Paraneoplastic syndromes

UNUSUAL PRESENTATIONS OF MALIGNANCY

Paraneoplastic syndromes

Key points C

Paraneoplastic syndromes (PNSs) are systemic effects of malignant disease that are not caused by direct effects of secondary spread

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PNSs include endocrine, neurological, cutaneous, rheumatological, haematological, gastrointestinal and non-specific disorders

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PNSs can predate overt signs or symptoms of a malignancy

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Some specific presentations mandate investigation for malignancy

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PNSs can improve or resolve when the malignancy is treated

Loretta Sweeney Theresa Howe

Abstract Malignancy uncommonly presents with a paraneoplastic syndrome rather than as a direct result of the primary tumour or its metastases. Paraneoplastic syndromes are a heterogeneous group of syndromes that represent the non-metastatic systemic effects of malignant disease. Pathogenesis varies among syndromes but several humoral and immune mediators are implicated. Although some syndromes are rare, they can be very specific for an underlying malignant diagnosis. Recognition of the syndrome, treatment of the malignancy and supportive measures for the paraneoplastic syndrome can improve morbidity and mortality.

usually exclusively found in the nervous system. It is the crossreactivity with these that has been hypothesized to result in neurological symptoms.3 The pathogenesis of other categories of PNS has largely yet to be elucidated.

Keywords MRCP; neoplastic antibodies; paraneoplastic endocrine syndromes; paraneoplastic neurological syndromes; paraneoplastic syndromes

Endocrine paraneoplastic syndromes (Table 1) Syndrome of inappropriate antidiuretic hormone (SIADH) secretion: this is commonly found in small cell lung cancer. A chest X-ray is mandatory in patients with SIADH with no identifiable cause. Resultant serum hyponatraemia can be an incidental finding or present with symptoms ranging from postural hypotension to confusion and seizures. Hyponatraemia usually resolves within weeks of starting anticancer therapy. It can respond to fluid restriction, but this is challenging for the patient and sometimes ineffective. Pharmacological treatments include demeclocycline (which blocks the renal action of ADH) and specific (V2) vasopressin receptor antagonists known as vaptans. In severe acute cases, intravenous hypertonic sodium chloride is required.

Introduction Malignancy presents with a paraneoplastic syndrome (PNS) in up to 40% of patients with specific cancers.1 This heterogeneous group, classified according to the organ system affected, represents the non-metastatic systemic effects of malignant disease. Presentation varies widely, ranging from non-specific cachexia to pathognomonic syndromes, for example Bazex’s syndrome. A PNS presentation can significantly predate a diagnosis of malignancy. This overview discusses endocrine, neurological and dermatological PNS; it does not cover rheumatological, haematological or renal presentations.

Pathogenesis

Cushing’s syndrome: resulting from ectopic adrenocorticotropic hormone, corticotropin-releasing factor or cortisol production, this often presents before the associated cancer is diagnosed. It is associated with primary lung malignancies. The onset can be rapid, with associated cachexia. Patients can present with hypokalaemic metabolic alkalosis. The diagnosis of ectopic secretion is confirmed by the high-dose dexamethasone suppression test, imaging (including computed tomography (CT) of the thorax/abdomen/pelvis) and tumour markers. Bilateral inferior petrosal sinus sampling may be necessary to definitively exclude a pituitary source.

Endocrine PNSs have been shown to result from the production of functional hormones, peptides and/or cytokines by tumour cells.2 Neurological PNSs arise by immune-mediated mechanisms. Normal immune function results in the generation of anti-tumour antibodies and anti-tumour-specific T lymphocytes. Certain tumours, however, ectopically express neuronal antigens that are

Loretta Sweeney MB BCh MRCP FRCR is a Consultant Clinical Oncologist with an interest in urology and breast cancer at Velindre Cancer Centre, Cardiff, South Wales, UK. Competing interests: none declared.

Neurological paraneoplastic syndromes (Table 2) These can predate diagnosis of a cancer by weeks or years. The presence of certain onconeural or paraneoplastic antibodies aids diagnosis, but not all syndromes have detectable antibodies. Paraneoplastic antibodies can attack the central or peripheral nervous system and the neuromuscular junction. Magnetic

Theresa Howe MB BCh BMedSci MRCP FRCR is a Clinical Oncology Consultant with an interest in breast cancer at Velindre Cancer Centre, Cardiff, South Wales, UK. Competing interests: none declared.

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Please cite this article as: Sweeney L, Howe T, Paraneoplastic syndromes, Medicine, https://doi.org/10.1016/j.mpmed.2019.11.015

UNUSUAL PRESENTATIONS OF MALIGNANCY

Endocrine PNSs Syndrome

Hormone/hormone-like peptide

Clinical features

Specific management

Associated malignancy

SIADH

ADH

Fluid restriction Demeclocycline Vaptans

SCLC Central nervous system primary tumours or metastases

Cushing’s syndrome

Adrenocorticotropic hormone Corticotropin-releasing factor Cortisol

Ketoconazole Metyrapone Octreotide

SCLC Carcinoid MTC Gastrointestinal carcinomas

Hypercalcaemia

Parathyroid hormone-releasing hormone Rarely parathyroid hormone Rarely vitamin D

Anorexia and nausea Malaise Confusion Y Serum sodium Y Serum osmolality [ Urine sodium [ Urine osmolality Pigmentation Muscle weakness Hypertension Hyperglycaemia Oedema Nausea and vomiting Pain Weight loss Constipation Depression

Fluids Bisphosphonates RANKL inhibitor Calcitonin

Hypocalcaemia

Calcitonin

Replace calcium

Hypoglycaemia

Insulin

Perioral paraesthesias Tetany Confusion Coma Seizures

Many, including: Breast NSCLC Prostate Myeloma Lymphoma MTC

Carcinoid syndrome

Serotonin Kallikrein Histamine

Glucose Corticosteroids Glucagon Octreotide Octreotide

Insulinomas Mesothelioma Gastrointestinal carcinomas Sarcomas Carcinoid

Diarrhoea Bronchoconstriction Paroxysmal flushing Heart failure

MTC, medullary thyroid carcinoma; NSCLC, non-small cell lung carcinoma; RANKL, receptor activator of nuclear factor kB ligand; SCLC, small cell lung carcinoma.

Table 1

is mandatory to investigate the aerodigestive tract for squamous cell carcinoma. It typically presents with a symmetrical psoriasiform hyperkeratotic eruption affecting the nose, ears and digits but can involve the limbs and trunk. It is associated with alopecia and psoriasiform nail changes.

resonance imaging, positron emission tomography-CT, cerebrospinal fluid examination and electrophysiology can help diagnosis. Treatment of the malignancy can result in an improvement or resolution of symptoms, unless permanent damage to nonrepairable critical nervous tissue has occurred. Early use of immunomodulatory therapy (corticosteroids, immunoglobulins, plasma exchange) has a role.

Erythema gyratum repens is strongly suggestive of malignancy. It is usually, but not exclusively, caused by lung adenocarcinoma.4 Concentric, often pruritic, migrating erythematous rings cover a large proportion of the body.

Dermatological paraneoplastic syndromes Acanthosis nigricans presents as velvety, hyperpigmented plaques often affecting flexure creases. It is strongly associated with insulin resistance. However, florid presentations in atypical sites such as palmar or plantar locations strongly suggest malignancy.4 Patients tend to have unintentional weight loss. Gastric adenocarcinoma is the underlying malignancy in approximately 50% of malignancy-associated acanthosis nigricans.

Necrolytic migratory erythema is associated with glucagonoma (pancreatic a-cells) and only occasionally with extrapancreatic malignancy. This wet eczematous skin condition is often associated with constitutional symptoms of anorexia, cachexia and venous thromboembolism.

Bazex’s syndrome (acrokeratosis paraneoplastica) is a rare phenomenon always associated with underlying malignancy.4 It

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Dermatomyositis is associated with varied malignancies including breast, gynaecological tract, gastrointestinal tract and

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UNUSUAL PRESENTATIONS OF MALIGNANCY

Neurological PNSs Presenting symptoms

Classical PNS (high likelihood of underlying malignancy) LamberteEaton Proximal muscle weakness myasthenic syndrome Recovery of function and tendon reflexes after brief exercise Cerebellar degeneration

Limbic encephalitis

Opsoclonusemyoclonus (dancing eyeedancing feet syndrome) Subacute sensory neuropathy

Rapid onset: Ataxia Dysarthria Dysphagia Downbeat nystagmus Mood change Seizures Dementia Opsoclonus (arrhythmic, multidirectional conjugate saccades without intervals) Myoclonus Subacute, progressive, multifocal sensory disturbance Pain Paraesthesia Sensory ataxia

Associated malignancy

Frequency

Anti-CV2 (9%) Anti-amphiphysin (8%) Anti-Hu (6%)

SCLC

Anti-Yo (100%) Anti-Tr (96%) Anti-Ri (50%) Anti-Hu (18%)

Lung Ovarian Breast Hodgkin’s lymphoma SCLC Breast Testicular Breast SCLC Neuroblastoma

60% are associated with cancer 3% of SCLC patients are affected 50% are associated with cancer

Anti-Ma2 (71%) Anti-Hu (14%) Anti-Ri (36%)

Non-classical PNS (commonly non-neoplastic syndromes) Myasthenia gravis Muscle weakness: Initially ocular and/or oropharyngeal Limbs Responds to cholinesterase inhibitors Stiff person syndrome Progressive axial rigidity and spasms

Retinopathy

Most frequently implicated antibodies

Cancer-associated: bilateral reduced acuity and photosensitivity

20% are associated with cancer

Anti-Hu (40%) Anti-CV2 (27%) Anti-amphiphysin (22%)

SCLC (80% of PNS cases) Breast Ovary Sarcoma Hodgkin’s lymphoma

20% are associated with cancer

Anti-acetylcholinesterase receptor Anti-muscle specific tyrosine kinase Anti-amphiphysin

Thymoma

15% are associated with thymoma

Breast Colon Thymoma SCLC

20% are associated with cancer

Melanoma

Rare

Various including anti-carcinoma-associated retinal antigen antibody Autoantibodies against rod bipolar cells

Melanoma-associated: sudden shimmering, night blindness

20% are associated with cancer

Rare

SCLC, small cell lung cancer. Adapted from Gozzard and Madison (2010).5

Table 2

lungs. There is a proximal myopathy with an erythematous skin rash, periorbital heliotrope rash, Gottron’s papules and periungal telangiectasia. A

2 Lippitz B. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol 2013; 14: 218e28. 3 Dalmau J, Gultekin H, Posner J. Paraneoplastic neurological syndromes: pathogenesis and physiopathology. Brain Pathol 1999; 9: 275e84. 4 Thiers B, Sahn R, Callen J. Cutaneous manifestations of internal malignancy. CA Cancer J Clin 2009; 59: 73e98. 5 Gozzard P, Maddison P. Which antibody and which cancer in which paraneoplastic syndromes? Pract Neurol 2010; 10: 260e70.

KEY REFERENCES 1 Gadall SM, Rajan A, Pfeiffer R, et al. A population-based assessment of mortality and morbidity patterns among patients with thymoma. Int J Cancer 2011; 128: 2688e94.

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UNUSUAL PRESENTATIONS OF MALIGNANCY

TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. What is the most appropriate immediate course of action? A. Intravenous fluid therapy with 5% dextrose, followed by calcitonin treatment B. Intravenous fluid therapy with 0.9% sodium chloride, followed by calcitonin treatment C. Intravenous fluid therapy with 5% dextrose, followed by intravenous bisphosphonate D. Intravenous fluid therapy with 0.9% sodium chloride, furosemide, followed by intravenous bisphosphonate E. Intravenous fluid therapy with 0.9% sodium chloride, followed by intravenous bisphosphonate

Question 1 A 68-year-old man presented with a gradual onset over 3 weeks of difficulty getting up out of his usual chair and being generally clumsy. He was unable to get out to do his shopping or use the stairs. He found he would tire easily. He also complained of aching in the arms and legs, occasional dizziness, droopy and dry eyes. On clinical examination he had slowly reactive pupils, proximal muscle weakness in the lower limbs, reduced tendon reflexes with improvement after brief exercise. Investigations  Chest X-ray showed a hilar mass and widened mediastinum  Positron emission tomography-CT of the chest confirmed this finding, with no other abnormality

Question 3 A 74-year-old man presented for review complaining of nausea, tiredness and headache. Three months previously, he had undergone partial debulking of a glioblastoma. Clinical examination found no obvious abnormalities.

What is the most likely mechanism for the mobility problems? A. Hypercortisolism and hypokalaemia B. Antibodies to proteins in the post-synaptic membrane of the motor endplate C. Antibodies to voltage gated calcium channels in presynaptic membrane in the motor end plate. D. Hyponatraemia E. Degeneration of anterior horn cells

Investigations  Sodium 127 mmol/litre (137e144)  Plasma osmolality 250 mosmol/kg (278e300)  ‘Spot’ urine osmolality 425 mosmol/kg (100e1000)  ‘Spot’ urine sodium 55 mmol/litre  MR scan of the head showed no evidence of cerebral oedema or ventricular obstruction How should he be managed initially? A. Give hypertonic sodium chloride (3% sodium chloride) plus furosemide B. Restrict fluid intake to 1e1.5 litres over 24 hours C. Restrict fluid intake to 1e1.5 litres over 24 hours and give demeclocycline by mouth D. Allow free fluids and give tolvaptan by mouth E. Restrict fluid intake to 1e1.5 litres over 24 hours and give oral tolvaptan

Question 2 A 62-year-old woman presented with a 3-week history of sickness, tiredness, constipation and pain. On clinical examination there were no abnormal findings. . Investigations  Corrected calcium 3.69 mmol/litre (2.2e2.6)  Parathyroid hormone 0.6 pmol/litre (0.9e5.4)

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