Paraneoplastic syndromes and Systemic effects of Cancer

What is the difference between paraneopalstic syndromes?

• Paraneoplastic syndrome: consequence of cancer but not due to location

• Systemic effects: consequential to location of the tumour

What are the three main paraneoplastic syndromes related to the GI tract?

• Cachexia and anorexia

• Gastroduodenal ulceration

• Protein losign enteropathy

Explain how cancer can cause cachexia and anorexia

1. Anaerobic resp due to glucose utilisation + tumoural hypoxia leads to incr lactate prod + altered insulin sensitivity

2. Altered metabolism due to cancer related cytokines and inflam

3. Poor appetite in some patient

What are the CS of cancer cachexia + anorexia?

• wt loss

• reduced fat mass

• lean muscle loss

• poor treatment tolerance

How can you treat cancer cachexia and anorexia?

• Maintain/ increase caloric intake giving low carb high fat diet

• Omega 3 PUFA (may be beneficial to reduce inflam)

What CS are seen with gastric/duodenal ulceration?

• Bleeding can lead to anaemia as a systemic effect.

• Melena or haematoemesis occasionally seen

• risk rupture

How can gastroduodenal ulceration occur 2° to cancer?

• GI tumour

• Some tumours prod hormones/ metabolites that cause gastric acid prod + ulceration

  • MCT produce histamine —> GI signs, ulceration + bleeding

  • Gastrinoma's produce gastin —> GI signs, ulceration + bleeding

  • GI neuroendocrine tumours (GI bleeding poss due to hormone / cytokine production)

How can protein losing enteropathy occur 2° to cancer?

• systemic effect

• Damage to gut wall

  • Typically low TP, globlin, albumin often accompanied by diarrhoea

  • Low albumin -> ascites (transudate)

  • loss of proteins binding hormones, clotting factors etc.

• Seen partciularly with GI lymphoma

What are the mechanism of haeamatological effects 2° to cancer?

• Loss

• Reduced production

• Destruction

• Cytoses (incr prod)

• Mono-clonal gammopathies

• Coagulation disorders

What does acute vs chronic blood loss anaemia suggest? How do they present?

Acute: if no haematemesis or melaenia more likely splenic than GI

• TP drop before PCV

• shock

Chronic: many differentials are other GI or oral lesions

• lethargy, pallor (often adapt well)

• Poorly regenerative microcytic hypochromic anaemia due to iron deficiency

• Normal or elevated platelet count

What are reduced production cytopenias?

• Anaemia of chronic inflammatory disease (not just cancer)

  • Common

  • Mild-mod normochromic normocytic non-regen anaemia

    • Due to

      • disordered iron storage

      • shortened RBC life span

What is myelophthesis?

• Crowding out of stem cells in the bone marrow by tumour cells

• Some tumours produce suppressive cytokines

  • include lymphoma, leukaemias, multiple myeloma, rarely histiocytic sarcoma and mast cell tumour (when met to BM)

What does myelopthisis cause?

• One or several cytopenias

  • Neutropenia then thrombocytopenia then anaemia

    • Non regen, normochormic, normocytic anaemia

Dx by bone marrow aspirate

What tumour can cause hyperestrogenism?

Testicular tumours

(50% of dogs with Sertoli cell tumour)

What cytopenia do testicular tumours cause?

Neutopenia progressing to pancytopenia due to bone marrow hypoplasia

What are the CS of hyperoestrogenism? How can they possibly be reversed?

• feminisation signs and include symmetrical alopecia, pendulous prepuce, hyperpigmentation, penile atrophy, gynecomastia, prostatic metaplasia

• Castration can reverse many signs but bone marrow changes can be slow to recover or irreversible

What cancer does paraneoplastic IMHA and thrombocytopenia occur 2° to?

• Lymphoproliferative tumours (occassionally others)

  • must exclude before tx for IMHA

What are the features of microangiopathic anaemia secondary to cancer?

• Systemic effect

• Fragmentation and shearing of RBCs leads to anaemia

• Caused by fibrin networks

What is a key indicator of microangiopathic anaemia?

Schistocytosis

Which of the following conditions have been associated with schistocytosis

• DIC

• Lymphoma

• MCT

• Haemangiosarcoma

• STS

• Hyperadrenocorticism

• IMHA

• Metastatic carcinoma

DIC

Haemangiosarcoma

IMHA

(+ Metastatic carcinoma)

When can cause a paraneoplastic cytoses?

• Erythrocytosis

  • Renal tumours via inc EPO, lymphoma, nasal fibrosarc, TVT, hepatic tumours

    • erythrocytoses, PUPD, neuro signs (poor flow RBCs), seizures

• Neutrophilia

  • Seen with many tumours

  • tumour induced or immune response

• Eosinophilia

  • Due to IL-5 production

  • Most common with T cell lymphoma and MCT

How can erythrocytosis be treated?

• phlebotomy

• removal of inciting cause

• hydroxyurea

What causes a paraneoplastic mono clonal gammopathy?

Excess production of single immunoglobulin by tumour cells

• Elevated serum globulins on biochem

What are the clinical signs, diagnosis and treatment for a paraneoplastic monoclonal gammopathy?

• Clinical signs due to hyperviscosity (neurological including seizures and coma and cardiac signs), reduced immune function, renal failure, coagulopathies and ocular disorders.

• Dx: Electrophoresis of serum and urine (Bence-Jones proteins)

  

• Tx: plasmapheresis and tumour directed treatment

Which of the following are commonly associated wiht monoclonal gammopathies?

• Melanoma

• Myeloma

• Leukaemia

• Carcinoma

• Lymphoma

• Myeloma

• Leukaemia

• Lymphoma

How can coagulation be affected by neoplasms? What can these cause?

• Altered coagulation- altered platelet function

  • Infarct/ thromboembolism

• DIC (altered consumptive coagulation)

  • Thromboembolism in small vessels and bleeding due to consumption of platelets and clotting factors

  • Multi-organ failure and death

  • often in end stage patients

What will be seen on haem when DIC is present?

• Elevated APTT, PT, FDPs (fibrin degred prod)/ D dimers

• low fibrinogen

• low platelet count

• schistocytes

What are the main tumours associated with DIC?

Carcinoma and HSA

What endocrine alterations can occur paraneoplastically?

• Hypercalcaemia (apocrine gland anal sac carcinoma/anal sac adenocarcinoma)

• Hypoglycaemia

• Ectopic ACTH syndrome

• Hyperestrogenism

What mechanisms can cause paraneoplastic hypercalcaemia?

• Elevated PTH or PTH related peptide (mimic PTH)

• IL-1 beta, TGF beta, RANKL

• Bone lysis (osteolysis)

What are some non neoplastic differentials for hypercalcaemia?

lab error, renal failure, hypervitaminosis D, hypoadrenocorticism, granulomatous disease

What are the clinical signs of hypercalcaemia?

• PU/PD

• Dehydration

• GI signs – inappetence and vomiting

• Weakness

• Muscle fasciculations

• Calcification of soft tissues (especially kidneys) Ca x P >5

• Arrythmias

• Death

How do you treat hypercalcaemia? (urgent)

• Rehydrate with NaCl (3-4x maintenance) —> enhances calciuresis

  • fluids without Ca + with Na

• Then:

  • Continue fluids

  • Consider:

    • Furosemide —> incr calciuresis by incr Na loss

    • Bisphosphonates —> toxic to osteoclasts so slows Ca release from bone

    • Salmon calcitonin —> antagonise PTH (short-acting)

    • Prednisolone (only if lymphoprolif disease diagnosed or exluded)

• Remove inciting cause is only real tx

How would you work up a hypercalcaemia case?

• Assess tCa and iCa, also consider phosphate

• Ensure rectal exam negative for anal gland tumours

• Assess and aspirate LN

• Check history for diet and toxin exposure

• Imaging of thorax and abdomen and ultrasound neck esp. if iCa ↑ and Phos ↓

• PTH / PTHrp / vitamin D if appropriate history of exposure

  • Reference interval PTH is abnormal in a hypercalcaemic animal

• Bone marrow biopsy

• Consider ACTH stim if other signs are consistent with hypoadrenocorticism

What is the main neoplasm causing hypoglycaemia?

Insulinoma

• (Also hepatocellular carcinoma, smooth muscle tumours and number of others)

• Caused by insulin, IGF 1 or 2

What are the CS of hypoglycaemia?

• weakness

• disorientation

• seizures

• coma

• death

How do you manage a paraneoplastic hypoglycaemia?

• Emergency – IV glucose + CRI glucose if necessary

• Medical management – prednisolone (incr gluconeogenesis), diazoxide (decr insulin), octreotide (somatostatin, block insulin secretion)

• Removal of inciting tumour

What are the non neoplastic ddxs for hypoglycaemia?

• Sepsis,

• Starvation,

• Liver dysfunction,

• Hypoadrenocorticism,

• Lab error

• Some toxicities

What are the features of ectopic ACTH syndrome?

• Rare

• Reported in association with lung tumours

• Clinical signs similar to hyperadrenocorticism (Cushings)

• Diagnosis

  • Positive for hyperadrenocorticism tests

  • + localisable tumour

  • No signs of adrenal associated hyperadrenocorticism

• Management

  • Excision of primary lesion

What paraneoplastic neurological effects can you get?

• Systemic effects of neurological mass lesion

• PNS

  • Myaesthenia Gravis

  • Peripheral neuropathy

commonly type 2 hypersensitivity reaction

How does myaesthenia gravis present as a paraneoplastic syndrome?

• Immune mediated disease

• Most commonly seen with thyomoma

  • also osteosarcoma and lymphoma

What are the CS of myasthenia gravis and how is it dx?

• Weakness

• Exercise intolerance

• Dysphagia

• Megaoesphagus and regurgitation

• Presumptive diagnosis —> +ve ACHr antibodies and a relevant tumour

How is myasthenia gravis tx?

• remove tumour

• consider immunosuppression

• manage other problems

How does a peripheral neuropathy present?

• Wide range of tumour types associated

  • lung tumours, insulinoma, lymphoma, MCT, thyroid adenocarcinoma, melanoma

• Not very common clinically apparent lesions

  • Mild to moderate and symmetrical – vague signs such as weakness

What is seen on histo of patients with peripheral neuropathy?

Demyelination, myelin globulation and axonal degeneration

The the possible cutaneous paraneoplastic syndrome

• Alopecia and Malassezzia associated dermatitis

• Pancreatic associated panniculitis

• Superficial necrolytic dermatitis (SND)

• Paraneoplastic immune mediated disease – Pemphigus and Erythema multiforme

• Feline Thymoma-Associated Exfoliative Dermatitis (FTAED)

• Cutaneous flushing

• Nodular dermatofibrosis

What are the features of feline paraneoplastic alopecia?

• Alopecia

  • acute onset

  • non-pruritic

  • progressive symmetrical alopecia

  • initially ventral abdo then limbs

  • hair easily epilated

• Glistening skin

  • Alopecic skin inelastic and thin

  • smooth shiny appearance

• Footpad lesions

  • Concentric scale, crusting and painful fissure affecting FPs

• Malassezia dermatitis

  • brown greasy accumulations around the eyes, nose and claw beds

  • may be pruritic

What are the ddx of feline paraneoplastic alopecia?

dermatophytosis, demodicosis, SIA (pruritus, psychogenic), telogen defluxion, endocrinopathies, SND

What is pancreatic panniculitis?

Inflammation and hydrolysis of adipose tissue due to pancreatitis and pancreatic carcinoma and adenocarcinoma

Pancreatic enzymes (lipase, amylase, trypsin)

What is Superficial necrolytic dermatitis (SND) aka hepatocutaneous syndrome?

=hepatocutanoues syndrome, necrolytic migratory erythema

• Cause by hepatic disease and pancreatic neoplasia

• Assoc amino acid deficiency

• Red white and blue histo

• Footpad hyperkeratosis + crusting dermatitis

What are the CS of Superficial necrolytic dermatitis?

• Footpad hyperkeratosis

  • erythema, crusting, hyperkeratosis, fissure formation

• Crusting dermatitis

  • alopecia, erosions/ulceration,adherent crusts affecting pressure points, mucocutaneous junctions and feet

• Other clinical signs:

  • Early stages none

  • Lethargy

  • Inappetance

  • Systemic signs associated with hepatic / pancreatic disease or rarely glucagonoma

  • Some cases develop diabetes mellitus in association with hepatic disease

What is paraneoplastic pemphigus?

• Very rare cutaneous PNS

• Autoimmune-induced ulceration of the mucosae and mucocutaneous junctions

  • antibodies against tumour antigens cross-react with self-antigens

• Lymphoma, thymoma, splenic sarcoma, metastatic thymic mass

• Primary immune mediated pemphigus also seen

What are the CS of paraneoplastic pemphigu?

• Oral and mucocutaneous ulceration

  • Vesicles

  • severe oral ulceration + mucocutaneous junctions

  • often bilat symmetrical

  • clawbeds and pressure points poss effected

What is Feline Thymoma-Associated Exfoliative Dermatitis (FTAED)?

• Generalised exfoliative dermatitis

• Most cases associated with thymoma

What are the CS of Feline Thymoma-Associated Exfoliative Dermatitis

• Exfoliative dermatitis

  • non-pruritic

  • diffuse erythema and skin exfoliation/scaling

  • alopecia

  • head and pinnae, and then generalis

• keratosebaceous accumulations

  • brown, keratosebaceous debris interdigital skin, claw beds and ear canals

  • some cases associated with Malassezia dermatitis

• crusting and ulceration

What is cutaneous flushing?

• Periodic release of vasoactive substances by tumours leads to skin colour changes

• Rarely reported but reported with pheochromocytoma, lung tumours and MCT

• Ddx: Demodicosis, drug reactions and systemic lupus erythematosus

What is nodular dermatofibrosis?

• Nodules of well differentiated collagenous nevi mainly on limbs but also heads and trunk

• Seen in middle aged GSDs with bilateral renal cysts or cyst adenocarcinoma

(Inherited —> autosomal dominant)

What is hypertrophic osteopathy?

• Periosteal proliferation along shaft of long bones

• 2° to pulmonary (or abdo) tumours

• Inc blood flow to limbs due to afferent neurological stim

What are the CS of hypertrophic osteopathy and how is it dx?

• Shifting lameness

• Swelling / oedema

• Limbs feel warm and are uncomfortable to touch

Dx —> CS, Rx of long bones + pelvis

How is hypertrophic osteopathy treated?

• Remove inciting cause

• Prednisolone

• Pain relief

• Bisphosponates

What causes paraneoplastic pyrexia? What tumours is it seen with?

• Expression of inflammatory cytokines by or in response to the tumour.

• Seen with a variety of tumours especially lymphoma, renal cancers and hepatic tumours.

• Can lead to anorexia and malaise.

(exclude infec)

How is pyrexia tx?

• removal of the tumour

• NSAIDS / paracetamol

What is a common systemic cardioresp effect due to tumour exudation or bleeding?

Effusions (due to tumour exudation or bleeding)

• Pleural

  • Tachypnea and dyspnea and restricted breathing pattern

• Pericardial

  • Signs of right side heart failure, collapse, pulsus paradoxus and electrical alternans