Paraneoplastic and systemic effects of neoplasia Flashcards
What are paraneoplastic syndromes?
Paraneoplastic syndromes are a consequence of cancer but not due to the location of cancer cells
The systemic effects of neoplasia are due to…?
Consequential to the location of the tumour cells
i.e. pericardial effusion due to right atrial HSA is a systemic rather than paraneoplastic effect
List the 3 main effects of neoplasia on the GI system
Cancer cachexia and anorexia
Gastroduodenal ulceration
Protein losing enteropathy
Describe the mechanism of cachexia and anorexia due to neoplasia
Uncommon in pet cancer patients but likely indicates poor QoL
1. Anaerobic respiration due glucose utilisation and tumoural hypoxia -> increased lactate production and altered insulin sensitivity
2. Altered metabolism due cancer related cytokines and inflammation
3. Poor appetite in some patients
What are the main consequences of cachexia and anorexia in cancer patients?
Weight loss, reduced fat mass, lean muscle loss -> poor treatment tolerance
How can you treat cachexia and anorexia in cancer patients?
- Maintain caloric intake by giving low carbohydrate high fat diet
- Omega 3 PUFA may be beneficial in reducing inflammation related changes
Why is GI ulceration seen in cancer patients?
- GI tumours can -> gastric or duodenal ulceration
- Some tumours produce hormones / metabolites -> gastric acid -> ulceration
What are the consequences of gastric/duodenal ulceration?
- Bleeding can lead to anaemia as a systemic effect.
- Melena or haematoemesis occasionally seen
- Risk of rupture
Which tumours produce hormone that lead to gastric ulceration?
- Dogs with MCT have elevated blood histamine -> GI signs, ulceration and bleeding
- Gastrinoma’s produce gastrin -> GI signs, ulceration and bleeding
Describe how protein losing enteropathy occurs due to neoplasia and the consequences of this
Systemic effect
Diffuse GI lesions can allow protein loss
- Typically low TP, globulin and albumin often accompanied by diarrhoea
- Low albumin -> ascites
- Myriad of other effects due to loss of proteins binding hormones, clotting factors etc.
Not specific for cancer but seen particularly with GI lymphoma
Name the 6 mechanisms of haematological effects of neoplasia
- Loss
- Reduced production
- Destruction
- Cytoses
- Mono-clonal gammopathies
- Coagulation disorders
Describe acute blood loss anaemias
- If no haematemesis or melena more likely splenic than GI
- TP drops before PCV
- Signs of shock
Describe chronic blood loss anaemias
- Main differentials are other GI or oral lesions
- Clinical signs of lethargy, pallor
- Poorly regenerative microcytic hypochromic anaemia due to iron deficiency
- Normal or elevated platelet count
Reduced production cytopenia’s can be due to which 3 causes?
- Anaemia of chronic inflammatory disease
- Myelophthisis
- Hyperoestrogenism
Describe the main features of anaemia of chronic inflammatory disease
- Common
- Causes include cancer, but also many other diseases.
- Mild / moderate normochromic normocytic non-regenerative anaemia.
Anaemia due to: - Disordered iron storage
- Shortened RBC life span
What is Myelophthisis?
Crowding out of stem cells in the bone marrow by tumour cells
Why does Myelophthisis occur?
Some tumours produce suppressive cytokines
- Tumour types include lymphoma, leukaemias, multiple myeloma, rarely histiocytic sarcoma and mast cell tumour
- Prevents formation of the normal bone marrow cells
Describe the anaemia cause my Myelophthisis
- Neutropenia then thrombocytopenia before anaemia
- Non-regenerative normochromic normocytic anaemia
- Diagnosis by bone marrow aspirate
Hoes how hyperoestrogenism cause reduced production cytopenias?
- Testicular tumours: 50% of dogs with Sertoli cell tumours
- Neutrophilia progressing to pancytopenia due to bone marrow hypoplasia
- Other signs are feminisation 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
Describe the causes of destruction cytopenias
Paraneoplastic immune mediated anaemia and thrombocytopenia - secondary to lymphoproliferative tumours and occasionally other tumours
Before treating paraneoplastic immune mediated anaemia and thrombocytopenia, what must be excluded from the differentials?
Immune mediated haemolytic anaemia
Immune mediated thrombocytopenia
What is microangiopathic anaemia
Fragmentation and shearing of RBCs leads to anaemia
- Caused by fibrin networks
- Schistocytosis is a key indicator
Name 3 conditions associated with schistocytosis
Disseminated intravascular coagulation
Haemangiosarcoma
IMHA
What do polychromatophils seen on blood smears indicate?
Sign of regeneration
What are the causes of erythrocytosis
- Renal tumours via increased EPO, lymphoma, nasal fibrosarcoma, TVT, hepatic tumours
- Clinically significant erythrocytoses include PU/PD, neurological signs and seizures
Describe treatment for erythrocytosis
Phlebotomy, removal of inciting cause, hydroxyurea
Eosinophilia is seen due to the production of which interleukin?
IL-5
Eosinophilia is most commonly associated with which tumours?
Mast cell tumours
T-cell lymphoma
What are monoclonal gammopathies?
Excess production of a single immunoglobulin (antibody) by tumour cells
Elevated serum globulins on biochemistry
What are the clinical signs of monoclonal gammopathies?
- Hyperviscosity (neurological including seizures and coma and cardiac signs)
- Reduced immune function
- Renal failure
- Coagulopathies
- Ocular disorders.
How are gammopathies diagnosed?
Electrophoresis of serum and urine (Bence-Jones proteins)
How would inflammation appear on electrophoresis?
Polyclonal gammopathy
How is coagulation affected by neoplasia?
Altered platelet function often seen in association with neoplasia
Infarcts / thromboembolism can result
How is disseminated intravascular coagulation linked to neoplasia?
- Syndrome of altered consumptive coagulation
- Thromboembolism in small vessels and bleeding due to consumption of platelets and clotting factors
- Multi-organ failure and death
- Mainly in association with carcinoma and HSA
How is DIC diagnosed on blood tests/smears?
Elevated APTT, PT, FDPs / D dimers, low fibrinogen, low platelet count, schistocytes
Paraneoplastic syndrome is the case of what % of hypercalcaemia in dogs and cats?
2/3 canine hypercalcaemia and 1/3 feline hypercalcaemia
List the clinical signs of paraneoplastic hypercalcaemia
- PU/PD
- Dehydration
- GI signs: inappetence and vomiting
- Weakness
- Muscle fasiculations
- Calcification of soft tissues (especially kidneys)
- Arrythmias
- Death
Describe initial management of severe hypercalcaemia is an emergency
Rehydrate with NaCl 0.9%
3 - 4 x maintenance – also enhances calciuresis
Once initially hydrated describe further management of severe hypercalcaemia is an emergency
- Continue fluids
- Consider furosemide: increases calciuresis by increase Na loss – moderate effect
- Consider bisphosphonates: toxic to osteoclasts therefore slows Ca release from bone
- Consider salmon calcitonin: short acting (a few days) but often effective
- Consider prednisolone: only when lymphoproliferative disease diagnosed or excluded
- Removal of inciting lesion: only effective long term treatment
Describe the function of prednisolone in paraneoplastic hypercalcaemia cases
Increases calciresis also kills malignant lympho proliferative cells
Describe the 4 functions of calcitonin in paraneoplastic hypercalcaemia cases
- Inhibits Ca2+ absorption by the intestines
- Inhibits osteoclast activity in bones
- Stimulates osteoblastic activity in bones
- Inhibits renal tubular cell reabsorption of Ca2+ allowing it to be excreted in the urine
Describe a complete workup for paraneoplastic hypercalcaemic patients
- Ensure rectal exam negative for anal gland tumours
- Assess and aspirate lymph node
- 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
- Bone marrow biopsy
- Consider ACTH stim if other signs are consistent with hypoadrenocorticism
Paraneoplastic syndrome due to an insulinoma causes which condition?
Hypoglycaemia
What are the clinical signs of hypoglycaemia?
Weakness, disorientation, seizures, coma and death
Describe management/treatment of paraneoplastic hypoglycaemia
Emergency – IV glucose + CRI glucose if necessary
Medical management – prednisolone, diazoxide, octreotide
Removal of inciting tumour
What are some non-neoplastic DDx of hypoglycaemia?
Sepsis
Starvation
Liver dysfunction
Hypoadrenocorticism
Lab error
Some toxicities
What is ectopic ACTH syndrome?
Rare
Reported in association with lung tumours
Clinical signs similar to hyperadrenocorticism
How is ectopic ACTH syndrome diagnosed?
Positive for hyperadrenocorticism tests
+ localisable tumour
No signs of adrenal associated hyperadrenocorticism
Name two paraneoplastic neurological sydromes?
Myaesthenia Gravis
Peripheral neuropathy
Describe the clinical signs of Myaesthenia gravis
Secondary immune mediated disease
Weakness
Exercise intolerance
Dysphagia
Megaoesophagus and regurgitation
When can you presume a Myaesthenia gravis diagnosis?
+ve ACHr antibodies and a relevant tumour
Myaesthenia gravis is most commonly seen due to which tumour?
Most commonly seen with thymoma
Also reported wt osteosarcoma and lymphoma
How is Myasthenia gravis treated?
Remove tumour and consider immunosuppression, manage other problems
Which tumours have been associated with peripheral neuropathies?
Lung tumours, insulinoma, lymphoma, MCT, thyroid adenocarcinoma, melanoma
How do peripheral neuropathies appear on histology?
Demyelination, myelin globulation and axonal degeneration
Name some conditions caused by cutaneous paraneoplastic syndromes
- 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
Feline Paraneoplastic Alopecia (FPA) is most commonly seen in which cats?
Older cats (7-16 years)
No sex or breed predilection
Describe the alopecia caused by feline paraneoplastic alopecia
- Acute-onset, non-pruritic, progressive symmetrical alopecia
- Initially affects ventral abdomen and limbs then generalises
- Hair easily epilated
What are the other clinical signs of feline paraneoplastic alopecia
Glistening skin:
- Alopecic skin inelastic and thin
- Smooth, shiny appearance
Footpad lesions: concentric scale, crusting and painful fissures affecting FPs
Malassezia dermatitis:
- Brown greasy accumulations around the eyes, nose and claw beds
- May be pruritic
List some DDx for feline paraneoplastic alopecia
Dermatophytosis
Demodicosis
SIA (pruritus, psychogenic)
Telogen defluxion
Endocrinopathies
Superficial necrolytic dermatitis (SND)
What is pancreatic panniculitis?
Inflammation and hydrolysis of adipose tissue
No age, breed or sex predilection
Pancreatic panniculitis is caused by which tumours?
Pancreatitis and pancreatic carcinoma and adenocarcinoma
Superficial necrolytic dermatitis (SND) can also be called?
Necrolytic migratory erythema
Hepatocutaneous syndrome
Describe the main features of superficial necrolytic dermatitis
Dogs and cats
Hepatic disease and pancreatic neoplasia
Associated amino acid deficiency
Distinctive histo and U/S
What are the main skin lesions seen in superficial necrolytic dermatitis?
Footpad hyperkeratosis - Erythema, crusting, hyperkeratosis, fissure formation
Crusting dermatitis - alopecia, erosions/ulceration, adherent crusts affecting pressure points, mucocutaneous junctions and feet
List some other clinical signs of superficial necrolytic dermatitis
- Early stages none
- Lethargy
- Inappetence
- Systemic signs associated with hepatic / pancreatic disease or rarely glucagonoma
- Some cases develop diabetes mellitus in association with hepatic disease
What is paraneoplastic pemphigus?
Autoimmune-induced ulceration of the mucosae and mucocutaneous junctions
Very rare cutaneous PNS
Describe the aetiopathogenesis of paraneoplastic pemphigus
- Lymphoma, thymoma, splenic sarcoma, metastatic thymic mass
- Primary immune mediated pemphigus also seen
- Exact pathomechanism unknown
- Antibodies against tumour antigens cross-react with self-antigens
What are the cutaneous clinical signs of paraneoplastic pemphigus
- Vesicles (rapidly rupture)
- Severe ulceration of oral cavity and mucocutaneous junctions
- Lesions often bilaterally symmetrical
- Clawbeds and pressure points may be affected
Describe the main features of feline Thymoma-Associated Exfoliative Dermatitis (FTAED)
Generalised exfoliative dermatitis
Most cases associated with thymoma
Some may be idiopathic
Older cats, no sex or breed predilection
Describe the cutaneous clinical signs of feline Thymoma-Associated Exfoliative Dermatitis
- Exfoliative dermatitis
- Non-pruritic
- Diffuse erythema and skin exfoliation/scaling
- Alopecia
- Head and pinnae, and then generalised - Kerato-sebaceous 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
What is nodular dermatofibrosis
Nodules of well differentiated collagenous nevi mainly on limbs but also heads and trunk
Nodular dermatofibrosis is seen in which animals?
Seen in middle aged GSDs with bilateral renal cysts or cyst adenocarcinoma
Inherited in autosomal dominant fashion
What is hypertrophic osteopathy
Palisading periosteal proliferation along the shafts of long bones.
What are the clinical signs of hypertrophic osteopathy?
Shifting lameness
Swelling / oedema
Limbs feel warm and are uncomfortable to touch
How is hypertrophic osteopathy diagnosed?
Clinical signs and radiography of long bones and pelvis
How is hypertrophic osteopathy treated?
Remove inciting cause
Prednisolone
Pain relief
Bisphosphonates
What are the effects of paraneoplastic syndromes on the cardiorespiratory system?
- Effusions are a systemic effect due to tumour exudation or bleeding
- Pleural: tachypnoea and dyspnoea and restricted breathing pattern
- Pericardial: signs of right side heart failure, collapse, pulsus paradoxus and electrical alternans
Which 3 tumours are commonly associated with pericardial effusion?
Haemangiosarcoma
Chemodectoma
Mesothelioma
What is the cause of paraneoplastic fever?
Sue to 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
