PARANEOPLASTIC

SYNDROMES

Dr. ABHILASH GAVARRAJU

JR-II

Introduction Group of clinical disorders associated with

malignant diseases that are not directly related to the physical effects of the primary or metastatic tumor.

The syndromes may be due to

- Tumor production of substances causing distant symptoms

- Depletion of normal substances

- Host response to the tumor

Successful treatment leads to disappearance of syndrome but many do not predictably resolve with treatment

Paraneoplastic Endocrine

SyndromesSYNDROME CLINICAL

PRESENTATION

LABS ASSOC

CANCERS

TREATMENT

SIADH Gait disturbance,

falls, hedache,

nausea, fatigue,

cramps, anorexia,

confusion,

lethargy, seizures,

coma

Hyponatremia:

mild, sodium 130-

134 mEq/L;

moderate,

sodium, 125-129

mEq/L; severe,

sodium <125

mEq/L; Increased

urine osmolality

SCLC,

Mesotheliom

a, Bladder,

Endometrial,

Prostate,

Oropharynx,

Thymoma,

Lymphoma,

Breast, GI,

Adrenal

Restrict fluids

and encourage

adequate salt

and protein

intake;

Demeclocycline

300-600mg BD

Conivaptan, 20-

40mg/d iv;

Tolvaptan 10-

60mg/d oral

Hyperclcemia Altered mental

status, weakness,

ataxia, lethargy,

hypertonia, renal

failure, HTN,

bradycardia

Mild – 10.5-

11.9mg/dl

Mod- 12-

13.9mg/dl

Severe->14mg/dl

Low to normal

PTH

Breast, MM,

RCC,

NSCLC,

Lymphoma,

Ovarian,

Endometrial

Saline,

Diuretics,

Pamidronate,

Zoledronate,

Steroids,

Calcitonin

SYNDROME CLINICAL

PRESENTATIO

N

LABS ASSOC

CANCERS

TREATMENT

Cushing’s

Syndrome

Muscle

Weakness,

peripheral

edema, HTN,

Weight gain,

Centripetal fat

distribution

Hypkalemia,

Elevated

Cortisol, normal

to elevated

midnight serum

ACTH

SCLC,

Bronchial

Carcinoid,

Thymoma,

MCT, GI,

Pancreas,

Ovarian

Ketoconazole

600-

1200mg/d,

Octrotide,

Aminoglutethe

mide,

Metyrapone,

Mitotane,

Etomidate,

Mifepristone

Hypoglycemi

a

Sweating,

anxiety, tremors,

palpitations,

hunger,

weakness,

seizures,

confusion, coma

Non islet cell

tumor

Low glucose,

low insulin, low

C-peptide

Insulinomas

Low glucose,

elevated insulin,

elevated c-

peptide

Mesotheliom

a, sarcomas,

GI, Lung

Glucose,

Dexamethaso

ne,

Prednisone,

Diazoxide,

Octreotide,

Human GH

Paraneoplastic Hematologic

SyndromesSYNDROME CLINICAL

FEATURES

LABS ASSOC

CANCERS

TREATMENT

Eosinophilia Dyspnea,

Wheezing

Hypereosino

philia;

Elevated IL-

2,3,5

HL, NHL,

CML, ALL,

Lung, GI,

Thyroid,

Renal, Breast

Inhaled steroids,

Prednisone,

1mg/kg/d orally

Granulocytosis Asymptomatic Elevated

Neutrophils,

Elevated

LAP

GI, Lung,

Breast, GU,

Brain, HL,

sarcoma

Specific

treatment not

indicated

PRCA Dyspnea,

Pallor, Fatigue,

Syncope

Anemia,

Platelets and

WBC WNL

Thymoma,

Leukemia/Lym

phoma, MDS

Blood

transfusions,

Prednisone,

Cyclosporine,

Cyclophosphami

de, Plasma

Exchange,

Splenectomy

DISORDERS OF CUTANEOUS

DISCOLOURATION AND DEPOSITIONDISEASE DESCRIPTION MALIGNANCY

Acanthosis Nigricans Gray brown symmetric

velvety plaque on

neck, axilla, flexor

areas and anogenital

region

Gastric

Adenocarcinoma

Tripe Palms Hyperpigmented

velvety thickened

palms with hyper

keratotic ridges

Gastric, Lung

Generalized

Melanosis

Diffuse gray brown

skin pigmentation

Melanoma, ACTH

producing tumors

Pachydermoperiostosi

sa

Thickening of skin,

lips, ears, lids, scalp,

excessive clubbing

Lung

Amyloidosis Macroglossia,

Superficial waxy

yellow and pink

Multiple Myeloma or

Waldenstrom’s

Macroglobulinemia

Cutaneous Manifestations of

Cancer They may precede, be concurrent

with, or follow the discovery of the

underlying malignancy.

Appropriate Systematic Evaluation

A TRUE paraneoplastic process

satisfies two criteria : Strong

association of dermatoses with

malignancy and its parallel course

Papulosquamous EruptionsDISEASE DESCRIPTION MALIGNANCY COMMENT

Bazex Disease Symmetric, psoriasiform

acral hyperkeratosis

SCC of

Esophagus, HNC,

Lung

Male

predominance

Paget Disease Erythematous keratotic

patch over genital areas

Breast, Uterine,

Ovarian, Prostate,

Anal

<3% of breast

cases

Erythema Gyratum

Repens

Advancing concentric

rings of erythema

Lung, Breast,

Uterus, GI

80% assoc

with

malignancy

Necrolytic

Migratory

Erythema

Macules and Papules

progressing to epidermal

necrolysis

Glucaganoma Clinically

similar to Zn

deficiency

Exfoliative

dermatitis

Progressive erythema f/b

scaling

Mycosis

Fungoides, HD

10-20% of all

exfoliative

dermatitis

Acquired

Ichthyosis

Generalized dry,

crackling skin,

hyperkeratosis

HD, Multiple

Myeloma,

Kaposi’s Sarcoma

Differentiate

from

Hereditary

Renal Manifestations Membranous Nephropathy – Lung, Colon,

Stomach

Sympt – Proteinuria, HTN, Microscopic

Hematuria

Immune complexesare thought to play a

role

Minimal Change Disease – Hodgkin’s,

Pancreas, Mesothelioa

FSGS – CLL, AML, T cell Lymphomas

Membranoproliferative Glomerulonephritis –

CLL, Burkitt’s, Hairy Cell, Melanoma

Neutrophilic Dermatoses

DISEASE DESCRIPTION MALIGNANCY COMMENT

Sweet

Syndrome

Erythematous,

painful juicy

cutaneous

plaques on face,

neck, upper

extremities

AML is MC

cause

Hematological

malignancies

Responds to

steroids

Pyoderma

Gangrenosum

Painful papules,

ulcers,

violaceous

borders and

purulent

exudates

Multiple

Myeloma, SCC,

Mycosis

Fungoides

Responds to

steroids, may be

assoc with IBD,

RA

Vascular Abnormalities

Vasculitis observed in 4.5 – 8%

malignancies.

NSCLC, SCC of esophagus, Prostate,

Hematological malignancies

Purpura – Thrombocytopenia, DIC,

vascular injury, vasculitis

Multifocal migratory thrombophlebitis -

<50 yrs, GI, lung, prostate, ovarian

cancer

Mondor disease – Cordlike

thrombophlebitis of anterior chest seen

in Breast Cancer.

Endocrine and Metabolic

DisordersDISEASE DESCRIPTION MALIGNANCY COMMENT

Systemic Nodular

Panniculitis

Violaceous

Nodules,

Polyarthralgia,

Fever,Eosinophilia

Adenocarcinoma

Pancreas

Necrolytic

Migratory Erythema

Eryhtema, Papules,

vesicles and

Pustules

Glucagonoma Clears after

resection of tumor

Flushing Episodic reddening Carcinoids, MCT

Hypertrichosis

lanuginosa

acquisita

Rapid development

of fine, long, silky

hair on forehead

Unknown High association

with cancer

Localized

Amyloidosis

Waxy yellow

plaques and

nodules

Multiple Myeloma,

Waldenstrom’s

macroglobulinemia

Assoc with Primary

Systemic

Amyloidosis

Pruritis Lymphomas,

Leukemia, Multiple

Myeloma, Hepatic

Unknown Systemic

Evaluation

Bullous disorders Paraneoplastic Pemphigus is most frequently

seen in B-cell lymphopriferative disorders in cluding lymphomas, CLL, Castleman disease, thymoma, Waldenstrom’s macroglobulinemia and Spindle cell neoplasms.

Painful oral stomatitis, conjunctival ulcers and erosive skin lesions.

Internal organ involvement is common with 30% patients having respiratory failure.

Severe mucosal involvement and pathology reminiscent of erythema multiforme –HALLMARK OF PARANEOPLASTIC PEMPHIGUS

Rx – Steroids, Cyclosporine, Mycophenolatemofetil

Collagen Vascular Diseases

Dermatomyositis (DM) linked to malignancy in 25% cases.

Heliotrope rash of periorbital skin, Shawl Sign, V neck erythema and Gottron Sign, proximal muscle weakness.

MC associated with cancers of reproductive organs in women (MC Breast) and Lung, respiratory tract in both genders.

Most frequent pattern is onset of cancer within 1 year of diagnosis of DM.

Skin Neoplasms Assoc with

Internal MalignancyDISEASE DESCRIPTION MALIGNANCY HEREDITY

Muir-Torre

Syndrome

Sebaceous

Gland Neoplasm

Colon, Lymphoma AD

Cowden

Syndrome

COBBLESTONE

Tongue,

Fibromas

Thyroid, Breast,

Endometrial, RCC

AD

Gardner

Syndrome

Epidermal and

sebaceous cysts,

desmoid,

lipomas

Adenocarcinoma

Bowel, Thyroid

AD

Peutz-Jeghers Polyps of GI and

pigmentation of

lips, face

GI

Adenocarcinoma,

Pancreatic Cancer

AD

NF 1 Café au lait

spots,

neurofibromas

Pheochromocytom

a

AD

Tuberous

sclerosis

Angiofibromas,

pigmented

macules,

Neurological

malignancy

AD

DISEASE DESCRIPTION MALIGNANCY HEREDITY

VHL Syndrome Skin

ecchymoses,

retinal

malformation,

papilloedema

RCC,

Pheochromocytom

a

AD

Sturge Weber

Syndrome

Port wine stains

in C.N V

distribution

Rare neurological

malignancy

Somatic

mutation in

fibronectin

gene

AT Telangiectasis Lymphomas,

Leukemias

AR

Bloom

Syndrome

Photosensitivity,

telangiectasis,

butterfly

erythema of

face

Leukemias,

Lymphomas

AR

Chediak Higashi

Syndrome

Recurrent

pyoderma,

partial albinism

Lymphomas AR

Werner

Syndrome

Scleroderma

like, premature

aging, leg

Sarcomas,

Meningiomas

AR

Miscellaneous Lesions

Multicentric Reticulohistocytosis

- Violaceous papules over joints with

arthritis mutilans in 50% patients.

- Ca. Pancreas, SCC Lung, Melanoma

- Due to destructive effects of

proteinases.

Pruritis

- HD, Polycythemia vera, Mycosis

Fungoides

Neurological Manifestations of

CancerSYNDROME % PARANEOPLASTIC

Lambert-Eaton myasthenic

syndrome

60

Subacute Cerebellar Degeneration 50

Subacute Sensory Neuronopathy 20

Opsoclonus-myoclonus (children) 50

Opsoclonus-myoclonus (adults) 20

Sensory motor peripheral

neuropathy

10

Encephalomyelitis 10

Dermatomyositis 10

Approach to a patient with

Paraneoplastic Neurological

Disease Complete history and Neurological examination

MRI with and without contrast

MRI and FDG-PET – Monitor response to therapy

PET-CT – Most sensitive to identify occult tumors

CSF Examination

Effective tumor ablation either with surgery or systemic therapies is more effective then immunosuppression.

Immunosuppression with steroids, plasma exchange, IvIg (frequent choice), immunoasorption is variably effective.

Limbic Encephalitis Clinical symptoms range from rapid onset

psychotic symptoms to status epilepticus May be mistaken for Herpes Simplex

Encephalitis. MRI – Mesial temporal contrast

enhancement or T2 signal hyper intensities. CSF – Elevated protein, lymphocytic

pleocytosis. SCLC, Testicular Cancer, Breast Cancer,

HL, NHL. Treatable forms of CNS Paraneoplasms Rx – Treatment of Primary +

Immunosuppression

Autonomic Neuropathy

25% patients with anti-Hu syndrome and SSN-EMN have autonomic dysfunstion

Usually associated with SCLC

Autonomic dysfuction may occur in patients with Myasthenia Gravis

GI dysmotility is usually a core complaint with orthostatic hypotension, hypoventilation, sleep apnea and cardiac dysrhythmias.

Treatment may stabilize disease but usually unable to reverse

Progressive Cerebellar

Degenaration (PCD)

Difficulty with walking, diplopia,

vertigo, loss of dexterity, dysarthria,

oscillopsia

CSF – lymphocytic pleocytosis, mild

elevated protein, oligoclonal bands

Breast Cancer, Ovarian Cancer,

Hodgkin’s Disease

Antibody negative PCD may occur in

conjunction with Lambert-Eaton

syndrome. MC associated tumor is

SCLC

Paraneoplastic Visual Loss

Photoreceptor degeneration causes night blindness, photopsias, and blurred vision. Colour perception loss if cones are involved. ERG is abnormal.

MC antibody – anti carcinoma associated retinal antigen antibody; target antigen is recoverin.

SCLC, NSCLC, Breast Cancer

Progressive vision loss with retinal pigment changes – Melanoma or Adenocarcinoma of gut

Melanoma associated retinopathy

Opsoclonus-Myoclonus

Disorder of ocular motility and

multifocal myoclonus.

Described in children with

Neuroblastoma

No one antigen seems to be common

Anti-Ri Breast or Gynecological

Cancer

Paraneoplastic OM without Ri

antibodies assoc with Hodgkin’s

Lymphoma

Paraneoplastic MND

Separated into three groups in a

series by MSKCC

1. Anti-Hu antibodies

2. Assoc with Breast cancer

3. Assoc with underlying solid tumors

Patients with HL and NHL also

reported

Patients present with multifocal motor

weakness

Paraneoplastic Peripheral

Neuropathies Subacute sensorimotor neuropathy usually

presents with progressive distal, symmetric sensory loss and weakness in legs. Lung Cancer is MC associated

Nerve Biopsy – Axonal injury and demyelination

Can also occur in women with breast cancer.

Demyelinating neuropathies may respond to therapy but axonal neuropathies respond poorly to immunosuppresion

Acute polyradiculoneuropathy (APN) increased frequency with Hodgkin’s lymphoma which responds to plasmapharesis and IvIg.

Contd..

Secondary amyloidosis may also

cause painful sensorimotor

neuropathy in patients

Waldenstrom’s – Rx is Fludarabine,

Rituximab, Stem Cell Transplant

Myeloma – POEMS Syndrome

Painful mononeuritis multiplex –

SCLC, Prostate, Endometrial,

Lymphoma, RCC

Inflammatory Brachial Neuritis - HL

Neuromuscular Junction

Disorders Typical myasthenia assoc with

Thymoma in 15% cases. All patients to undergo CT chest to rule out thymoma.

Lambert Eaton syndrome assoc with SCLC – Proximal weakness, paresthesias, erectile dysfunction; Most patients benefit from plasmapharesis and immunosuppressants

Augmentation of compound motor action potential with repetitive stimulation

Paraneoplastic Syndrome with

Muscle Rigidity

Stiff-person syndrome- stiffness and rigidity in paraspinal and

abdominal muscles- Breast, HL, Colon- Antibodies against amphiphysin or glutamic

acid decarboxylase Neuromyotonia- spontaneous and continuous muscle fiber

activity of peripheral origin- Myasthenia in thymoma, HL, Plasma cell

dyscrasia, SCLC Peripheral nerve hyper excitability

disorders

Movement Disorders

Hyperkinetic syndromes predominate

Chorea – SCLC, ALL, RCC, HL

Parkinson’s – extremely rare; reported

in a man with multiple myeloma;

mechanism unclear.

Hypokinetic parkinsonism like features

reported in testicular seminoma

Movement disorders also reported in a

patient of B-cell lymphoma.