinoid-type bronchial adenoma, pancreatic carcinoma, and gastric carcinoma. [13]
• Hyperaldosteronism: It is caused due to excessive secretion of aldosterone, mainly in patients with adrenal adenoma, Non-Hodgkin's lymphoma, and ovarian carcinoma.[14]

Rheumatological  [15] [16]

• Paraneoplastic polyarthritis commonly involves large joints and is characterized by migratory, non-erosive, asymmetric polyarthritis.[15][16]
• Polymyalgia rheumatica: Manifested as pain and stiffness in the shoulder girdle, neck, and hip girdle.[17] It is most commonly associated with myelodysplastic syndrome.
• Multicentric reticulohistiocytosis: Clinically characterized by papules, nodules, and destructive polyarthritis.
• Hypertrophic osteoarthropathy: Clinically manifested as digital clubbing, joint swelling, and pain.[15][16]

Hematological

Patients may be asymptomatic but can present with pallor, fatigue, dyspnea, and venous thromboembolism. These patients may have thrombocytosis, granulocytosis, eosinophilia, pure red cell aplasia, disseminated intravascular coagulation, and leukemoid reactions.

• Polycythemia: It is caused due to excessive erythropoietin secretion in renal carcinoma, Cerebellar hemangioma, uterine myoma, and hepatocellular carcinoma.[18][19][20] 

Dermatological 

• Acanthosis nigricans manifests as thickened hyperpigmented skin, usually in the axilla and neck region. Gastric adenocarcinoma is most commonly associated with acanthosis nigricans.[21]
• Paraneoplastic pemphigus: it is characterized by blistering and erosion of the trunk, palms, and soles; it may involve mucous membranes causing pain due to mucosal erosions. It is commonly seen in patients with B-cell lymphoproliferative disorder.[22]
• Sweet syndrome: is also known as acute febrile neutrophilic dermatosis. It manifests as acute onset of painful, erythematous plaques, papules, and nodules accompanied by fever and neutrophilia.
• Leukocytoclastic vasculitis: it typically manifests as palpable purpura on the lower extremities, but a patient may also experience cyanosis, pruritus, pain, and ulceration of the affected skin.
• Dermatomyositis: it is characterized by a heliotrope rash on the upper eyelids, Gottron papules on phalangeal joints, and an erythematous rash on the face, neck, back, chest, and shoulders.[21] Patients can present with inflammatory myopathies with proximal muscle weakness and muscle tenderness when muscles are involved.
• Necrolytic migratory erythema: mainly seen in patients with glucagonoma.
• Trousseau syndrome presents as migratory thrombophlebitis, mainly seen in pancreatic and bronchogenic carcinoma. It is caused by excessive secretion of mucins that activate clotting factors.

Renal

• Patients may present with electrolyte imbalances (hypokalemia, hypo or hypernatremia, hyperphosphatemia), causing nephropathy and acid-base disturbance due to ectopic hormones produced by tumor cells such as ACTH and ADH.[23]
• Nephrotic syndrome, membranous glomerulonephritis: patients can present with acute kidney injury, massive proteinuria, and fluid overload. It is caused due to tumor antigens and immune complexes. [24]

Miscellaneous

Neoplastic fever, cachexia, anorexia, dysgeusia[25]

Evaluation

Paraneoplastic syndrome is a diagnosis of exclusion, and all possible etiologies should be ruled out. 

When suspected, a patient should be evaluated with a complete panel of laboratory, imaging, electrodiagnostic studies, and biopsy of specific tissues.

• Complete blood count with differential
• Comprehensive metabolic panel
• Urinalysis
• Tumor markers
• Ectopic hormones level like PTHrP, ACTH, ADH
• Cerebrospinal fluid analysis (CSF)
• Protein electrophoresis of serum and CSF
• Assay of paraneoplastic antibodies in the blood and CSF
• Skin biopsy
• Muscle biopsy is recommended in patients with suspected tumor-related dermatomyositis. Pathological findings include CD4+ T cells and perimysial inflammation.

An international neurologist panel developed criteria for paraneoplastic syndrome affecting the nervous system into definite and possible categories based on the classical neurological syndrome, presence of paraneoplastic antibodies, and timing of diagnosis of the occult malignancy.[26][27] Classical syndromes include encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, opsoclonus-myoclonus syndrome, Lambert Eaton myasthenic syndrome, subacute sensory syndrome neuropathy, chronic gastrointestinal pseudoobstruction, and dermatomyositis.

• Definite Paraneoplastic Syndrome: a classical neurological syndrome with confirmed paraneoplastic syndrome antibodies where malignancy, if undiagnosed, is expected to be diagnosed within five years of the diagnosis of paraneoplastic syndrome. 

• Possible Paraneoplastic Syndrome: a classical neurological syndrome without paraneoplastic antibodies or cancer but at high risk for an underlying malignancy, a classical or nonclassical neurologic syndrome with partially characterized antibody but no cancer, a nonclassical syndrome without paraneoplastic antibodies but diagnosed with cancer within two years of developing the neurological syndrome.

Treatment / Management

Management of a patient with paraneoplastic syndrome is based on the type, severity, and location of the paraneoplastic syndrome. If occult malignancy is diagnosed, then the first step is to treat the underlying malignancy with chemotherapy, radiation, or surgery when possible. A paraneoplastic syndrome is an auto-immune process; patients may benefit from immunosuppression with high-dose corticosteroids, intravenous immunoglobulins, plasma exchange, or plasmapheresis.

Tumor-related hypercalcemia: Patients with calcium levels>14mg/dl (3.5mmol/L) require aggressive treatment with intravenous fluids. If they develop fluid overload, consider intravenous Lasix. If calcium is still high, consider giving intravenous calcitonin with Bisphosphonates (Subcutaneous Zolendronic acid or intravenous pamidronate). Calcitonin will decrease the calcium levels acutely, but there is a risk of developing tachyphylaxis. Bisphosphonates will take 1 to 2 days to decrease calcium levels.[28][29][30]

Differential Diagnosis

Toxic-metabolic encephalopathy: rule out underlying infections and electrolyte abnormalities.

Infectious Encephalitis: rule out any bacterial, viral, or fungal etiologies.

Personality disorders: patients may have underlying depression.

Myelitis: rule out infectious or inflammatory causes.

Bone marrow failure: rule out other causes, may need a bone marrow biopsy.

Chronic fatigue syndrome: patients may present with non-specific symptoms. They need close follow-ups.

Mixed connective tissue disorder: check for specific antibodies, anti-ribonucleic acid Ab ( anti-RNP). They may have co-existing rheumatological disorders like systemic lupus erythematosus, scleroderma, and polymyositis.

Non-tumor-related dermatomyositis: check for specific antibodies; they have anti-Jo-1 and anti-Mi-2 antibodies. Rule out ovarian, breast, and gastrointestinal cancers.

Polymyalgia rheumatica: mostly seen in elderly patients and involves shoulder girdle. These patients have elevated erythrocyte sedimentation rate (ESR) and respond dramatically to low-dose steroids.

Nephrotic syndrome: rule out all other etiologies.

Prognosis

Paraneoplastic syndromes have diverse clinical manifestations, and hence prognosis may vary. Few paraneoplastic disorders may resolve spontaneously or with primary cancer treatment, as in paraneoplastic hypertrophic osteoarthropathy.[1]  In a study, 30-day inpatient mortality in patients with paraneoplastic hypercalcemia was 50%.[31] Patients with paraneoplastic thrombocytosis have the worst outcomes and usually present at an advanced cancer stage.[1] Death may result from the underlying progression of cancer, from complications of cancer treatments, or an irreversible system impairment, usually acute respiratory failure, congestive heart failure, or kidney failure.[1]

Complications

Paraneoplastic disorders may affect diverse organ systems, and complications mainly involve endocrine, neurologic, dermatologic, rheumatologic, and hematologic systems. Complications should be suspected when clinical symptoms are much more severe and the patients are less responsive to the traditional treatment regimen. [1]

Most notable laboratory complications at initial presentation include:

• Endocrine:

               Severe hypo-osmotic, euvolemic hyponatremia: Serum Sodium level at presentation may be less than 125 meq/l.

               Moderate to severe hypercalcemia: Calcium levels may be 12 to 14 mg/dl.

               Severe hypoglycemia: Serum glucose may be as low as 20mg/dl.

• Hematologic:     Secondary thrombocytosis: Platelets >400 X 10/L.           Pure RBC aplasia: hematocrit <20.       Secondary granulocytosis: granulocyte (neutrophil) count >8 X 10/L     Eosinophils: >0.5 X 10/L

Other complications to note include treatment-related complications. Paraneoplastic syndromes are mainly treated with immune-modulatory medications (corticosteroids, Intravenous Immune globulins (IVIG), Interferon alpha, plasmapheresis, medications like cyclophosphamide, methotrexate, etc.) However, as the main treatment for paraneoplastic syndrome is treating the primary cancer with chemotherapy and radiation, treatment-related complication rates are high in these patients. They are at increased risk for hepatotoxicity, nephrotoxicity, cardiotoxicity, and pulmonary toxicity.

Deterrence and Patient Education

Patients with paraneoplastic syndromes should be counseled about the course of the disease. The risk of treatment-specific complications associated with high morbidity and mortality should be explained to the patients and their families. These patients usually present with advanced-stage cancer with a limited life expectancy. These seriously ill patients should be encouraged to participate in early goals of care discussions with the medical team to promote goal-congruent care.

Enhancing Healthcare Team Outcomes

Paraneoplastic syndromes are very rare, and management of these syndromes is very challenging. Because of the complex diagnostic work-up, the condition is best managed by an interprofessional team that includes a pathologist, oncologist, radiologist, hematologist, rheumatologist, neurologist, endocrinologist, dermatologist, and hospitalist. Nursing staff and pharmacists are also part of this interprofessional team. All team members are to engage in open communication with the rest of the team whenever they have concerns about the patient's progress and must document all interactions and interventions in the patient's medical record so that everyone on the team operates from the same up-to-date information. This interprofessional approach will drive optimal patient outcomes. [Level 5]

These seriously ill patients need comanagement from multiple specialists, and they should be transferred immediately to a tertiary hospital when such services are unavailable at the presenting facility.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010 Sep;85(9):838-54. [PMC free article: PMC2931619] [PubMed: 20810794]

2.

Zuliani L, Graus F, Giometto B, Bien C, Vincent A. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J Neurol Neurosurg Psychiatry. 2012 Jun;83(6):638-45. [PMC free article: PMC3348613] [PubMed: 22448032]

3.

Honnorat J, Viaccoz A. New concepts in paraneoplastic neurological syndromes. Rev Neurol (Paris). 2011 Oct;167(10):729-36. [PubMed: 21890156]

4.

Baijens LW, Manni JJ. Paraneoplastic syndromes in patients with primary malignancies of the head and neck. Four cases and a review of the literature. Eur Arch Otorhinolaryngol. 2006 Jan;263(1):32-6. [PubMed: 15986184]

5.

Zaborowski MP, Michalak S. Cell-mediated immune responses in paraneoplastic neurological syndromes. Clin Dev Immunol. 2013;2013:630602. [PMC free article: PMC3932176] [PubMed: 24575143]

6.

Spinazzé S, Schrijvers D. Metabolic emergencies. Crit Rev Oncol Hematol. 2006 Apr;58(1):79-89. [PubMed: 16337807]

7.

Chan AM, Baehring JM. Paraneoplastic neurological syndromes: a single institution 10-year case series. J Neurooncol. 2019 Jan;141(2):431-439. [PubMed: 30607708]

8.

Grisold W, Giometto B, Vitaliani R, Oberndorfer S. Current approaches to the treatment of paraneoplastic encephalitis. Ther Adv Neurol Disord. 2011 Jul;4(4):237-48. [PMC free article: PMC3131173] [PubMed: 21765874]

9.

van Sonderen A, Wirtz PW, Verschuuren JJ, Titulaer MJ. Paraneoplastic syndromes of the neuromuscular junction: therapeutic options in myasthenia gravis, lambert-eaton myasthenic syndrome, and neuromyotonia. Curr Treat Options Neurol. 2013 Apr;15(2):224-39. [PubMed: 23263888]

10.

Barbosa SL, Rodien P, Leboulleux S, Niccoli-Sire P, Kraimps JL, Caron P, Archambeaud-Mouveroux F, Conte-Devolx B, Rohmer V., Groupe d'Etude des Tumeurs Endocrines. Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature. Thyroid. 2005 Jun;15(6):618-23. [PubMed: 16029131]

11.

Peri A, Grohé C, Berardi R, Runkle I. SIADH: differential diagnosis and clinical management. Endocrine. 2017 Jan;55(1):311-319. [PubMed: 27025948]

12.

Bodnar TW, Acevedo MJ, Pietropaolo M. Management of non-islet-cell tumor hypoglycemia: a clinical review. J Clin Endocrinol Metab. 2014 Mar;99(3):713-22. [PMC free article: PMC5393479] [PubMed: 24423303]

13.

Gade AK, Olariu E, Douthit NT. Carcinoid Syndrome: A Review. Cureus. 2020 Mar 05;12(3):e7186. [PMC free article: PMC7124884] [PubMed: 32257725]

14.

Mulatero P, Rabbia F, Veglio F. Paraneoplastic hyperaldosteronism associated with non-Hodgkin's lymphoma. N Engl J Med. 2001 May 17;344(20):1558-9. [PubMed: 11368052]

15.

Khan F, Kleppel H, Meara A. Paraneoplastic Musculoskeletal Syndromes. Rheum Dis Clin North Am. 2020 Aug;46(3):577-586. [PubMed: 32631605]

16.

Azar L, Khasnis A. Paraneoplastic rheumatologic syndromes. Curr Opin Rheumatol. 2013 Jan;25(1):44-9. [PubMed: 23026875]

17.

Muller S, Hider S, Helliwell T, Partington R, Mallen C. The real evidence for polymyalgia rheumatica as a paraneoplastic syndrome. Reumatismo. 2018 Mar 27;70(1):23-34. [PubMed: 29589400]

18.

Da Silva JL, Lacombe C, Bruneval P, Casadevall N, Leporrier M, Camilleri JP, Bariety J, Tambourin P, Varet B. Tumor cells are the site of erythropoietin synthesis in human renal cancers associated with polycythemia. Blood. 1990 Feb 01;75(3):577-82. [PubMed: 2297568]

19.

Suzuki M, Takamizawa S, Nomaguchi K, Suzu S, Yamada M, Igarashi T, Sato I. Erythropoietin synthesis by tumour tissues in a patient with uterine myoma and erythrocytosis. Br J Haematol. 2001 Apr;113(1):49-51. [PubMed: 11328280]

20.

Kew MC, Fisher JW. Serum erythropoietin concentrations in patients with hepatocellular carcinoma. Cancer. 1986 Dec 01;58(11):2485-8. [PubMed: 2429757]

21.

Dourmishev LA, Draganov PV. Paraneoplastic dermatological manifestation of gastrointestinal malignancies. World J Gastroenterol. 2009 Sep 21;15(35):4372-9. [PMC free article: PMC2747056] [PubMed: 19764087]

22.

Wick MR, Patterson JW. Cutaneous paraneoplastic syndromes. Semin Diagn Pathol. 2019 Jul;36(4):211-228. [PubMed: 30736994]

23.

Dhanapriya J, Dineshkumar T, Sakthirajan R, Surendar D, Gopalakrishnan N, Balasubramaniyan T. Paraneoplastic glomerulopathies associated with hematologic malignancies. Saudi J Kidney Dis Transpl. 2018 Mar-Apr;29(2):452-455. [PubMed: 29657219]

24.

Christiansen CF, Onega T, Sværke C, Körmendiné Farkas D, Jespersen B, Baron JA, Sørensen HT. Risk and prognosis of cancer in patients with nephrotic syndrome. Am J Med. 2014 Sep;127(9):871-7.e1. [PubMed: 24838191]

25.

Zell JA, Chang JC. Neoplastic fever: a neglected paraneoplastic syndrome. Support Care Cancer. 2005 Nov;13(11):870-7. [PubMed: 15864658]

26.

Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, Honnorat J, Smitt PS, Vedeler Ch, Verschuuren JJ, Vincent A, Voltz R. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1135-40. [PMC free article: PMC1739186] [PubMed: 15258215]

27.

Greenlee JE. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1090. [PMC free article: PMC1739162] [PubMed: 15258205]

28.

Zagzag J, Hu MI, Fisher SB, Perrier ND. Hypercalcemia and cancer: Differential diagnosis and treatment. CA Cancer J Clin. 2018 Sep;68(5):377-386. [PubMed: 30240520]

29.

Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcaemia. BMJ. 2015 Jun 02;350:h2723. [PubMed: 26037642]

30.

Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, Yunus F, Bell R, Body J, Quebe-Fehling E, Seaman J. 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 Jan 15;19(2):558-67. [PubMed: 11208851]

31.

Ralston SH, Gallacher SJ, Patel U, Campbell J, Boyle IT. Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med. 1990 Apr 01;112(7):499-504. [PubMed: 2138442]

Disclosure: Bicky Thapa declares no relevant financial relationships with ineligible companies.

Disclosure: Neetu Mahendraker declares no relevant financial relationships with ineligible companies.

Disclosure: Kamleshun Ramphul declares no relevant financial relationships with ineligible companies.