Raised platelet levels have emerged as a cancer risk marker, according to a large population-based study published in 2017(link is external). According to the study, 12 percent of men and 6% of women with thrombocytosis were diagnosed with cancer within a year. These figures increased to 18% in men and 10% in women if a second platelet count was taken within 6 months of the first and showed an increased or stable elevated platelet count.

The researchers discovered that thrombocytosis linked to cancer is most common in colorectal and lung cancers, and it is linked to a worse prognosis. Furthermore, one-third of the cancer patients in the study had no other symptoms that would have prompted an immediate cancer referral.

The exact mechanism by which these cancers cause thrombocytosis is unknown, but one theory proposes the existence of pathogenic feedback loops between malignant cells and platelets, with a reciprocal interaction between tumour growth and metastasis, as well as thrombocytosis and platelet activation. Another hypothesis is that thrombocytosis occurs independently of cancer but aids in its spread and progression.

The findings show that routinely testing for thrombocytosis could cut the time it takes to diagnose colorectal and lung cancer by at least two months. In the UK, this could result in around 5500 earlier cancer diagnoses per year.

Because the positive predictive value of thrombocytosis in middle age for cancer (10%) is higher than the positive predictive value for a woman in her 50s presenting with a new breast lump (8.5%), this is clearly an important research paper that should be used to adjust future clinical practise. The current NICE guidelines predate these new research findings, so we’ll have to wait and see how they affect cancer referral guidelines in the UK.

Because there are so many possible cancers associated with thrombocytosis, the treating clinician should take a thorough history and perform a thorough clinical examination if a patient is diagnosed with it. Further investigation and the most appropriate referral route should be aided by this information.

It’s worth noting that the patients in the study had their blood tests done for a medical reason rather than as a random screening test.

If there are no other symptoms to guide investigation and referral (one-third of the patients in the study had no other symptoms), keep in mind that the two most common cancers encountered were colorectal and lung cancer, so a chest X-ray and a faecal immunochemical test (FIT) for faecal blood may be reasonable initial investigations.

Activated leukocytes, adipocytes, and endothelial cells all release interleukin 6 (IL-6), a significant proinflammatory cytokine. The main downstream mediator of the acute phase response is C-reactive protein, which is predominantly produced by IL-6–dependent hepatic biosynthesis.

ALL is the most common leukaemia in children, with a peak incidence between the ages of 2 and 5.
ALL has a wide range of clinical symptoms, but many children present with an acute illness that resembles coryza or a viral infection. ALL also has the following features:
Weakness and sluggishness all over
Muscle, joint, and bone pain that isn’t specific
Anaemia
Petechiae and unexplained bruising
Oedema
Lymphadenopathy
Hepatosplenomegaly

The following are typical features of a full blood count in patients with ALL:
Anaemia (normocytic or macrocytic)
Leukopenia affects about half of the patients (WCC 4 x 109/l).
Around 25% of patients have leucocytosis (WCC > 10 x 109/l).
Around 25% of patients have hyperleukocytosis (WCC > 50 x 109/l).
Thrombocytopaenia

Cytokines are a family of chemical messengers, secreted by leucocytes, that act over short distances by binding specific receptors on target cell surfaces. They include: interleukins (act between leucocytes), interferons (inhibit replication of viruses within cells and activate macrophages and natural killer cells), growth factors, and tumour necrosis factors (kill tumour cells). Effects include: induction of fever and acute phase response, stimulation of leucocyte differentiation and maturation, leucocyte recruitment and activation and increased antibody production.

Dipyridamole inhibits both the reuptake of adenosine and phosphodiesterase, preventing the degradation of cAMP and thus blocking the platelet aggregation response to ADP.

The release of cytokines from Reed-Sternberg cells can cause fever in patients with Hodgkin lymphoma, which increases and decreases in a cyclical pattern of 1 to 2 weeks. This is called Pel-Ebstein or Ebstein-Cardarelli fever, specifically seen in Hodgkin lymphoma. The fever is always high grade and can reach 40 degrees or higher.

Cyclical fever in other conditions is common but is not termed as Pel-Ebstein fever. This term is reserved only with Hodgkin lymphoma.

Features of cell damage that tend to be reversible include: swelling of endoplasmic reticulum and some mitochondrialoss of ribosomescell stress response
Features of cell damage that tend to be irreversible include: loss of nucleolus, no ribosomes, swelling of all mitochondria, nuclear condensation, membrane blebs and holes, lysosome rupture, fragmentation of all inner membranes, nuclear breakup

The presence of dyspnoea makes alpha-1 antitrypsin deficiency the more likely diagnosis as biliary atresia does not cause respiratory symptoms. Deficiency of the enzyme alpha-1 antitrypsin causes uninhibited elastase activity and a decrease in elastic tissue. This causes liver cirrhosis leading to an elevation of conjugated bilirubin and emphysema in the lungs.

Rhesus disease, hereditary spherocytosis and breast milk jaundice cause an elevation of unconjugated bilirubin thus ruling it out in this case. Breast milk jaundice occurs due to an inability of the newborn to metabolize the proteins in breast milk.

Rhesus disease occurs when an Rh negative mother gives birth to an Rh positive baby. The jaundice would have been accompanied by anaemia and oedema.

Hereditary spherocytosis occurs due to extravascular haemolysis as defective RBCs are removed by the spleen. The patient would present with jaundice, splenomegaly and possibly an aplastic crisis (if Parvovirus B19 infection).

Anti-nuclear antibodies are auto-antibodies directed against a variety of nuclear antigens. There are different staining patterns and each pattern is suggestive of a different disorder.

Speckled staining is suggestive of mixed connective tissue disease.

Nucleolar staining is suggestive of scleroderma, while homogenous staining is suggestive of lupus.

Anti-double stranded DNA is suggestive of SLE while anti-histone antibodies are suggestive of drug-induced lupus.

ELISA testing is cheaper but not the most accurate means of testing for ANAs. Indirect immunofluorescence testing is the most accurate.

The presence of ANAs in rheumatoid arthritis is suggestive of Felty’s syndrome. Felty’s syndrome is characterized by a combination of rheumatoid arthritis, splenomegaly and neutropenia.

Minimal Change Disease is the most common cause of Nephrotic Syndrome in the paediatric population. It may be caused by NSAID use. Electron microscopy shows the fusion of foot processes while light microscopy will appear normal.

Focal segmental glomerulosclerosis causes Nephrotic Syndrome in adults. It is associated with Heroin use and HIV infection. There is a limited response to steroids, and the disease progresses to end-stage renal failure in 5-10 years.

Diabetic nephropathy occurs after a long period of diabetes due to the deposition of amyloid protein leading to a decrease in glomerular filtration.

There is no history of Hepatitis B in this patient and no symptoms of liver disease such as jaundice.

Membranous glomerulonephritis would present with features of Nephritic Syndrome. These would be oedema, haematuria; red blood cell casts in the urine and hypertension.