Paraneoplastic Syndromes
Resource: 1. Harrison’s Principles of Internal Medicine, Vol.1, 18th
ed.; “Paraneoplastic syndromes,” pg. 827-838;
Longo, Fauci, Kasper, Hauser, Jameson, Localzo et all.; Mc Graw Hill, 2012. 2. Davidson’s Principles & Practice of
Medicine, 22nd
ed., “Oncology,” pg. 259-283.; Compiled by Andrei Cociug, © 2020.
Definition In addition to local tissue invasion and metastasis, neoplasms can produce a variety of products
that can stimulate hormonal, haematological, dermatologic and neurologic responses.
Paraneoplastic syndrome = “disorders that accompany benign or malignant Tu. but are not
directly related to mass effect or invasion.” The most common are as such:
A. Endocrine paraneoplastic sy.:
B. Haematological
C. Neurological
D. Neuromusculoskeletal
E. Cutaneous
A) Endocrine Paraneoplastic Syndromes: Aetiology
Paraneoplastic syndrome Ectopic hormone Tumour types
Common
Hypercalcemia of malignancy
(HM)
PTH-related protein (PTHrP) SCC (H&N; Lung; Skin), Breast, GU & GI CA.
1,25 dihydroxyvitamin D Lymphomas
SIADH (Syndrome of
inappropriate ADH secretion)
Vasopressin (ADH) Lung CA (SCC; Small Cell), GI, GU & Ovarian CA.
Cushing syndrome
(10-20% of cases of Cushing
syndrome cases are due to
ectopic ACTH production.)
ACTH Lung CA (Small Cell [50% of cases]; Bronchial
carcinoid; Adenocarcinoma; SCC), Thymus
[15%], Pancreatic islet, Medullary thyroid CA.
CRH & other hormones are
rare.
Less Common paraneoplastic syndromes incl.:
• Tumour-induced hypoglycaemia (caused by ectopic secretion of IGF or Insulin)
• Male feminisation (hCG-secreting Tu.)
• Diarrhoea or interstitial hypermotility (Calcitotin- & VIP-secreting Tu.)
Rare paraneoplastic syndromes incl.:
• Oncogenic osteomalacia (FGF23-secreting Tu.), aka Tumour-induced osteomalacia (marked softening of
the bones.) Usually caused by mesenchymal tumours.
o Characterised by markedly ↓ serum [PO4
3],
muscle weakness, and bone pain.
o Serum [Ca2+
] and PTH levels are normal, whilst 1,25 dihyrdroxyvitamin D is low.
o Resection of the tumour reverses the disorder.
• Acromegaly (GNRH- or GH-secreting Tu.)
• Hyperthyroidism (TSH-secreting Tu.)
• Hypertension (Renin-secreting Tu.)
*Legend: CA = Cancers; Tu. = Tumour; H&N = Head and Neck; GU = Genitourinary; GI = Gastrointestinal; FGF23 =
Fibroblast-growth factor 23.
A) Endocrine Paraneoplastic Syndromes: Dx. & Treatment
Paraneoplastic syndrome Dx. Tx.
Hypercalcemia of
malignancy
(HM)
• Usually incidental (no clinical features
beforehand)
• When serum [Ca2+
] is > 3.5 mmol/L,
Pz. may experience fatigue, mental
status changes, dehydration,
symptoms of nephrolithiasis.
• Pz. present w. ↓ serum PTH level,
hypophosphatemia,
• ↑ serum 1,25 dihydroxyvitamin D or
PTHrP
• Diet restrictions
• Oral PO4
3and
saline rehydration (to
dilute the Ca2+
and replenish the
phosphate)
• ± Forced diuresis w. furosemide
• Bisphosphonates (Zoledronate, 4-8
mg IV)
• Dialysis should be considered in
severe hypercalcaemia.
SIADH (Syndrome of
inappropriate ADH
secretion)
• Usually incidental (Pz. are
asymptomatic, though their serum
[Na+
] is ↓).
• Symptoms may incl. weakness,
lethargy, nausea, confusion,
depressed mental status and
seizures.
• To confirm Dx. Exclude other causes
of hyponatremia (renal, adrenal or
thyroid insufficiency, physiologic
compensatory mechanisms, etc.)
ADH measurement is not usually
necessary.
• Correct hyponatremia gradually (fluid
restriction to less than urine output)
unless mental status is altered or
there is risk of seizures (which may
req. infusion w. hypertonic solution –
i.e. 3% saline).
• Beware of the possible complication
– central pontine myelinolysis – that
occur w. rapid correction of [Na+
]
Cushing syndrome • Pz. w. Cushing’s due to ectopic ACTH
production exhibit less marked
symptoms (weight gain, centripetal
fat redistribution, etc.)
• A few distinct features incl.: marked
fluid retention and hypertension,
hypokalaemia & hypernatremia (due
to the stimulation of aldosterone
receptors,) metabolic alkalosis, glc.
intolerance and occasionally
psychosis (.
• ↑ serum [ACTH] leads to ↑skin
pigmentation.
• ↑ urine [cortisol], ↑plasma [ACTH]
irresponsive to glucocorticoid
suppression are diagnostic.
• Pz. w. ectopic ACTH syndrome may
experience depression or personality
changes, they may have metabolic
derangements (incl. DM), etc.
• Poor wound healing and
predisposition to infection can
complicate causal surgical Tx.
• Infections caused by opportunistic
agents (e.g. Pneumocystis and
mycoses are often the cause of
death.)
• Tx. should, like in every other cases,
focus on the underlying malignancy.
• Attempt to reduce [cortisol] w.
ketoconazole, metyrapone and
mitotane (dose tampered to
maintain low cortisol prod.)
B) Haematologic Paraneoplastic Syndromes: Aetiology
NOTE: The elevation of granulocyte, platelet, and eosinophil counts in most Pz. w. myeloproliferative disorders is
caused by the proliferation of the myeloid elements due to the underlying disease rather than a paraneoplastic
syndrome.
Paraneoplastic syndrome Ectopic hormone Tumour types
Erythrocytosis Erythropoietin (EPO) Renal cancers (incidence: 3%), HCC (incidence:
10%), Cerebellar haemangioma (incidence: 15%)
Granulocytosis
(30% of Pz. w. solid Tu.)
Granulocyte Colony
Stimulating factor
(G-CSF) & IL-6
Lung (incidence: 40%), GU, GI, Ovarian,
Hodgkin’s disease
Thrombocytosis
(35% of Pz. w. thrombocytosis have
cancer)
IL-6
? Thrombopoietin (TPO)
Lung (incidence: 40%), GI, Ovarian, Breast CA,
Lymphoma
Eosinophilia
(1% of Pz. w. cancer)
IL-5 Lung CA, Lymphoma (incidence: 10%),
Leukaemia
Thrombophlebitis
(DVT and PE are the most common
thrombotic cond. in Pz. w. cancer.
15% of Pz. w. thrombophlebitis
have cancer)
Procoagulants and
cytokines released from
tumour cells or assoc.
inflammatory cells.
Lung, GU, GI, Ovarian, Prostate, Breast CA,
Lymphoma
B) Haematologic Paraneoplastic Syndromes: Dx. & Treatment
Paraneoplastic syndrome Dx. Tx.
Erythrocytosis • ↑ HCT (>52% and > 48% in )
which can be detected on routine
CBC. In most cases this is
asymptomatic
• Cancer therapy
• Phlebotomy may control any
symptoms rel. to ↑ HCT
Granulocytosis • Granulocyte count >8000 cells/mcL
detected on routine CBC. Most Pz.
are asymptomatic.
• Cancer therapy
Thrombocytosis • Platelet count >400 000/mcL • Cancer therapy
Eosinophilia • Eosinophil count >5000 cells/mcL
• Pz. may present w. shortness of
breath (in the context of eosinophilic
lung infiltrates.)
• Cancer therapy
• Symptoms may be relieved by
inhaled glucocorticoids.
Thrombophlebitis • Migratory or recurrent
thrombophlebitis may be the initial
manifestation of cancer.
The coexistence of peripheral venous
thrombosis w. visceral carcinoma is
called Trousseau’s syndrome.
• Dx. by DDimers, U/S & Venography ±
CXR, ECG, CTA or V/Q scan.
• IV UFH or LMWH for > 5 days
• Concomitant administration of
warfarin (aim for INR 2 to 3.) for 3
months
• Consider the placement of an inferior
vena cava (Greenfield) filter in case
anticoagulation Tx. Is CI
• Breast CA Pz. req. prophylaxis Tx.
*Legend: mcL = microlitre;
C) Neurologic Paraneoplastic Syndromes: Aetiology
NOTE: PND (Paraneoplastic Neurologic Disorders) are cancer-related syndromes that can affect any part of the NS
In 60% of cases, the neurologic symptoms precede the cancer diagnosis.
PNDs affect about 2-3% of Pz. w. neuroblastoma or SCLC, and 30-50% of Pz. w. thymoma or sclerotic myeloma.
Classic syndrome: Cancer-associated Non-classic syndrome: May occur in the absence of cancer
• Encephalomyelitis (PEM)
• Limbic encephalitis
• Cerebellar degeneration (PCD)
• Opsoclonus-Myoclonus
• Gastrointestinal paresis
• Lambert-Eaton myasthenic syndrome
• Cancer-assoc. retinopathy
• Brainstem encephalitis
• Stiff-person syndrome
• Necrotising myelopathy
• Motor neuron disease
• Guilliam-Barre syndrome
• Polymyositis
• Subacute and chronic mixed sensory-motor
neuropathy
Pathogenesis:
• Most PNDs are mediated by immune responses triggered by neuronal proteins (onconeuronal antigens)
expressed by tumours.
• In PNDs of the CNS, many antibody-assoc. immune resp. have been identified. These Atbs. react w. the
patient’s Tu. and their detection in serum or CSF usually predicts the presence of cancer.
o Disorders assoc. w. immune resp. against intracellular antigens are, unlike disorders assoc. w.
immune resp. against surface antigens, less responsive to immunotherapy.
Cancer Antibody Associated PND
SCLC Against intracellular antigens:
• Anti-Hu Encephalomyelitis
• Inflammatory process w. multifocal involvement of the NS,
incl. brain, brainstem, cerebellum and spinal cord.
• Anti-CV
• Anti-Ri Cerebellar degeneration
• Usually preceded by dizziness, blurry or double vison, nausea
and vomiting.
• A few days-weeks later, Pz. Develop dysarthria, gait and limb
ataxia, and variable dysphagia.
• Anti-amphiphysin Stiff-person syndrome,
Encephalomyelitis
• (see above)
Against surface antigens
• Anti-AChR (neuronal) Autonomic neuropathy
• Anti-VGCC Cerebellar degeneration
• (see above)
• Anti-AMPA R. Limbic encephalitis
• Inflammation of the temporal lobe(s) characterized by
confusion, depression, agitation, anxiety, severe short-term
memory deficits and seizures.
• Anti-GABA R.
Cancer Antibody Associated PND
Thymoma Against intracellular antigens:
• Anti-CV Encephalomyelitis
• See above
Against surface antigens
• Anti-AChR (muscle) Myasthenia gravis
• Anti-VGKC Neuromyotonia
• Anti-AMPA R. Limbic encephalitis
Dx.
• Three key concepts are imp. for the Dx. and management of PND
1. Symptoms typically appear before the presence of a tumour is known
2. The neurologic syndrome usually develops rapidly, producing severe deficits in a short time
3. There is evidence that prompt tumour control improves the neurologic outcome
• Dx. is based on clinical, radiologic (esp. MRI), electrophysiologic and CSF findings (esp. pleocytosis.)
• Identify the antibodies responsible for the condition in blood or CSF
• Demonstrate the cancer
Tx.
• Involves infusion w. IVIg & Tu. Removal.
D) Cutaneous Manifestations of Cancer
Many cancers present w. skin manifestations that are not due to metastases
Sign/Symptom Cancer
• Pruritus (= itch)
o Symptomatic relief w. antihistamines and
menthol-containing preparations.
• Polycythaemia Vera, Lymphoma, Leukaemia and CNS
tumours
• Acanthosis nigricans
o Formation of dark, velvety discolorations
in body folds and creases (armpits, groin
and neck.)
• May precede cancer by many years and is
particularly assoc. w. gastric cancer.
• Vitiligo
o Focal hypopigmentation
o It’s indicated to protect the depigmented
patches from sun exposure.
o Narrowband UVB is the most effective repigmentary
treatment
• May be assoc. w. malignant melanoma, and is possib.
due to an immune resp. to melanocytes.
• Pemphigus
o Blistering disorder
• Lymphoma, Kaposi’s sarcoma, and Thymic tumours
• Dermatitis herpetiformis
o Autoimmune blistering disorder that is
strongly assoc. w. gluten intolerance.
• May precede GI tumours (e.g. lymphoma, MALToma)