Pancytopenia of uncertain pathogenesis
Short Summary

74-year-old female evaluated for pancytopenia of unknown etiology, which required blood transfusions. Bone marrow aspirate and biopsy showed a hypocellular bone marrow with trilineage maturation. The treatment include immunosuppressive agents and erythropoietin.

Patient's Questions
  1. What is the most likely diagnosis?
  2. What further clinical tests or examinations would you suggest?
  3. What treatment would you suggest?
  4. What is the prognosis?
 

 

 

Medical Background

  • Bilateral saphenectomy
  • Haemorrhoidectomy
  • Left meniscectomy;
  • approx. 3 years ago, polypectomy during colonoscopy;
  • osteoporosis and arthrosis.
 
History:
Admitted to the internal medicine department , diagnosed with “pancytopenia and myelodysplasia" (currently in the process of being assigned a histological definition); arterial hypertension; obesity; and monolateral (left) multicystic kidney”.
 
Following further tests at the day hospital, without reaching any diagnostic certainty as to the pancytopenia (WT-1 gene analysis repeatedly negative; hypo cellular haemopoietic bone marrow with regular trilinear maturation); regular (every 4 days) need for transfusion support for red blood cells and platelets.
In order to obtain a better clinical assessment of the case, initial values are provided, to allow for comparison with a more recent patient hemochrome:
 
 
 
 
RESULTS Interval of reference
red blood cells 2460000 x mmc(4000000–5600000 L)
haemoglobin 8.8 G/DL 12.0 16.0
Hematocrit 26.7% 36 48
MCV 108.5 fl 81.0 98.0
MCH 35.7 pg 27.0 33.0
MCHC 32.9 G/DL 31.5 36.0
RDW-SD 63.5 fl 37.0 54.0
RDW-CV 16.30 11.88 14.32
PLATELETS 25000 x mmc (140000-440000)
MPV 11.1 fl 9.0 14.0
PDW 12.3 fl 9.0 17.0
P-LCR 32.7 % 13.0 43.0
LEUKOCYTES 3370 x mmc 4000 10000
NEUTROPHILS 1310 x mmc 1600 7400
LYMPHOCYTES 1779 x mmc 760 4800
MONOCYTES 279 x mmc 80 1100
EOSINOPHILS 0 x mmc 8 700
BASOPHILES 0 x mmc 0 150
 
 
7 months later red blood cells 2630000 x mmc(4000000–5600000 L)
haemoglobin 7.9 G/DL 12.0 16.0
Hematocrit 23.8% 36 48
MCV 90.4 fl 81.0 98.0
MCH 30.0 pg 27.0 33.0
MCHC 33.1 G/DL 31.5 36.0
RDW-SD 49.8 fl 37.0 54.0
RDW-CV 16.60 11.88 14.32
PLATELETS 36000 x mmc (140000-440000)
MPV 11.0 fl 9.0 14.0
PDW 13.1 fl 9.0 17.0
P-LCR 33.6 % 13.0 43.0
LEUKOCYTES 2070 x mmc 4000 10000
NEUTROPHILS 728 x mmc 1600 7400
LYMPHOCYTES 1250 x mmc 760 4800
MONOCYTES 80 x mmc 80 1100
EOSINOPHILS 10 x mmc 8 700
BASOPHILES 0 x mmc 0 150
 
 
 
In addition:
The report made following bone marrow needle aspiration:
The lymphocytes and monocytes show no phenotypical abnormalities. Blastic levels are within normal limits. The myeloid population would appear to show a slight maturative unbalance with a reduction of the most differentiated component. The erythroblast levels would appear to basically fall within normal limits”.
Erithropoietin 493 mUI/mL.
Last admitted to the department of internal medicine at the hospital, because following a check-up at the day hospital, severe anaemia and thrombocytopenia was reported, with tarry stools in the ampulla of the rectum.
 
Diagnosis upon discharge was:
  • pancytopenia of uncertain pathogenesis;
  • Erythematosus gastritis;
  • Arterial hypertension;
  • Obesity;
  • Monolateral (left) multicystic kidney.
 
During the hospital stay:
    1. emergency transfusions of concentrated red blood cells and platelets carried out
    2. esophagogastroduodenoscopy performed, reporting erythematosus gastritis without haemorrhaging.
    3. improvement of the patient’s condition, and with no further haemorrhaging; repeated blood transfusions.
    4. transfusion of platelet concentrates and GRF 2 units.
    5. immunosuppressant treatment started with cyclosporine, in view of a hypothesised autoimmune pathogenesis of pancytopenia.
 
Advised home treatment:
Sandimmun 100 mg 1 tablet twice a day
Pantorc 20 mg 1 tablet to be taken in the morning.
 

 

Expert's Opinion

The differential diagnosis of pancytopenia in a 74-year old woman is broad, but I will mention the more common and more likely possibilities:
  • Myelodysplastic syndrome (MDS): The age, pancytopenia, the high MCV and some myelodysplasia in the marrow – all consistent with this diagnosis. However, this should be confirmed by bone marrow analysis by an expert, also with at least cytogenetic analysis.
  • Liver disease with cirrhosis – this should be tested by blood tests (liver function tests, serology) ultrasound and sometimes liver biopsy (if indicated).
  • Immune pancytopenia, whether primary hematological disease, or secondary to connective tissue disease / vasculitis or secondary to lymphatic disease.
  • Other primary bone marrow diseases such as aplastic / hypoplastic anemia, PNH, myeloproliferative disease and others. BM analysis and specific tests can help.
  • Megaloblastic anemia – B12 and / or folic acid deficiency
  • Drug induced or viral induced (B19, EBV, CMV) BM suppression
 
Missing information / Documents:
  • History – symptoms, clinical picture
  • Routine blood tests – especially chemistry
  • Bone marrow report
  • Anemia work up
  • GI work up
  • Specific tests – see above
 
Once definite diagnosis is established, treatment can be discussed.
 
For instance, if MDS is the problem, than several options can be considered: Supportive treatment (RBC transfusions); Erythropoietin injections; Immune suppression (Globulins / ATG, cyclosporine); Thalidomide; Lenalidomide; Chemotherapy; Decitabine; 5-aza-cytabine – just to name a few options.
 
If the problem is immune – immune suppression can be the preferred approach
 
If the liver is the problem, than another approach should be considerd.
 
Final recommendation: An attempt to establish a definite diagnosis.
 
Second Report
 
It is important that a diagnosis be established between aplastic anemia due to the hypocellular nature of the specimen and a hypoplastic myelodysplastic syndrome. Although both of these entities can be treated with immunosuppressive agents such as ATG and Cyclosporin, it is my opinion that a repeat bone marrow aspirate and biopsy should be performed, including cytogenetic analysis, FISH analysis can be performed on the bone marrow specimen looking for chromosome 5, 7 and 8 abnormalities. In addition, the patient should be evaluated for the possibility of paroxysmal nocturnal hemoglobinuria with flow cytometries looking for the absence of CD55 and the absence of CD59 on granulocytes since this patient is heavily transfused. In addition, the bone marrow should be evaluated for iron stores if there are ring sideroblasts present in the bone marrow that would suggest myelodysplasia. Absence of iron would suggest paroxysmal nocturnal hemoglobinuria. These frequent transfusions may reflect enhanced hemolysis seen in patients with paroxysmal nocturnal hemoglobinuria so I feel that this diagnosis should be evaluated and, again, flow cytometry looking for CD55 and 59 expressions on peripheral blood granulocytes would be in the standard diagnostic approach.
 
Since the erythropoietin level is elevated it suggests that she is less likely to respond to erythropoietin, nonetheless, I would recommend that erythropoietin be started with weekly treatments. If the patient has a myelodysplastic syndrome then treatment options include the use of Revlimid which can be given especially if there is evidence for (5q) chromosome abnormality. If that is negative, then Vidaza (5 azacytidine) would be an appropriate choice in reducing transfusion requirements. On the other hand, the use of Cyclosporin and ATG is reasonable if this appears to be a hypoplastic myelodysplasia or aplastic anemia, but this would depend on a very good morphological evaluation of a repeat bone marrow, a cytogenetic analysis as well, to identify that diagnosis and, also, to rule-out the possibility of paroxysmal nocturnal hemoglobinuria causing this primary abnormality or resulting in the secondary defect causing the transfusion requirements that you are experiencing.
 
For now then, I think that additional diagnostic studies are required. The prognosis for this patient, if this is myelodysplastic syndrome, is poor, however, the newer treatments using Revlimid or Vidaza or Dacogen have been very helpful in improving quality of life and reducing transfusion requirements and reducing the time to blast transformation. Aplastic anemia can be treated successfully with Cyclosporin, ATG and prednisone with very good results. So the prognosis is really dependent on the diagnosis that is established. Paroxysmal nocturnal hemoglobinuria can be treated successfully now with a new antibody directed against compliment. This antibody, given weekly, can reduce the transfusion requirements and also reduce the risk of possible thromboembolic complications.
 

 

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