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Leucocytosis (DRAFT)

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Overview & Assessment in Primary Care

Definition:  White cell count >10.5 x 109/l.

Assessment in primary care: 

Is there a specific lineage of increased white cells, if not, no further assessment is required.

Leucocytosis is most commonly a normal response to systemic illness. In those without an overt reactive cause it may be important to exclude a primary (clonal) haematological diagnosis.

  • Is there an obvious reactive cause (infection, inflammation or neoplasia)?
  • Is it due to an increase in the lymphocytes, neutrophils, monocytes or a combination? (If lymphocytosis and neutrophilia reactive cause is more likely than a clonal haematological disorder)
  • Is the leucocytosis persistent and stable or progressive (and time scale of the latter)?
  • Is it isolated or associated with any other cytopenias?
  • Smoking commonly causes a low level neutrophilia and/or lymphocytosis.
  • Are there symptoms or signs associated with a myeloproliferative or lymphoproliferative condition (especially ask about sweats, fevers, weight loss, itching and examine for spleen and lymph nodes).
  • A blood film and CRP are useful initial investigations.

Please see attached flowchart to aid with triage

Neutrophilia

A neutrophilia is a common occurrence and rarely secondary to a haematological disorder. Bacterial infection is the commonest cause and (suspected by clinical context, high CRP, myeloid left shift with toxic granulation on the blood film)

Common causes:

  • Infection
  • Necrosis
  • Inflammation
  • Ischaemia
  • Drugs (corticosteroids)
  • Pregnancy
  • Smoking
  • Myeloproliferative neoplasms (MPN)

 Who to refer:

 Urgent haematology assessment:

  • New suspected chronic myeloid leukaemia (FBC, film comment) by Cancer Fast Track, or by telephone if with either white cell count >100 x 109/L or hyperviscosity symptoms (headache, breathless, visual loss, thrombosis)

Urgent outpatient assessment:

  • With leucoerythroblastic blood picture (from blood film report)

Referral for routine specialist opinion should be considered for:

  • Persistent unexplained white cell count >20 x 109/L
  • Persistent unexplained monocytosis >1 x 109/L with cytopenia
  • Unexplained neutrophilia >15 x 109/L
  • Eosinophilia or basophilia 

Haematological referral is usually not appropriate for:

Evidence of acute or chronic reactive cause of neutrophilia or monocytosis (e.g. elevated CRP). Suggest treating the underlying cause and reassessing the FBC following resolution of the causal illness. In uncertain cases, request a blood film and consider discussion with a haematologist.

For patients not meeting the criteria for referral, consider repeating the FBC in 3 months to assess for progression (or sooner if clinical context changes).

Red  Flags

Associations that may need urgent action:

  • Rapidly increasing WCC
  • An unwell patient
  • Splenomegaly
  • Cytopenias
  • Abnormal blood film
  • Basophilia may suggest MPN

Lymphocytosis

Definition: Lymphocytosis is defined as a lymphocyte count > 4 x 109/l.

Reactive lymphocytes seen on a blood film indicates that the most likely cause is infection, typically viral.

Important points:  A transient, reactive lymphocytosis is frequently seen in acute viral infection, particularly infectious mononucleosis. This may take several weeks to resolve therefore in the absence of other cytopenias or major symptoms the usual approach is to retest in 4-6 weeks.

Chronic lymphocytosis is characteristic of chronic lymphocytic leukaemia (CLL), the incidence of which peaks between 60 and 80 years of age. In its early stages this condition is frequently asymptomatic with treatment only being required on significant progression.

 Who to refer:

Urgent outpatient assessment:

  • Suspected acute leukaemia (immediate telephone referral)
  • Any patient with red flags (see below)

 Referral for specialist opinion is usually appropriate for:

  • Lymphocytosis in excess of 20 x 109/l
  • Associated lymphadenopathy
  • Confirmed presence of clonal B-cells / chronic lymphocytic leukaemia cells by haematology (immunophenotyping/flow cytometry) laboratory
  • If immunophenotyping/ flow cytometry demonstrates a polyclonal lymphocytosis then this indicates a reactive cause.

Referral for specialist opinion is an option for:

  • Persisting lymphocytosis > 10 x 109/l not fulfilling criteria above (In elderly, frail patients consider discussion with haematology first as monitoring in the community may be the most appropriate option).

Red Flags

Lymphocytosis in association with:

  • B symptoms (weight loss >10%, drenching sweats, unexplained fevers)
  • Splenomegaly or progressive lymphadenopathy
  • Anaemia, thrombocytopenia or neutropenia

Investigation in primary care for patients with lymphocyte count > 5 x 109/l not meeting criteria for referral:

In addition to investigations carried out under leucocytosis (above)

  • Glandular fever screen if appropriate
  • Consider HIV screen
  • Repeat FBC in 4-6 weeks – viral lymphocytoses are frequently transient
  • Lifestyle modification – smoking is a well-recognised cause of reactive lymphocytosis (plus mild neutrophilia). 

Monoclonal B Lymphocytosis

Definition:

Monoclonal B lymphocytosis (MBL) is defined as a clonal B-cell population in the peripheral blood with a total B lymphocyte count less than 5 × 109/L and no other signs of a lymphoproliferative disorder. The majority of cases of MBL have the immunophenotype of chronic lymphocytic leukaemia (CLL).

The diagnosis is usually suggested when a full blood count sample shows a persistent low level lymphocytosis and flow cytometry is triggered to assess further.

Important points:

Studies indicate that when assessed with standard diagnostic tests the incidence of MBL rises with age from around 4% in the 5th decade of life to as high as 10% of those over 60 years of age. Although all cases of CLL appear to be preceded by MBL, the majority of individuals with MBL will not develop a haematological malignancy.

In clinical practise new cases of MBL can be assumed to have B lymphocyte count >0.5 x 109/l unless otherwise reported by the flow cytometry laboratory. This form of MBL progresses to CLL (or small lymphocytic lymphoma – SLL) requiring therapy at a rate of 1% to 2% per year.  Monitoring is done in the same way as for CLL.

Who to refer:

Urgent outpatient assessment:

  • Not indicated

Referral for specialist opinion is usually appropriate for:

  • Presence of other features that suggest the diagnosis may not be MBL:
    • anaemia, thrombocytopenia or neutropenia
    • splenomegaly or progressive lymphadenopathy
    • B symptoms (weight loss >10%, drenching sweats, unexplained fever)

Referral for specialist opinion is an option for:

  • Persisting lymphocytosis > 10 x 109/l not fulfilling criteria above (In elderly, frail patients consider discussion with haematology first as monitoring in the community may be the most appropriate option).

Management in the community:

  • Low-count MBL is at low risk of progression, has no clear clinical implications, and requires no specific clinical follow-up.
  • In high-count MBL, given the risk of progression to CLL or SLL requiring treatment the recommendation is for an annual full blood count and periodic examination for lymph nodes and hepatosplenomegaly.

Referral

URGENT ADVICE: 9am to 5pm via hospital switchboard for haematology SpR. ONLY for emergency advice. Out of hours and weekends – emergency advice may be obtained from the on-call haematology clinician via hospital switchboard.

NON-URGENT ADVICE: use haematology advice and guidance service 

REFERRAL: through NHS e-referral system or cancer fast track pathways as indicated

Minimal information: the referral letter should include abnormal clinical findings (location, size, any associated features) and any abnormal full blood count results or other relevant test results, particularly if these investigations were not done in laboratories of the hospital to which the referral is made.

Resources

  • Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. T D Shanafelt , P Ghia, M C Lanasa, O Landgren & A C Rawstron. Leukemia volume 24, pages 512–520 (2010).
  •  Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Paolo Strati and Tait D. Shanafelt. Blood  2015  126:454-462.


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