Case 110 – summary

Thankyou for all your help this week

This week we had a look at 4 films where there were visible organisms.

Film 1 – babesia

Film 2 – malaria – p.vivax

Film 3 – malaria – p.falciprum

Film 4 – diplococci – neisseria meningitidis

When looking at films where there is a suspicion on infection clinical details are very important. This will enable the appropriate tests and blood film preparations to be made to aid diagnosis. Travel history is very important to aid diagnosis.

Film 1 – babesia.

Babeosis is a tick borne protozoan infection that is see in Europe, Asia and north west and north eastern america. Humans are usually affected by babesia microti. Many patients will have no, or only mild symptoms. Symptoms can include fever, headache, myalgia and nausea/vomiting. In patients who are asplenic or immunocompromised severe disease may occur.

Symptoms are usually related to the parasitaemia of red cells by babesia. Infected red cells can contain more than one merozoite. The ring forms may be mistaken morphologically for p.falciprum malaria so travel history is very important when looking at individual cases.

Haemolytic anaemia and haemoglobinuria can be present in severe infections. Some patients may also develop ARDS and/or multi organ failure.

Although the majority of cases are transmitted via bites from infected ticks. Transmission has also been seen from blood transfusions from infected donors. Perinatal and transplacental infection can also occur.

Symptoms can persist for several months after initial infection, and can also recur, particularly in asplenic patients and those on immunosuppressive treatment.

In patients with lower parasitaemia multiple thin films or stained buffy coat preperations may be needed to identify the parasite. Wright or giemsa stained thin films can show the ring forms. In some cases the ‘maltese cross’ made up of merozoites. P.falciprum can be mistaken for babesia, Maltese crosses are not seen in p.falciprum, there is also a lack of hemozoin in babesia.

Serological testing and PCR to investigate for babesia can be performed.

Patients with babeosis will need treatment with antibiotics and may need HDU/ITU care in severe cases. All suspected cases should be discussed with local infectious disease/microbiology team. In severe cases exchange transfusion may be considered.

Case 2 – p.vivax malaria

Case 3 – p.falciprum malaria

Travel history is again very important when malaria is suspected. Not only when trying to establish the likely parasite, but also establish the likelihood of drug resistance.

P.vivax is the most common human malaria transmitted globally, although p.falciprum has a higher mortality.

Patients may present with fever, myalgia, headache, nausea/vomiting, and can present with symptoms of haemolysis and organ failure in more severe cases. Occasionally patients can present with features of cerebral malaria including seizures and altered consciousness.

When examining blood films identification of parasites can be made on thin films, however it is important to look at think films as low levels of parasites may be missed on thin films. Thick films should be stained with giemsa or field stain, and thin films with giemsa or leishman stain. A thick film should be examined for around 10 minutes, which equates to around 200 oil immersion fields before it is declared negative. Each thick film should be reviewed by 2 people.in p.falciprum and p.knowelsi the percentage of cells with parasites should be calculated and reported as this may effect the choice of treatment. If there is doubt as to whether parasites can be seen on the thick film, the entire thin film should be reviewed.

Rapid diagnostic tests(RDT) can be used when suspecting malaria, but are not a substitute for microscopy.

Quantification of parasites should be done daily until no parasites are seen

Patients who have traveled to the Asia-Pacific area who are thought to have p.malariae should have samples sent urgently to the malaria reference lab for pcr as p.malariae and p.knowlesi are very difficult to distinguish from one another.

Samples should be sent to a malaria reference lab if there are positive results, if there is discrepancy between films and

RDT or if there is strong clinical suspicion after discussion with ID team but no positive results. If films are negative then team should consider repeating the film in 12-24 hours, and then again at 24 hours.

PCR is more sensitive than microscopy for malarial parasites however is not widely available, but is used in the reference lab, and can be particularly useful in patients with mixed infection.

All labs involved in testing for malarial parasites should be involved in EQA schemes for parasites.

When diagnosing p.vivax, it is important to consider testing for g6pd deficiency as treatment may involve primaquine which can precipitate haemolysis in patients with g6pd deficiency.

As p.vivax can lie dormant in liver cysts recurrent infections can occur.

The treatment of p.falciprum is guided by the severity of the disease. Severe infection can be rapidly fatal so prompt treatment can be life saving.

In severe cases of malaria red cell exchange can be considered.

Links at the bottom show some aids to diagnosing malaria from the CDC. There is also a link to the bsh guidelines for malaria diagnosis.

Film 4 – diplococci – neisseria meningitidis

In this case a patient was admitted collapsed and unwell with no collateral history and they were subsequently diagnosed with neisseria meningitidis bacteraemia and suspected meningitis.

The blood film demonstrates diplococci. It is unusual to see bacteria on blood films and when this is seen it should rapidly be reported to the caring physician to enable appropriate treatment as these patients are usually extremely unwell. If the patient has no signs or symptoms of infection then contamination can be considered.

Thankyou for all your help this week. This week we looked at 4 cases where microscopy was important in the diagnosis of infections.

Are there any questions following this week’s case?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

Bsh guideline on laboratory diagnosis of malaria

https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12572

CDC information on malaria

https://www.cdc.gov/dpdx/malaria/index.html

CDC bench aid to p.vivax diagnosis

https://www.cdc.gov/dpdx/resources/pdf/benchAids/malaria/Pvivax_benchaidV2.pdf

CDC bench aid to p.falciprum diagnosis

https://www.cdc.gov/dpdx/resources/pdf/benchAids/malaria/Pfalciparum_benchaidV2.pdf

CDC bench aid to p.ovale diagnosis

https://www.cdc.gov/dpdx/resources/pdf/benchAids/malaria/Povale_benchaidV2.pdf

CDC bench aid to p.malariae diagnosis

https://www.cdc.gov/dpdx/resources/pdf/benchAids/malaria/Pmalariae_benchaidV2.pdf

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Case 110 – part 4

Welcome to the last part of this case.

You get a phone call from the lab for a patient who has attended a&e. The patient has no fixed abode and has been found collapsed in the steet. They are unable to give a history, but have attended the department after being found collapsed following drug overdoses previously.

Hb 110 plt 20 wcc 17 neuts 12

What does the film show. How would you proceed?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

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Case 110 – part 3

Here is the 3rd part of this week’s case.

A patient has come in to a&e very unwell, with fever and has had a seizure whilst in the department. The patient came back yesterday from a trip to Malawi.

Hb 80 plt 30 wcc 12 neut 12

We have been asked to look at the film.

What does the film show? How would you proceed?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

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Case 110 – part 2

Welcome to the second part of this week’s morphology based case.

A&E have asked for a film for a patient who has come in with fever.

Hb 90 plt 50 wcc 15 neuts 8

What does the film show? What other investigations should be done? What would you do next?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

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Case 110 – part 1

Welcome to this week’s case!

This week we will have some short morphology cases.

Our first case starts with a call from the lab.

A patient has attended a&e unwell and the lab have made a film. There is something unusual on it and we have come in to have a look.

Hb 90 plt 50 wcc 14 neuts 8

How would you report this? What could the diagnosis be? What would your next steps be?

Join us on Twitter @TeamHaem and let us know what your thoughts are, what questions you have and what you want to do as we see this case evolve over the next week. Remember to use #teamhaem on all your posts to help us follow the case! Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality. TeamHaem are not a position of authority. It is an educational platform to allow discussion and learning

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Case 109 – summary

Thanks for all your help this week. This week’s case focused on Thrombocytopenia pregnancy that ultimately was ITP responsive to steroid therapy.

Mild gestational thrombocytopenia (with platelet counts <150×10^9/L) is common affecting up 5-10% of pregnant women.

Pregnant women with mild thrombocytopenia of platelets 100-150×10^9/L and normal blood film/screening blood tests should stay in primary care with monthly FBC and advice to refer to secondary care if platelet counts fall below 100×10^9/L.

Only 1% of pregnant women will have a platelet count less than 100×10^9/L which is the international working groups definition of thrombocytopenia and this is the range where further specialist investigation and referral to secondary care is appropriate.

A suggested approach to thrombocytopenia in preganancy is outlined below:

History:

• Previous FBC results: Thrombocytopenia prior to pregnancy points to causes other than gestational thrombocytopenia.

• Family history: Type IIb VWD although rare can present as thrombocytopenia in pregnancy.

• Medication History: Any changes in medications. Many drugs in common use can cause isolated thrombocytopenia – worth checking a patients medications.

• Features of Connective tissue diseases (CTD): Fatigue, Rashes, Joint stiffness, sore eyes etc.

• Gestation at onset: Later in pregnancy more likely to be due to pregnancy specific causes like Pre-eclampsia, HELLP, Acute Fatty liver of pregnancy etc. Gestational thrombocytopenia is more common in second and third trimesters.

• Personal Bleeding history: BAT score may help indicate if underlying bleeding disorder, particularly useful if no previous blood tests available and family history of bleeding.

 

Initial investigations:

• FBC repeat plus CD61 platelet count or citrate count: Confirm genuine thrombocytopenia.

• Blood film: Film crucial to exclude underlying marrow disorder and to look for fragmentation, signs of haemolysis, hereditary thrombocytopenia with giant platelets or white cell inclusions or for signs of infection.

• U&E, LFT’s: May be abnormal if HELLP/Pre-eclampsia/HUS.

• Coagulation screen inc D-Diner: Abnormal if DIC/HELLP.

• VWD screen: Useful particularly if family history to exclude type IIb VWD.

• Antiphospholipid antibodies

• ANA

• HIV, Hep B, Hep C

• B12/Folate: Rarely a cause of isolated thrombocytopenia

• Physical examination: Look for mucosal bleeding petichiae and any signs of Connctive tissue diseases.

Optional testing depending on findings:

  • TFT’s: Thyroid problems may be associated with ITP in pregnancy as part of autoimmune spectrum.
  • Ig levels: If history of frequent infections.
  • Other viral serology: if indicated from history or film.
  • H.Pylori serology.
  • DAT, LDH and Retics: If concern Evans syndrome due to spherocytes on film.
  • ADAMTS 13 testing if fragmentation on film.
  • Bone Marrow: If suspicion of primary blood disorder from film.

 

Establishing the Diagnosis:

Broadly speaking thrombocytopenia in pregnancy is best thought of in five distinct categories depending on the investigations above.

 

1) Normal Blood film and other investigations (most likely scenario):

• Gestational thrombocytopenia (GT) – accounts for 75% total

• ITP – 5%

 

Useful features to distinguish the two diagnoses:

Rare for GT to cause platelet count <50×10^9/L.

GT usually occurs mid-late second trimester and during the third trimester where as ITP can occur earlier (as in this case).

There may also be a history of previous thrombocytopenia in pregnancy that fully resolves post-partum in GT. hence very important to monitor platelet counts post partum.

 

2) Atypical lymphocytes on film, raised inflammatory markers:

• Infection

 

3) Microspherocytes, agglutination or clumping on film and positive DAT:

• Evans syndrome

 

4) Blasts on film

• Pimary bone marrow disorder

 

5) Schistocytes on film – 15% of patients

• TTP

• HUS

• DIC

• Pre-eclapsia/HELLP/Acute fatty liver of pregnancy

 

The rest of this case focuses on our lady who had a normal blood film and isolated thrombocytopenia. It is important that the possible cause of thrombocytopenia is established before embarking upon management as the approaches for management of HELLP or TTP vary greatly to the management of ITP for example.

 

Monitoring patients with Isolated thrombocytopenia thought to be ITP:

All patients should be referred for secondary care review if platelets <100×10^9/L and have an antenatal anaesthetics review.

There is little evidence to suggest what appropriate monitoring should be and it should be tailored to platelet count and the rates of decline seen rather than a rigid time based check for example every 4 weeks. The consensus seems to be monitoring should be somewhere between 2-6 weekly Depending on the individual. In the third trimester particularly after 34 weeks weekly checks if plt <80×10^9/L are suggested especially if treatment is given.

Patients with thrombocytopenia in pregnancy should be advised of who to contact in case of bleeding or concerns. They should also be asked to avoid IM injections, though BCSH guideline makes it clear low dose aspirin prescribed for obstetric reasons should not be automatically withheld unless high bleeding risk.

All patients should have repeat FBC 1-3 months post-delivery to check for spontaneous resolution of thrombocytopenia. This is important particularly if GT was thought to be the cause of thrombocytopenia as by this timepoint the thrombocytopenia should have resolved.

Treating patients with Isolated thrombocytopenia thought to be ITP:

BCSH guidelines suggest treatment for ITP should be in order to achieve “safe” platelet counts and not necessarily normalise platelet counts.  BCSH guidelines state that although no robust trials it is reasonable to leave asymptomatic pregnant women with platelet counts of 20-30×10^9/L without treatment until the third trimester.

Treatment approaches for ITP during pregnancy vary slightly but generally treatment is with prednisolone first line starting at 10-20mg dose of prednisolone with IVIG reserved in case of bleeding or as second line therapy.

Treatment is usually prednisolone for a week, adjusting to minimum dose of prednisolone that maintains a response. Response time is usually around 3-7 days. It is recommended that tapering of doses is suspended near term as often platelet count falls at term. Slow taper also recommended post-partum as quick tapering can affect the mother’s psychological state.

The treatment aims to achieve  a minimum platelet count of 50×10^9/L for vaginal delivery. Platelet counts of >80×10^9/L will usually be needed for neuroaxial anaesthesia.

Although steroids are relatively safe in pregnancy common side effects are impaired glucose tolerance, hypertension, mood change and weight gain.

Second line therapies and agents for ITP are less clear and would require discussion in an MDT setting depending on the individual patient.

Delivery planning for patients with ITP:

Mode of delivery should be based on obstetric indications there is no need for Cesarean section in ITP patients as no evidence to show this reduced ICH rates in thrombocytopenic neonates.

Ideally delivery should be in a hospital with Haematology and obstetric care.

General consensus both in How I treat and RCOG review of thrombocytopenia in pregnancy is that a platelet count >50×10^9/L is required for vaginal and operative delivery. For epidural anaesthesia platelet count needs to be >80×10^9/Land an anaesthetic review before delivery is recommended to discuss alternative analgesia if thrombocytopenia at delivery.

Platelet transfusions should be available in case of complications but should not be routinely administered.

Neonates born to mothers who have ITP do have a risk of thrombocytopenia due to passage of Ig G Ab across the placenta. 15-30% of babies born to mothers with ITP are thrombocytopenic though only 5% have counts <20×10^9/L. It is worth stating that antenatal steroids and IVIG have no effect on the fetal platelet counts. The passage of antibodies is unpredictable therefore mothers platelet counts won’t always indicate the likelihood of associated thrombocytopenia in the baby. A history of sibling with thrombocytopenia at birth, mother with previous splenectomy or platelet count <50×10^9/L at delivery are predictors of an increased risk of neonatal thrombocytopenia. This means all babies born to mothers with presumed ITP should be treated as possibly being thrombocytopenic. Fetal scalp electrodes and instrumental deliveries are ideally avoided and cord blood should be taken at delivery to confirm the platelet count. IM vitamin K should also be avoided. Platelet counts should also be checked at day 1 and 4 post delivery, as platelet nadir around this time. If platelets less than 50×10^9/L or symptomatic transcranial USS should be performed.

Postnatal care should include daily FBC of mother until day 5 post partum.

Prenatal counselling of mothers with ITP:

Pre-pregnancy counselling for a lady with ITP as recommended by RCOG should include:

• Discussion that ITP relapses may occur during pregnancy.

• Around a third of women will need treatment in pregnancy usually in third trimester.

• An epidural may not be possible if thrombocytopenic.

• There is an increased chance of a sibling being affected with thrombocytopenia if a mother has had splenectomy or previous baby with neonatal thrombocytopenia.

• Risk of adverse delivery outcomes for mother or major bleeding in neonates is thankfully low with correct planning and monitoring.

 

References:

Provan et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010 115:168-186.

B Myers. Diagnosis and management of maternal thrombocytopenia in preganancy. BJHaem, 2012, 158, 3-15.

B.Myers. Review Thrombocytopneia in pregnancy. RCOG 2009.

T Gernsheimer et al. How I treat thrombocytopenia in pregnancy. Blood 2013. 121.

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Case 109 – update 4

Thanks for your help so far. The lady thankfully had an uneventful normal vaginal delivery. She had chance to have an anaesthetics review prior to labour and had been attending joint obstetric and haematology clinic. Her pre prepared birth plan included the following points:

Mode of delivery based solely on obstetric indications.

Delivery should ideally be in a hospital with Haematology and obstetric care.

Target platelet count >50×10^9/L for vaginal and operative delivery.

For epidural anaesthesia platelet count needs to be >80×10^9/L.

Platelet transfusions should be available in case of complications.

Haematology team to be contacted if any concerns regarding platelet count or bleeding.

Neonates born to mothers who have ITP do have a risk of thrombocytopenia due to passage of Ig G Ab across the placenta. 

15-30% of babies born to mothers with ITP are thrombocytopenic. All babies born to mothers with presumed ITP should be treated as possibly being thrombocytopenic. When writing birth plans and the following points need to be communicated to obstetric and paediatric team as happened in this case.

Foetal scalp electrodes and instrumental deliveries are ideally avoided.

Cord blood should be taken at delivery to confirm the platelet count.

IM vitamin K should also be avoided.

If platelets less than 50×10^9/L on cord blood or symptomatic transcranial USS should be performed.

Our lady had a healthy baby boy with a normal platelet count of 370×10^9/l on cord blood sampling.

Does the baby require any further platelet count monitoring? If so when would you check platelet count again?

The lady is keen to know of the implications of her ITP on future pregnancies, how likely is she to need treatment for ITP in further pregnancies?

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Case109 – update 3

The lady’s platelet count responded to 20mg Prednisolone and is now at 65×10^9 at 38 weeks gestation. 

The obstetric team are keen for a plan for delivery what advice would you give the team? 

What advice would you give to the neonatal team?

How common is transient neonatal thrombocytopenia in mothers who have ITP?

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Case 109 – update 2

You suspected ITP or possibly gestational thrombocytopenia and embarked on monitoring her platelet counts every few weeks. The lady is now 34 weeks pregnant and is otherwise well. Her platelet count has started to fall over the past 6 weeks and is now 30×10^9/L. She is well with no bleeding.

What is the most likely diagnosis now?

How would you manage this patient at this stage?

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Case 109 – update 1

The lady had a repeat FBC that confirmed isolated thrombocytopenia with a platelet count of 80×10^9/l Her blood film is shown below you check carefully and there are no platelet clumps. Her CD61 platelet count is 75×10^9/l

You establish that she has had a previous normal FBC two years ago. She is usually fit and well and takes no medications. She has no family history of thrombocytopenia. This is her first pregnancy and he has been well so far with no problems. She has not had any recent heparin.

What does the blood film show?

What is the differential diagnosis?

How would you monitor the patient  and who should do the monitoring?

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Case 109 – the beginning

A 32 year lady is 11 weeks pregnant. She has had her booking blood tests performed by her midwife and her FBC has shown an isolated thrombocytopenia of 90x10^9. 

What History would you like ask her?

What investigations would you like to perform?

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Case 108 – Summary!

Thank you for everybody’s contributions throughout the week!

We focused upon a 32 year old man who presented with asymptomatic unilateral cervical lymphadenopathy and was subsequently diagnosed with limited stage nodular lymphocyte predominant hodgkin lymphoma (NLPHL). He was treated with radiotherapy alone. As is classical of this disease he had a late relapse at 5 years with stage III disease involving splenomegaly and was treated with R-CHOP. 18 months after this he developed transformed T cell/histiocyte rich B cell lymphoma and was treated with salvage regime and ASCT with TLS prophylaxis and CNS prophylaxis due to the extent of disease. Below is a summary of NLPHL.

 Nodular Lymphocyte Predominant Hodgkin Lymphoma 

NLPHL is a rare subtype of Hodgkin Lymphoma (~5%) but is clinically and pathologically distinct from classical Hodgkin Lymphoma. Indeed it is often considered to have been misclassified originally due to the marked differences between the two diseases).

It is associated with an excellent OS (similar to normal-age matched controls) it is important to reduce long-term toxicity with therapies.

Clinical features

  • Bimodal age distribution – childhood (median age 13 years) and adults (median age 30-40 years)
  • Male preponderance
  • Typically present with early stage disease with peripheral lymphadenopathy (predominantly cervical lymph nodes)
  • Mediastinal disease, B symptoms and bulky disease is uncommon
  • Typically has an indolent clinical course with an overall favourable prognosis. However multiple, often late, relapses are characteristic and there is a risk of transformation to high-grade disease. Long-term follow-up is key.
  • PET avid and should be assessed by PETCT.

Morphology

  • Lymphocyte predominant cells (‘popcorn cell’ – multilobulated nucleoli) surrounded by rosette of small lymphocytes (follicular helper T cells). All within nodules of small B lymphocytes and histiocytes.
  • Plasma cells and eosinophlis are uncommon as opposed to classical Hodgkin lymphoma.
  • There are 6 histopathological variant patterns
    • Pattern A + B – LP cells embedded within B cell nodules
    • Pattern C-F – variation of location in relation to nodules, diffuse, pattern, T cell rich backgrounds.

Immunohistochemistry

Lymphocyte Predominant cells – CD20+, CD45+, CD79a, PAX5+, epithelial membrane antigen expressed. CD15-, EBV-, rarely express CD30.

Follicular helper T cells – CD4+CD57+PD1+

Differential diagnosis

  • Lymphocyte rich classical Hodgkin lymphoma
    • Reed-sternberg cells, CD30+, CD15+, CD20-
  • Progressive transformation of germinal centres
    • Don’t contain lymphocyte predominant cells, no T cell rosettes, BCL2+.
    • Rarely exist within the same lymph node as NLPHL
  • T cell/histiocyte rich B cell lymphoma
    • Difficult to distinguish but absence of follicular dendritic cell meshwork and loss of background of small B cells.

Prognostic factors

Inferior PFS / OS associated with:

  • Advanced stage
  • Albumin <40g/l
  • Anaemia (Hb <105g/l)
  • Histiopathological variant C-F
  • Lymphopenia (<8% of WCC)
  • Male sex

 

Management

Early Stage Disease Guidelines:

  • ESMO guidance
    • Stage IA and no clinical risk factors: Radiotherapy alone (IFRT 30Gy)
    • Stage IIA and no clinical risk factors: 2#R-ABVD + 20Gy RT
    • Early stage and unfavourable risk factors: 4-6# ABVD + 30Gy IFRT
  • NCCN guidance:
    • Stage I-IIA and no clinical risk factors: Radiotherapy alone (IFRT 30-36Gy)
    • Early stage and unfavourable risk factors: 4-6# ABVD + 30Gy IFRT

Early stage Disease Info:

  • Associated with overall survival >90%
  • Observation
    • Can be considered in selected patients – asymptomatic, fully resected stage IA without unfavourable features.
  • RT alone for stage IA associated with 10yr PFS/OS 89%/96% (Chen et al)
  • No prospective data comparing combined modality treatment versus radiotherapy and most regimens extrapolated from classical Hodgkin lymphoma.
  • Single agent rituximab not appropriate (responses are not durable)

 

Advanced Stage Disease

 ESMO / NCCN Guidance

  • Offer option of R-CHOP and R-chemo (treatment regimes identical to treatment for classical HL with addition of anti-CD20 antibody)

 Advanced Stage Disease Info:

  • ~20% present with advanced stage disease
  • Associated poorer prognosis
  • Ensure biopsy from appropriate site as advanced stage is significant risk factor for transformation
  • R-CHOP associated with better PFS vs R-ABVD

Relapsed Disease

  • Late relapses are characteristic of NLPHL
  • Re-biopsy essential to exclude transformation

Limited Stage Relapse

  • Single agent rituximab (greater benefit also if had long disease free interval)
  • Radiotherapy (ISRT)

Advanced Stage Relapse (or short disease free interval)

  • High dose chemotherapy and ASCT (e.g R-CHOP)

 

Transformed Disease

  • ~15% transformed to an aggressive large B cell NHL by 10 yrs
  • Typically transforms to T cell/histiocyte rich B cell lymphoma
  • Risk factors for transformed disease:
    • Advanced stage disease
    • Infradiaphramatic involvement
    • Splenic involvement
    • Histopathological variant patterns C-F
  • Always important to re-biopsy ‘relapsed’ disease to ensure no transformation
  • No standard treatment
  • NCCN / ESMO guidance: as per standard treatment regime for de novo DLBCL
  • Associated with prognosis similar to de novo DLBCL

 

References

  1. Spinner et al. Modern Principles in the management of NLPHL. British Journal of Haematology. 2019. 17-29.
  2. Eichenauer et al. Hodgkin Lymphoma: ESMO Clinical Practice Guidelines. 2018. https://oncologypro.esmo.org/Guidelines/Clinical-Practice-Guidelines/Haematological-Malignancies/Hodgkin-Lymphoma
  3. Advani et al. How I treat NLPHL. Blood. 2013. 122:4182-4188
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Case 108 – Update 4!

Our patient achieved complete metabolic remission following #6 R-CHOP chemotherapy for his relapsed advanced stage NLPHL.

Unfortunately 18 months after completing treatment he attended with drenching night sweats, intermittent fevers and marked malaise. His spleen was palpable just below the costal margin but examination was otherwise unremarkable. A biopsy is pending following his repeat PET scan (see image below):

PET

Questions:

  1. What is the most likely diagnosis? What risk factors were there for this?
  2. What further investigations would you want to perform?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 108 – Update 3!

Thank you for the ongoing contributions to our case!

Our patient achieved a complete response following radiotherapy treatment alone (30Gy) and remained under haematology follow-up.

Unfortunately 5 years later he attends the haematology clinic earlier than scheduled as he has unintentionally lost 2kg over the past 4 months and more recently has noted an inguinal mass.

A repeat PET scan which shows non-bulky, stage 3 disease including 5cm splenomegaly.

Questions:

  1. How would you manage our patient now? Any further investigations?

 

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 108 – Update 2!

Thank you for everyone’s contributions in obtaining the diagnosis of Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)!

The lymph node morphology demonstrates large atypical cells with multiple nucleoli (lymphocyte-predominant cells) embedded within follicles.

The IHC is as follows:

  • Lymphocyte-predominant cells:CD20+, CD45+, CD75+, PAX5+, CD5-, CD15-, CD30-, EBV-
  • Follicles (T cell rosettes around the LP cells): CD4+, CD57+, PD1+

This histopathological form is consistent with the typical pattern of NLPHL (pattern A or B).

A PETCT has revealed stage 1A disease with several non-bulky unilateral cervical lymph nodes.

Questions:

  1. How would you treat our patient?
  2. Any additional information you’d like to help aid your decision?

 

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Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

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Case 108 – Update 1!

Thank you to all the contributions so far!

We have now established that our 32 year old mans neck mass has been gradually increasing in size since he noted it 6 months ago. He has otherwise been well in himself except for feeling more tired. He has no other associated symptoms, no travel history, other medical conditions. he is not on any medications.

His examination reveals unilateral cervical lymphadenopathy (approx 3cm).

An ultrasound demonstrated the mass was indeed a lymph node with disrupted architecture with an uniformly hypo‐echoic enlarged node with the loss of the fatty hilum.

Subsequently histology was obtained by an excision biopsy:

Questions:

  1. Any suggestions on the diagnosis? What immunohistochemistry would you request to help?
  2. What further investigations would you perform?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 108 – Update 1

Thank you to all the contributions so far!

We have now established that our 32 year old mans neck mass has been gradually increasing in size since he noted it 6 months ago. He has otherwise been well in himself except for feeling more tired. He has no other associated symptoms, no other medical conditions and no significant travel history. He is not on any medications.

His examination reveals unilateral cervical lymphadenopathy (approx 3cm).

An ultrasound demonstrated the mass was indeed a lymph node with disrupted architecture with an uniformly hypo‐echoic enlarged node with the loss of the fatty hilum.

Subsequently histology was obtained by an excision biopsy:

 

Questions:

  1. Any suggestions on the diagnosis? What immunohistochemistry would you request to help?
  2. What further investigations would you perform?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 108 – The Beginning

You review a 32 year old man in outpatients who has been referred for a neck lump. On examination he has a 2cm cervical lymph node which he originally noticed approximately 6 months ago. He has had no night sweats but feels tired although states he has been working nights.

Questions:

  1. What is your differential diagnosis for a neck lump?
  2. What investigations would you perform?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 107 – summary

Thank you for your contribution in this week’s #teamhaem case.

This week we have been looking at Transient Leukaemia of Down Syndrome (TL-DS).

Background

Between 5%- 30% children with Down syndrome (DS) are born with Transient Leukaemia of Down syndrome (TL-DS), aka transient abnormal myelopoiesis (TAM) or transient myeloproliferative disorder (TMD).

  • A clonal disorder, with circulating megakaryoblasts and dysplastic changes in peripheral blood

  • TL-DS is driven by mutations in the haematopoiesis transcription factor gene GATA1, and is only seen in conjunction with trisomy 21, either constitutional or acquired

  • May present with overt clinical features but some are only identified through blood film and/or by GATA1 mutation analysis

  • Many cases resolve without treatment

  • 15-23% cases result in early death

  • 20-23% survivors will develop acute myeloid leukaemia of Down syndrome (ML-DS) in the first 4 years of life

  • Overall event-free survival 63-68%

  • Those with previous TL-DS has a Risk of ML-DS 150 times greater than non-DS children (AML risk in all DS is about 1-2%)
  • Risk of ALL in previous TL-DS 30 times greater than those without DS (and with poorer outcome)

Definitions, clinical features and diagnosis:

  • A congenital leukaemia unique to neonates with DS or mosaic trisomy 21

  • Clonal disorder

  • TL-DS cells spread throughout the body, infiltrating the liver, pleural and pericardial spaces, skin and to a LESSER extent, the bone marrow

  • Presence of an acquired N-terminal mutation in exon 2 or exon 3 of the key haematopoietic transcription factor gene GATA1, resulting in a truncated GATA1 protein

  • Paired TL-DS and ML-DS samples show the same GATA1 mutations, indicating that they are clonally linked conditions

  • GATA1 mutations are not detected in remission samples after treatment of ML-DS nor are they present in other DS and non DS leukaemias

  • GATA1 mutation(s) are not leukaemogenic in cells that are not trisomic for chromosome 21

  • Studies using next generation sequencing (NGS) indicate that cases classified clinically as TL-DS or by blast >10%, all have detectable GATA1 mutations

  • Of note, in studies, 98% of neonates with DS had circulating blasts, the great majority had no clinical features of TL-DS and no detectable GATA1 mutation

  • Hence TL-DS = the presence of a GATA1 mutation in a neonate with DS or mosaic DS, combined with an increased blast count, or features suggestive of TL-DS

Blast count threshold

  • > 10% peripheral blasts in the first week of life identifies all neonates with clinical features of TL-DS

  • Blast count requires careful examination of a peripheral blood film in the first week of life, ideally in the first 3 days of life, by a haematologist experienced in reviewing neonatal blood films
  • automated blast counts are not accurate
  • Blast count assessment after the first week of life may underestimate the prevalence of disease, as blast% falls rapidly after birth
  • Neonates with intra-uterine growth restriction (IUGR) or other history of placental insufficiency (e.g. maternal hypertension, pre-eclampsia or diabetes mellitus) may have lower blast counts despite large GATA1 clones

Clinical features

  • Clinical features can be variable and may be absent (or present in the absence of TL-DS)
  • they can spread locally, spill into the peripheral blood and infiltrate through the liver as well as distant tissues
  • Hepatomegaly, hepatic fibrosis
  • splenomegaly (30% cases, often due to portal vein obstruction, splenic infiltration is rare)
  • Malignant effusions in pleural and pericardial spaces
  • And/or as papular or vesicopustular rash due to skin deposits of blast cells (skin nodules are rare)
  • Hepatopathy – Jaundice, Abnormal LFTs (raised transaminases with conjugated hyperbilirubinaemia)
  • Hyperleucocytosis
  • Coagulopathy
  • Multi-organ failure
  • Thrombocytopenia (which is common in DS even without TL-DS)
  • Neutrophilia
  • Anaemia

Morphology

  • Leukaemic cells are megakaryoblastic, originate from abnormal megakaryocyte-erythroid precursors in the fetal liver
  • Blasts are pleomorphic, with prominent nucleoli and basophilic, blebbed cytoplasm, in keeping with erythroid-megakaryocytic origin
  • Megakarycotye fragments often a prominent feature

Immunophenotying

  • Distinct from other leukaemias
  • Variable co-expression of:
  • stem cell markers CD34 & CD117
  • Myeloid markers CD33/CD13
  • Platelet glycoproteins CD36, CD41, CD42, CD61
  • Aberrant expression of CD56, CD7, low expression of CD11a
  • HLA-DR in 30%
  • Negative for MPO, CD15, CD14, glycophorin A
  • Bone marrow examination is NOT useful, since blasts originate in the liver and marrow blasts are variable and lower than in peripheral blood. Bone marrow involvement does NOT correlate with disease severity

Investigations:

  • All neonates with known or a high suspicion of DS should be examined for features suggestive of TL-DS
  • FBC & blood film within first 3 days of life with formal assessment of blast %
  • Those with features of TL-DS should have additional tests:
    • LFTs including conjugated bilirubin
    • CXR
    • ECHO
    • AUSS
  • Those with features of TL-DS and blasts>10% should have peripheral blood tested for GATA1 mutation
  • Those who did not have a peripheral blasts performed in the first 3 days of life or where there was significant IUGR (where blast count may be suppressed) should be considered at risk in first 4-8 weeks of life and be monitored accordingly. Consider GATA1 mutation analysis

Silent TL-DS

  • Recent studies found that at least half of DS neonates with GATA1 mutations have blasts < 10% and have no clinical features of TL-DS.
  • The prevalence of GATA1 mutation in DS neonates with blast % 1-10% is around 20%
  • Where this is a GATA1 mutation and a peripheral blast =< 10% in the first week of life in a neonate with DS or mosaic trisomy 21 is termed Silent TL-DS or Silent TAM
  • These children have a much lower rate of transformation to ML-DS (<3%) compared to those with clinical TL-DS which has a transformation rate of 10-30%
  • Therefore routine screening for GATA1 is not recommended when blast % =<10%, unless blast % was not assessed or unreliable

Risk factors for poor outcome & life threatening symptoms

  • Most TL-DS resolve spontaneously without sequelae
  • Clinical TL-DS has an early mortality of 15-23%. This is in excess of any other childhood cancers in the UK
  • Risk factors/life threatening symptoms leading to early death:
    • Progressive hepatopathy with cholestasis (conjugated bilirubin > 83umol/L, ascites or massive hepatomegaly
    • Hepatosplenomegaly (beyond umbilicus or causing respiratory or feeding compromise)
    • WBC > 100 x 10^9/L or leucostasis
    • Multi-organ failure
    • Hydrops fetalis
    • Pleural or pericardial effusions
    • Renal failure
    • Disseminated intravascular coagulation/coagulopathy with bleeding

Treatment

  • Those with life threatening symptoms should be considered for treatment with cytarabine
  • TL-DS and ML-DS blasts are extremely sensitive to cytarabine
  • Very low doses of cytarabine can be successfully used
  • Cytarabine should be given urgently at a dose of 1-1.5mg/kg/day for 5-7 days either intravenously or subcutaneously
  • Monitor closely due to risk of neutropenia and sepsis
  • Repeated courses of cytarabine can be considered to achieve control if severe liver dysfunction persists
  • Exchange transfusion and leukapheresis may be used in acute count reduction but is not definitive treatment
  • Cytarabine should NOT be used to prevent later development of ML-DS

Monitoring & Follow up

  • Those without life threatening symptoms can be monitored without treatment, and most will resolve spontaneously
  • Peripheral blasts will disappear in days to months (most by 2 months)
  • Progression to ML-DS 20-23% in those with clinical TL-DS (numbers vary slightly in different studies)
  • FBC & blood film usually return to normal in most
  • TL-DS cases should be monitored with FBC, LFTs until spontaneous resolution
  • If persistent abnormal FBC, GATA1 mutation analysis should be considered
  • All children with previous TL-DS or silent TL-DS should be monitored for progression to ML-DS every 3 months till 2 years of age.
  • If FBC & film are normal, then monitor 6 monthly till 4 years of age, as most ML-DS will develop by the age of 2
  • Any abnormal blood counts should promt early bone marrow aspirate and trephine (as aspirate is frequently difficult due to marrow fibrosis and trephine biopsy is essential in diagnosing ML-DS)

References:

1. WHO Classification of Tumours of Haematopoetic and Lymphoid Tissues

2. Guidelines for the investigation and management of Transient Leukaemia of Down Syndrome – BSH Guidelines. 2018. BJH.

3. GATA factor mutations in Hematologic Disease. Blood Journal 2017

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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Case 107 – update 3

CXR and ECHO show no significant abnormalities. Abdo USS confirms hepatosplenomegaly but no ascites. There are no skin rashes and his blood tests are stable.

Blood film report:

Polycythaemic film. Pleomorphic blasts with evidence of cytoplasmic blebbing. Manual blast count 15%. Megakaryocyte fragments seen.

Immunophenotyping:

CD45 weak population = 12% of total nucleated cells.
CD34 variable (+/neg), CD13 weak, CD33+, CD7+, CD117+,

CD41a+
HLA DR variable (+/neg).                                                                

Flow cytometry has demonstrated a population of myeloid precursor cells with aberrant CD7 expression. There is megakaryocyte marker expression consistent with a picture of Transient Leukaemia in the context of Down syndrome (TL-DS).
Trisomy 21 and GATA1 mutation have been confirmed. Coagulation was checked and there is no evidence of DIC.

Questions:

1. What factors would determine whether treatment is required?

2. If treatment is indicated, what would you do?

3. How do you plan to follow up this baby and why?

Please reply to us (@TeamHaem) on Twitter and always include #TeamHaem to allow others to follow your comments. Please join in the debate and learn about haematological problems along the way. The case will continue to  evolve over the coming week so keep checking #TeamHaem on Twitter for more information.

Please note – all cases on TeamHaem are entirely fictional to protect patient confidentiality.

TeamHaem are not a position of authority.  It is an educational platform to allow discussion and learning.

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