Case series 138 – Summary

This week, we covered a series of cases in various clinical settings with patients presenting with very high white cell counts (>50 x 109 / L). The differential diagnosis is wide, including both haematological (hyperleukocytosis) and non-haematological (leukemoid reactions) causes. Rarely, a high WCC represents a haematological emergency and requires emergency treatment.

Leukemoid reaction vs CML

Leukemoid reactionChronic myeloid leukaemia
DefinitionWCC >50 x 109 / L due to non-leukaemic causesMyeloproliferative neoplasm => uncontrolled production of granulocytes
Aetiologyserious infections/sepsis, drugs (e.g. G-CSF), solid organ malignancyBCR-ABL1 fusion gene (Ph chromosome)
Clinical featuresclear precipitant (e.g. severe sepsis), patient is usually very unwell due to underlying causeusually relatively well (unless in blast crisis), incidental finding, splenomegaly, fatigue, weight loss
Pathologic featuresneutrophilia, left shifted granulocytes, toxic granulation of neutrophilsleukocytosis (often >100) with neutrophilia, basophilia (universal finding) and eosinophilia, left shifted granulocytes, “myelocyte bulge”, normocytic anaemia, thrombocytosis

Causes of hyperleukocytosis (leukaemic WCC >50 x 109 / L)

Mature lymphoid neoplasms: CLL, indolent NHLs (e.g. marginal zone, follicular), B- and T-PLL (rare and more aggressive)

Chronic myeloid neoplasms: CML, CMML, other rare myeloproliferative neoplasms (e.g. chronic neutrophilic leukaemia)

Acute lymphoblastic leukaemia

Acute myeloid leukaemia: FLT3 mutated, myelomonocytic/monocytic subtypes

Complications of hyperleukocytosis

Epidemiology: Complications of hyperleukocytosis usually affect patients with AML or ALL. They are very uncommon in patients with CLL and CML (with the exception of CML in blast crisis). Symptoms more commonly occur with a blast count > 100 x 109 / L.

Disseminated intravascular coagulation: can occur in either ALL or AML

Tumour lysis syndrome: more common in ALL than AML, usually complication of treatment but can occur spontaneously

Leukostasis: more common in AML than ALL, respiratory features (pulmonary infiltrates, hypoxaemia), neurological features (visual blurring, confusion, headahes, reduced GCS), associated with early mortality

Management of symptomatic hyperleukocytosis: supportive care (fluids, rasburicase, avoid red cell transfusions if possible) and cytoreduction (one or more of hydroxurea, leukapheresis, induction chemotherapy)



Posted in Uncategorised | Leave a comment

Case series 138 – part 3

You are a GP registrar working in primary care. It’s 5 pm on Friday and you are going through the last few blood results before the weekend. The final patient is a normally fit and well 69 year old man who had bloods done as part of an NHS Health Check.

Full blood count
Hb 128             (130-180)
MCV 92            (80-100)
Platelets 138   (150-450)
WCC 220          (4.0-11.0)
Lymph 212      (0.5-3.5)
Neut 6.0          (2.0-8.0)
Eosin 0.4         (0.1-0.5)
Baso 0.1          (0.0-0.1)
Mono 1.5         (0.2-1.2)

The last FBC from his last Health Check 5 years ago was completely normal.

You call the patient at home and he tells you that he feels “champion”.

The BMS has made a blood film.

Questions

1) What is the differential diagnosis here?

2) How would you report the blood film?

3) Does the patient need to be admitted to hospital? If so, why? If not, how urgently should they be seen by haematology?

4) Is this patient at risk of leukostasis (i.e. symptomatic hyperviscosity due to high WCC)?

Posted in Uncategorised | Leave a comment

Case series 138 – part 2

You are the critical care registrar on call and get called to A+E to review a 65 year old patient in resus.

The patient is in extremis with sats of 88% on 15 L non-rebreath mask and is septic with haemodynamic instability. His wife is present and says that he’s normally fit and well but has gradually deteriorated over the last 3 weeks with a sudden deterioration in the last 48 hours. He tested negative for COVID-19 three days ago.

A portable chest x-ray is arranged.

As you are about to organise transfer to intensive care, the haematology laboratory calls with abnormal blood results.

Full blood count
Hb 78               (130-180)
MCV 92            (80-100)
Platelets 46     (150-450)
WCC 390           (4.0-11.0)
Manual differential in progress.

An urgent blood film is made by the BMS.

Posted in Uncategorised | Leave a comment

Case series 138 – Part 1

You are the surgical SHO on call and get called by A+E to see a 23 year old patient with severe abdominal pain. The patient is septic and being treated with broad spectrum antibiotics and fluid resuscitation. Examination demonstrates severe abdominal tenderness with guarding, rebound tenderness and generalised abdominal rigidity. An urgent CT scan is performed which confirms perforated appendicitis.

As you prepare to get the patient to theatre, the haematology laboratory calls with abnormal blood results.

Full blood count
Hb 108               (130-180)
MCV 92            (80-100)
Platelets 670     (150-450)
WCC 75           (4.0-11.0)
Lymph 4.4      (0.5-3.5)
Neut 70          (2.0-8.0)
Eosin 0.1         (0.1-0.5)
Baso 0.1          (0.0-0.1)
Mono 3.4        (0.2-1.2)

The BMS has made an urgent blood film:

Posted in Uncategorised | Leave a comment

Case 137 – Summary

Thank you for your help in the management of our 53 year old man who presented with all of the CRAB constellation of symptoms of multiple myeloma (hypercalcaemia, renal impairment, anaemia and lytic bone lesions).

We talked a bit about hypercalcaemia where other more common causes include hyperparathyroidism and malignancy of the breast, lung, oesophageal, head and neck, skin, cervix, breast, kidney, and bladder. It can lead to problems including fatigue, confusion, memory problems, depression, nausea, vomiting, abdominal pain, weight loss, thirst, polyuria, constipation, abdominal pain and renal colic, or renal impairment.  It can also lead to a shortened QT interval; prolonged PR interval and cardiac arrhythmias such as ventricular fibrillation which is why if a patient has severe hypercalcaemia of unknown cause (>=3.4mmol/L), emergency hospital admission for management of this should be arranged.

We have already discussed myeloma in previous cases but as myeloma represents approximately 10% of haematological malignancies and patients may remain under follow up for a long period of time, it is always good to revisit. This case went on to develop therapy related MDS which is a very rare complication of treatment. 

Almost all cases of myeloma evolve from MGUS (monoclonal gammopathy of undetermined significance) which progresses to malignancy at approximately 1% per year, depending on the size and type of the paraprotein as well as underlying cytogenetics.

Paraprotein and serum free light chains are used to help diagnose myeloma and to monitor response to treatment, usually monthly during treatment and 3-4 monthly when not on treatment. Approximately 2% of patients have non-secretory disease with no measurable paraprotein or abnormal serum free light chain. 

Diagnosis:

  1. >= 10% clonal plasma cells in bone marrow or plasmacytoma proven on biopsy

+>=1 of the following

  1. Any of the CRAB criteria thought likely related to the plasma cell disorder
  2. bone marrow clonal plasma cells >=60%
  3. SFLC ratio >=100 but involved FLC>=100mg/L
  4. >1 focal lesion on MRI

Staging is with the Revised International Staging System R-ISS

Stage 1

All of:

  1. albumin >=35
  2. Beta 2 microglobulin <3.5
  3. No high risk cytogenetics: t(4;14), t(14;16), del(17p)
  4. Normal LDH

Stage 2

Not stage 1 or 3

Stage 3

  1. Beta 2 microglobulin >5.5

And 1 of

  1. High risk cytogenetics
  2. Raised LDH

Imaging

Low dose whole body CT, PET or MRI are best to detect bone disease

First line treatment for transplant eligible patient

VTD followed by autologous stem cell transplant is the current UK NICE recommendation

VRd followed by autologous stem cell transplant followed by lenalidamide or bortezomib based maintenance may be used elsewhere eg in the US

Supportive management includes aciclovir, co-trimoxazole, prophylactic antibiotics, VTE prophylaxis, zolendronic acid, pain management and input from the MDT, particularly the nurse specialists. 

The increase in therapy‐related MDS and AML in patients with myeloma has long been recognised and again more recently in patients on lenalidomide maintenance therapy, but the risk is low and the benefits outweigh the risk from myeloma by far.

Our patient developed pancytopenia several years after his autologous stem cell transplant and we undertook a bone marrow biopsy.  We looked at some morphological features of MDS in the bone marrow including abnormal myelopoiesis with pseudo Pelger-Huet neutrophils and hypogranular form, abnormal erythropoiesis with intercellular bridging and abnormally shaped nuclei and ringed sideroblasts.  This was in keeping with MDS with multi-lineage dysplasia and ring sideroblasts, but as he had previously had cytotoxic therapy, it was classified as therapy related MDS. 

Risk Stratification in MDS

IPSS‐R prognostic score values

Prognostic variable00·511·5234
CytogeneticsV Good
Good
IntermediatePoorV Poor
BM blast %≤2
>2–<5
5–10>10
Hb (g/l)≥100
80–<100<80


Plts  (×109/l)≥10050–<100<50



Neuts (×109/l)≥0·8<0·8

IPSS‐R cytogenetic prognostic subgroups

Very good−Y, del(11q)
GoodNormal, del(5q), del(12p), del(20q), double including del(5q)
Intermediatedel(7q), +8, +19, i(17q), any other single or double independent clones
Poor−7, inv(3)/t(3q), double including ‐7/del(7q), complex: 3 abnormalities
Very PoorComplex: >3 abnormalities

Therapy-related MDS is associated with higher risk cytogenetic abnormalities and a poorer prognosis. Our patient was young and fit and had mild anaemia and very poor risk cytogenetics giving him an IPSS-R of 5.  As he had high risk disease we discussed him at the MDT where the decision was made to aim for an allogeneic bone marrow transplant.

References

Rajkumar S, Multiple myeloma: 2020 update on diagnosis, risk-stratification and management, American Journal of Haematology, 2020;95:548–567.

NICE Clinical Knowledge Summaries; Hypercalcaemia  https://cks.nice.org.uk/topics/hypercalcaemia/

Killick S et al, Guidelines for the diagnosis and management of adult myelodysplastic syndromes, British Journal of Haematology, 2014; 164;4, 503-525

Posted in Uncategorised | Leave a comment

case 137 – Update 5

It is now nearly 3 years since our patient completed his treatment for myeloma and you noticed that he had started to become a little anaemic with Hb 97, neuts 1.9 and plts 120.

You asked for more information. Film showed MCV 112 but film fairly unremarkable otherwise. Renal, liver, bone profile, LDH, paraprotein and SFLCs normal.

You asked for a bone marrow biopsy. Some pictures are shown below:

What features do you note and what are your thoughts?

How would you risk stratify this patient and what further information do you require to do this?

How might you manage this patient?

Posted in Uncategorised | Leave a comment

Case 137 – Update 4

Thanks for all your help with management of this chap. We have confirmed his diagnosis of multiple myeloma on bone marrow biopsy and completed imaging with plain films of his long bones as he has already had a whole spine MRI.

He was aggressively rehydrated and given IV bisphosphonate and his calcium improved. We started him on a pulse of steroids pending starting treatment with VTD chemotherapy and his renal function and hypercalcaemia improved significantly.

We started VTD chemotherapy and additional supportive treatment included VTE prophylaxis with LMWH which we changed to rivaroxaban when his renal function normalised, acyclovir to prevent shingles, and co-trimoxazole. We also thought about levofloxacin prophylaxis.  We asked him to get a dental review as soon as possible and started him on monthly zolendronic acid.

He responded quickly to treatment and his paraprotein was undetectable with a normal serum free light chain ratio after 4 months. His cytogenetics came back showing only a t(11;14) which was pleasing. He went on to have an autologous stem cell transplant and remained under regular review.

However, it is nearly 3 years since he completed his treatment and you notice that he has started to become a little anaemic with Hb 97, neuts 1.9 and plts 120.

What is your differential?

What actions do you take?

Posted in Uncategorised | Leave a comment

Case 137 – Update 3

You have undertaken a bone marrow biopsy and the aspirate (shown below) and flow are back.

There is a population of abnormal CD20+, CD38+, CD138+, CD56+ cells.

Cytogenetics awaited

His calcium is a little better at 3.1 but his renal function is fairly static with a creatinine of 185 and urea 8.3.

LDH is normal. 

B2m 5.6

Albumin 36

What would be your choice of treatment?

What supportive management would you undertake along side this?

It’s a Friday evening and you can’t start definitive treatment until next week.  Anything you want to do in the meantime?

Posted in Uncategorised | Leave a comment

Case 137 – Update 2

You have treated our gentleman with AKI and hypercalcaemia with IVT and once well hydrated, you added an IV bisphosphonate.  His calcium is a little better at 3.2 and his renal function is also a little better with creating improved to 190.

We discussed that it is important to recognise and treat hypercalcaemia as it can be related to drowsiness, confusion, weakness, constipation, vomiting, polydipsia, polyuria, dehydration, shortened QT interval, prolonged PR interval and arrhythmias.  NICE guidelines suggest admission for urgent management if hypercalcaemia is severe (>3.4mmol/L) or symptomatic. 

We have discussed some of the more common causes of hypercalcaemia and our differential included malignancies, particularly lung cancer, multiple myeloma, and renal cell carcinoma as well as breast and colorectal cancers and also hyperparathryroidism. 

We have finally got back the results we have been waiting for

Bloods: Serum electrophoresis: IgG K paraprotein 13.2g/L, K light chains 9802

MRI whole spine: extensive lytic lesions throughout spine and right clavicle. Compression fracture at T4. No concerns regarding nerve impingement or cord compression.

What is your next course of action?

What further investigations do you need to do?

Posted in Uncategorised | Leave a comment

Update 1

Your 53 year old male patient seems very vague and his partner tells you that he has been very forgetful and low in mood recently. He feels weak and achey and has to force himself to go downstairs to eat. He has not left the house for 2 weeks. 

He can’t remember when he last opened his bowels but he is thirsty so is drinking and peeing plenty.  He doesn’t really know if he has lost any weight. He has felt under the weather for a few months now.

He had a back injury 8 months ago.  He can’t really remember what happened, just that it seems to have gotten worse rather than improved over time. 

Medication: Paracetamol and ibuprofen for back pain

Examination: No organomegaly or lymphadenopathy

Bloods:

FBC: Hb 78g/L but otherwise fairly normal.

Blood film: some rouleaux but otherwise fairly unremarkable.

Retics 84

LFTs normal

Cre 284

Urea 15.2

Haptoglobin normal

Coombs test negative

Ferritin, B12 and folate normal

CRP 14

What is on your list of differentials for hypercalcaemia?

Why is hypercalcaemia an emergency?

How do you manage hypercalcaemia?

Posted in Uncategorised | Leave a comment

Case 137 – The beginning

You are a medical SHO and have been asked to see a 53 year old man who has been referred in by his GP with symptomatic anaemia with a Hb of 78g/L. He feels weak, achey and tired but his GP was particularly concerned as last Autumn he was training for the Great North Run and he is now struggling to get out of bed. There are no previous results on the system for the patient. 

How do you go about investigating his anaemia?

Posted in Uncategorised | Leave a comment

Case 136 – the summary

This week we followed the case of a 71 year old patient with multiple co-morbidities who required optimisation of her haemoglobin level before an elective operation. The crux of this case is Patient Blood Management, which is something we all have a responsibility to practice.

Definition of Patient Blood Management (PBM): “A multidisciplinary, evidence-based approach to optimising care of a patient who might need a blood transfusion, aimed at avoiding inappropriate use of blood components, improving patient outcomes and ensuring wise use of resources.”

Often describes as three pillars:

  • Optimise red cell mass/haematopoiesis
    • E.g. using iron or EPO
  • Minimise blood loss
    • E.g. surgical technique, intraoperative cell salvage, tranexamic acid
  • Harness and optimise physiological tolerance of anaemia
    • E.g. single unit transfusion and review, post-op iron

Many PBM principles have been ratified in NICE quality standard QS138:

  • Quality standard 1: People with iron-deficiency anaemia who are having surgery are offered iron supplementation before and after surgery
  • Quality standard 2: Adults who are having surgery and are expected to have moderate blood loss are offered tranexamic acid
  • Quality standard 3: People are clinically reassessed and have their haemoglobin levels checked after each unit of red blood cells they receive, unless they are bleeding or are on a chronic transfusion programme
  • Quality standard 4: People who may need or who have had a blood transfusion are given verbal and written information about blood transfusion

The NICE guidance (NG24) around EPO in the pre-operative setting are quite restrictive, and limit their recommendations to those who decline blood transfusion due to religious belief or if the appropriate blood is not available due to atypical red cell antibodies. Many clinicians will, however, consider a trial as an alternative to pre-operative transfusion after taking into consideration the risks and benefits for each individual patient.

As is always the case, no patient should come to harm due to withholding transfusion, a risk/benefit decision, with the patient’s input if possible, should be made in each individual case.

Useful resources to learn more:

NICE guideline 24: https://www.nice.org.uk/guidance/ng24

NICE quality standard 138: https://www.nice.org.uk/guidance/qs138

Blooducation podcast: https://blooducation.co.uk/portfolio/patient-blood-management

NHSBT toolkit: https://hospital.blood.co.uk/patient-services/patient-blood-management/education/

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.

Posted in Uncategorised | Leave a comment

Case 136 – update 2

We are trying to optimise a 71 year old lady for orthopaedic surgery. You voted in the poll to proceed with IV iron – this has been administered at the correct weight-based dose for her Hb. Repeat bloods 6 weeks after iron infusion is shown below. The surgeons would like her Hb to be around 100 g/l:

Hb                   89 g/L

Ferritin            628 ug/l

Serum iron      5 umol/L

Transferrin      1,580 mg/L

Tsat                 16%

TIBC                 47 umol/L

Is there a role for EPO in this situation?

What peri-operative strategies would you advise the surgical team to consider?

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.

Posted in Uncategorised | Leave a comment

Case 136 – update 1

We are advising the orthopaedic SpR, Ms Fi Moor, about a 71 year old lady listed for urgent THR who has a normocytic anaemia (Hb 84) and requires optimisation pre-op. You have requested the following info:

PMH: Hypertension, type 2 diabetes, rheumatoid arthritis, CKD stage 2

No recent surgery, trauma. Diet normal.

DH: Ramipril, metformin, atorvastatin, methotrexate, aspirin, folic acid

Main symptoms are pain and lack of mobility in hip. No SOB, not dizzy, no chest pain.

Surgeons think procedure is low bleeding risk, but ‘you never know.’ They would ideally like Hb > 100 g/l.

Further tests as requested:

Ferritin            180 ug/l

Serum iron      5 umol/L

Transferrin      1,480 mg/L

Tsat                 10%

TIBC                 43 umol/L

B12                  239 ng/L

Folate              >20.0 ug/l

U&Es               Na 141, K 4.5, Ur 12.2, Cr 180, eGFR 65

LFTs                 Normal

Bone profile    Normal

CRP                  48

ESR                  40

Film has been reviewed by BMS: ‘Minor anisopoikilocytosis with occasional left-shifted neutrophil. No primitive cells, no dysplasia.’

Surgery is planned in the next few months.

Do you require any further investigations?

What treatment would you suggest to optimise Hb before surgery?

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.

Posted in Uncategorised | Leave a comment

Case 136 – the beginning

You are the haematology SpR holding the on-call phone. You are called by an orthopaedic SpR regarding a 71-year-old lady she has reviewed in clinic with significant osteoarthritis of the right hip. The patient’s mobility and quality of life have been so impacted that the team plan to expedite a total hip replacement in the coming weeks/months. In view of the patients FBC, they have requested a 2 unit RBC transfusion in the coming days to optimise the patient prior to surgery. Her FBC is below:

Hb       84 g/L

WCC    8.3 x 109/L

Plt        455 x 109/L

MCV    95.2 fL

MCH    29.0 pg

Neuts   5.9 x 109/L

Lymph 1.6 x 109/L

Mono 0.5 x 109/L

Eosin   0.2 x 109/L

Baso    0.1 x 109/L

The patient has a valid Group and Screen and is Group A Rh D +ve with a negative antibody screen. She has not been transfused previously.

The transfusion BMS has questioned the appropriateness of the transfusion and has requested that the clinical team discuss with yourself.

What clinical information would you request from the orthopaedic team?

What further tests would you request?

Would you authorise the transfusion?

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.

Posted in Uncategorised | Leave a comment

Many thanks for all your thoughts and suggestions this week.

The case this week was an 81 year old lady who presented with AIHA. She had an incidental finding of mild lymphocytosis, small Ig M Paraprotein and splenomegaly and was diagnosed with Splenic Marginal Zone lymphoma (SMZL). 

She was successfully managed for haemolysis with 60mg prednisolone for 3 weeks and slow steroid weaning. She subsequently developed thrombocytopenia, anaemia and enlarging splenomegaly needing therapy. She received weekly Rituximab for 4 weeks and Rituximab maintenance to good effect and remains in remission.

The case this week was designed to consider the practical issues in managing AIHA in an older patient and to consider the challenges faced in diagnosis and management of SMZL.

Autoimmune Haemolytic Anaemia:

BSH guidelines are helpful in assisting with an approach to diagnosis of this condition

1. Is there Haemolysis?

Raised Reticulocytes, Unconjugated bilirubin and LDH

Low Haptoglobins (Consumed as binding free Hb)

Spherocytes or Polychromasia on blood film. It should be remembered that this pattern is not always seen for example in our case the patient had normal reticulocytes due to marrow infiltration.

2. Is it immune? 

DAT Ig G and C3d – can be non specifically positive in autoimmune conditions so needs careful interpretation. It can be positive in 7-8% of hospital inpatients.

3. Special situations?

Tx within three months?

 HSCT patient?

?HDN in newborns

?Drug induced?

Initial management of AIHA:

General measures:

Folic acid 5mg daily

Oral calcium and vitamin D for all patients

If >50years treat with Bisphosphonate if steroid dose >7.5mg for more than 3 months.

VTE Prophylaxis:

Should be given for all inpatients with haemolysis. If ambulatory it is reasonable to consider thromboprophylaxis if Hb <85g/l. BSH guidelines state rate of thrombosis for these patients is 20% without prophylaxis.

Transfusion:

ABO, Rh and Kell matched blood if problems with serological cross match (30% patients with AIHA will have allo Ab usually to Rh or Kell Ag)

Steroids:

80% patients respond to Prednisolone doses of 60-100mg/day and two thirds of patients will achieve a complete remission. It is important to remember that response can take several weeks. Steroid refractory disease can only be declared after 21 days. 

BSH guidelines suggest high dose therapy for 3 weeks then reduce to 20-30mg over 4-6 weeks then 5mg monthly after this. Important to remember the gastric side effects of steroids and consider PPI. 

IVIG :

Consider if life threatening anaemia 40% respond to 0.5mg/kg/day for 5 days.

Plasma Exchange: 

Reserved for life threatening anaemia.

For older patients 1mg/kg may lead to toxicity, this was the concern for our patient and hence steroid dose was capped at 60mg. Dose adjustment for elderly patients needs to be made on individual basis.

Marginal Zone lymphomas:

The Marginal Zone B cell lymphomas represent 5-15% of all non-Hodgkin lymphomas. 

They comprise of three very different subgroups:

Extranodal MZL of mucosal associated lymphoid tissue (previously described as MALT lymphomas) (66% of MZL) .

Splenic MZL with or without villous lymphocytes (20% of MZL).

Nodal Marginal Zone lymphoma with or without monocytes B cells (10% of MZL)

Splenic Marginal Zone lymphomas:

This is characterised by splenic involvement and usually the diagnosis can be obtained on peripheral blood/bone marrow morphology and flow cytometry without a splenectomy. 

Initial work up for suspected SMZL:

FBC, Blood film, Retics, U&E, LFTs, LDH, Ig screen, HIV and Hepatitis screen and DAT indicated (20% of SMZL will have an associated immune problem related to it as in our case).

Staging CT scan 

A bone marrow biopsy is indicated for a suspected case of SMZL.

Flow cytometry and SMZL:

Classical SMZL : CD 19+ CD 5 Neg CD 10 Neg CD 103 neg CD79b + sIg ++

It is important to appreciate that aberrant expression on flow can be seen in both SMZL and other B cell lymphomas:

This table has been adapted from Huan-You et al (see references below):

Pattern of ImmunophenotypeLymphoma subtype% of cases with phenotype
CD 5+ CD 10 NegMCL93-95%
 CLL80-92%
 SMZL20%
 LPL9-43%
   
CD5 Neg CD10 NegSMZL80%
 LPL50-90%
 CLL8-20%

In our case we had weakly positive CD 5 expression. This can be seen in up to 20% of SMZL cases. It would be important to consider MCL and CLL and we did check CCND1 to exclude MCL in the patients case.

We were also left with the possibility the patient in our case had Lymphoplasmacytic lymphoma rather than SMZL. 

This again can be tricky to determine but there are a few helpful features that may assist in correct diagnosis:

LPL:

Higher Ig M PP levels more commonly >3g/l are seen. 

Trephine infiltration pattern is usually paratrabecular in pattern and there may also be increase in eosinophils. 

MYD88 mutation is positive in 80-90% of LPL patients but up to 20% of MZL patients can have MYD 88 positivity so it isn’t diagnostic alone. Our patient was MYD 88 negative.

SMZL:

Often expresses Ig D and this may be a helpful pointer to the diagnosis.

Trephine biopsy can show intrasinusoidal trephine infiltrate

Staging of SMZL:

ESMO guidance suggests the use of a prognostic score but stress this shouldn’t be used to influence decisions to treat.

There are two commonly used scores:

The ILL score based on 300 SMZL patients useful in clinical practice as simple to perform. Parameters are Hb <12g/l, albumen <35g/l and elevated LDH. 

The HPLL score this was developed by the SMZL study group and validated on 600 patients. It uses Hb concentration, Platelet count, LDH and extrahiliar lymphadenopathy to identify three discrete risk groups 

Five‐year survival for Groups A, B and C was 94%, 78% and 69%

SMZL treatment:

Asymptomatic patients should embark on 3-6 monthly watch and wait.

Indications for therapy as per ESMO guidance:

Hb <10g/l

Plt <80

Neu <1

AIHA or ITP with SMZL is not a reason for treatment of lymphoma if responsive to steroids.

Splenectomy:

Traditionally provided PFS 50-60% over 5 years and OS 70-80%. Morbidity and Mortality associated with this procedure.

Rituximab:

375mg/m2 weekly for 4-8 weeks can provide ORR >80% with CR >40%. Long lasting with 10 year PFS >60%. Likely Rituximab Maintenance 2 monthly for 2 years can improve PFS further although no evidence to show it improves OS.  It can be very useful for frailer patients and for those who have autoimmune complications associated with SMZL as may allow steroid independence.

Chemoimmunotherapy:

This can be considered but generally is held in reserve due to excellent results with Rituximab monotherapy. May be indicated if young and troublesome constitutional issues or if disseminated disease or concern of High grade transformation.

Our patient is elderly and also has been troubled by previous haemolysis and therefore Rituximab monotherapy was felt to be the most appropriate therapy after discussion at MDT.

Thank you for all your contributions and I hope this case has been interesting, feel free to add any comments

References:

Zantek et al. The direct antiglobulin test: A critical step in the evaluation of hemolysis.Am. J. Hematol. (2012) 87:707–709.

Hill et al. The diagnosis and management of primary autoimmune haemolytic anaemia. BJ Haem (2017);176:(3) 395–411.

Available at: https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.14478


Zucca E et al. Marginal zone lymphomas: ESMO Clinical Practice Guidelines. Ann Oncol (2020); 31(1): 17-29. 
Available at: https://www.annalsofoncology.org/article/S0923-7534(19)35465-1/pdf

Wang HY et al. Diagnostic algorithm of common mature B cell lymphomas by immunohistochemistry. Arch Pathology Lab Med. (2017) 207(141)1236-1246.

Montalban et al.Stratification Approach for Splenic Marginal Zone Lymphoma Based on Hemoglobin, Platelet Count,High LDH and Extrahilar Lymphadenopathy: The HPLL/ABC System. Blood (2011) 118 (21) 1583.

Montalban et al. Risk stratification for Splenic Marginal Zone Lymphoma based on Haemoglobin concentration, platelet count, high lactate dehydrogenase level and extrahilar lymphadenopathy development and validation on 593 cases. BJ Haem (2012) 159:(2): 164-171.

Posted in Uncategorised | Leave a comment

Case 135 – Update 1

Thanks for your help so far…

We have now established that our 81 year old lady with AIHA has been feeling tired for several months and has noted some exertional dyspnoea. She has noted recently that she has lost some weight (around 3kg) and has found her trousers feel tight despite this. She is also most troubled by drenching night sweats that have been present for several months.

On examination you find a palpable spleen protruding 3cm from costal margin. She has no other lymphadenopathy.

On review of her blood counts she has a mild lymphocytosis of 5×10^9 and there is a comment of “atypical lymphocytes’ alongside the description of spherocytes.

She went on to have a CT scan that confirms a 19.5 cm spleen but no other findings. You decide that you should proceed with a bone marrow biopsy before starting steroids. The results are awaited.

On balance, you felt you should be cautious given her age and gave 60mg Prednisolone with a PPI. She also started folic acid, VTE prophylaxis and Calcium/Vitamin D to manage her haemolysis.

She is discharged home with a Hb 98, Retics 50 (Normal), LDH 380 (prev 490) to return to the haematology day unit a few days later.

What is the differential diagnosis for the splenomegaly and AIHA?

How likely is she to respond to steroid therapy for AIHA?

How long would you leave the patient on high dose steroids before weaning if she responds?

Would you send the patient home on VTE prophylaxis at this stage?

Posted in Uncategorised | Leave a comment

Case 135 – update 3

20 months after initial treatment for AIHA you are asked to review the patient as she is noting increasing abdominal discomfort and has started to have drenching night sweats. You note she is becoming slowly more thrombocytopenic and anaemic but her haemolysis screen is negative.

A repeat USS confirms her spleen is now 24cm with no other lymphadenopathy

Bloods: Wcc 7, Hb 95, plt 75, neu 1.3, lymph 6. LDH 300 (normal), Retic 40 (Normal), DAT negative.

Film :Atypical lymphocytes, no spherocytes

Ig M PP 3.5g/l

HIV and Hepatitis negative

What treatment would you recommend to the MDT? – please answer poll question

Is there a role for maintenance ritux in this case?

Posted in Uncategorised | Leave a comment

Case 135 – Update 2

Our patient was discharged home and took 60mg Prednisolone for 3 weeks.

She successfully started a steroid wean following this and is slowly reducing down to 30mg of prednisolone daily at present.

Her Hb has normalised at 130g/l with a normal LDH 205. Her platelet count is 235, neu 3, lymph 5. Her renal and liver function are all within normal ranges. She had a small IgM kappa PP 2g/l detected and is negative for hepatitis and HIV. Her CT scan showed 19cm splenomegaly and no lymphadenopathy.

She had no B symptoms and reported no discomfort from the large spleen.

Her bone marrow biopsy showed she had a clonal population of B lymphocytes that were CD19 + CD5+/- CD 10 – CD103 – CD79b + sIg ++

MYD88 negative CCND1 negative

Bone marrow trephine showed infiltrate with intrasinusoidal pattern.

The MDT agreed the likely diagnosis was Splenic marginal zone lymphoma with associated AIHA.

Does she require any treatment for her SMZL at present?

If no treatment planned what features would make you treat?

She is asking you about prognosis – What prognostic scores can you use in SMZL?

Posted in Uncategorised | Leave a comment

Case 135 – The beginning

You are the medical SHO on call and get asked to review an 81 year old lady with symptomatic anaemia on a Friday evening. She has had no bloods taken for the preceding two years and her Hb has been confirmed to be 72g/l. The GP referral letter also tells you she has a normal B12/folate and ferritin. This is her blood film.

What history would you take?

What features should you examine her for? 

What other tests should be performed ?

Posted in Uncategorised | Leave a comment