Abstract
We present a case of an 81-year-old African male who presented with
progressive cough, respiratory distress and bilateral lower limb
swelling, and was diagnosed with life-threatening pericardial effusion
resulting from chronic myelomonocytic leukaemia following complete blood
count, peripheral blood film, bone marrow aspirate with trephine biopsy,
and flow cytometry studies.
Keywords: Chronic myelomonocytic leukaemia, pericardial
effusion, heart failure, ascites, pleural effusion
Introduction
Chronic myelomonocytic leukaemia
(CMML) is a haematological
malignancy characterised by both clinical and pathological features of
myeloproliferative and myelodysplastic syndrome. It is evidenced by
peripheral monocytosis and myeloid precursor cell
dysplasia.1 According to 2016 World Health
Organisation (WHO) classification of myeloid neoplasms and acute
leukaemias, CMML is classified under the group of
myelodysplastic/myeloproliferative neoplasms (MDS/MPN), together with
juvenile myelomonocytic leukaemia, atypical chronic myeloid leukaemia,
and ring sideroblasts with thrombocytosis. This group also constitutes
the MDS/MPN unclassified type.2,3
CMML is relatively a rare disorder, with a current reported incidence of
4 cases per 100,000 persons/year 4. It mainly affects
the elderly with a median age of 71 – 73 years. CMML presents
heterogeneously, with clinical features ranging from constitutional
symptoms, splenomegaly to cytopenias as well as extramedullary disease,
but rarely causes life threatening extramedullary complications such as
pericardial and pleural effusion as well as
ascites.5–7 We report a case of an 82-year-old male
patient with CMML who presented with pericardial effusion and acute
heart failure.
Case presentation/examination
An 82-year-old male patient was admitted to Moi Teaching and Referral
Hospital, Eldoret on 1st April 2022 with progressive
cough, difficulty in breathing and bilateral lower limb swelling for 4
weeks. He had a previous history of on and off cough since June 2021.
The cough was mostly dry, but sometimes associated with whitish sputum.
It was not variable by time of the day and was initially not associated
with hotness of body, paroxysmal nocturnal dyspnoea, orthopnoea, easy
fatiguability or lower limb swelling. However, four weeks prior to
admission, the cough became persistent and associated with difficulty in
breathing, dyspnoea on mild exertion, progressive bilateral lower limb
swelling, abdominal distension, and early satiety. He also reported
unintentional weight loss, but no history of other known chronic
illnesses such as diabetes mellitus, hypertension, asthma, chronic
obstructive pulmonary disease, and tuberculosis.
On physical examination, he had bilateral non-tender pitting oedema up
to the knee level. His BP was 120/70mmHg, PR 79bpm, RR 18bpm and
SPO2 75% room air (which improved to 96% on 7L of
O2 via non-rebreather mask), and temperature of
36.8oC. Cardiovascular exams revealed warm
extremities, normal volume peripheral pulses, muffled heart sounds but
no cardiac murmurs. Abdominal examination revealed non-tender abdominal
distension, hepatomegaly (4 cm below the costal margin), shifting
dullness but no splenomegaly. Respiratory and central nervous systems
were unremarkable.
Methods (Differential diagnosis, investigations and
treatment)
Complete blood count revealed WBCs of 75.32*109/L,
absolute neutrophils: 50.56*109/L (67.6%), monocytes:
18.50*109/L (24.0%), lymphocytes:
4.76*109/L (6.6%), Hb 12g/dl and platelets of
142*109/L. NT-proBNP was 4,800pg/ml (normal
<125pg/ml). Renal, liver and thyroid function tests were
largely unremarkable. Blood culture yielded no growth, ruling out
sepsis.
Electrocardiography showed low voltage QRS complexes with electrical
alternans (Fig 1). Echocardiography showed large
circumferential pericardial effusion (3.0cm), swinging heart, RA/RV free
wall collapse with evidence of pulmonary hypertension (RVSP of 43mmHg),
dilated non-collapsing IVC with normal left and right ventricular
function.
Chest and abdominal CT scan showed pericardial and bilateral pleural
effusion, and moderate ascites with multiple para-aortic and mesenteric
nodes (Fig 2). Peripheral blood film showed monocytosis, and
left shift with less than 1% blasts. Bone marrow aspirate with trephine
biopsy showed hypercellular marrow with myeloid hyperplasia but no
excess blasts, while flow cytometry was 94% positive for CD14, with
remarkable monocyte population with aberrant CD123 (94%) and CD56
(83%), highly suggestive for CMML. Based on these findings, we arrived
at a diagnosis of CMML presenting with acute heart failure (HF) due to
life threatening pericardial effusion.
Pericardiocentesis with placement of pigtail catheter was done, draining
a total of 1,800mls of haemorrhagic fluid (800mls on day 1, 750mls day
2, 150mls day 3 and 100mls day 4). This resulted in the relief of the
patient’s symptoms, including weaning from oxygen supplementation.
Pleural fluid was exudative, with the total protein of 63.5g/L against
total serum protein of 74.7g/L (pleural fluid: serum total protein ratio
of 0.85). Both pericardial and pleural fluid culture and gram-staining
for acid-fast bacteria were negative ruling out pericardial
tuberculosis. The patient was therefore started on diuretics: frusemide
and spironolactone for the heart failure, and hydroxyurea 1g twice daily
for the CMML.
Conclusion and Results (Outcome and follow-up)
The patient clinically improved and was discharged from hospital on day
21, with the discharge WBC being 36.92*109/L,
neutrophils 18.58*109/L (50.3%), monocytes
10.44*109/L (28.3%), lymphocytes
7.02*109/L (19.0%), Hb 10.6g/dl and platelets
35*109/L. He was scheduled for follow-up at the MTRH
haemato-oncology clinic in two weeks, for which he returned and was
doing well, with the WBC having reduced to
15.21*109/L, neutrophils 8.35*109/L,
monocytes 3.44*109/L, lymphocytes
2.66*109/L, Hb 11.2g/dl and platelets
100*109/L. Further details on the laboratory findings
are as shown in supplementary document.
Discussion
CMML is a rare haematological disorder, with most of the cases being
asymptomatic at presentation. This makes the diagnosis of CMML
challenging, especially in the low and middle-income settings where
diagnostic resources could be limited. Noting that CMML has an inherent
risk of transforming to acute myeloid leukaemia (AML) and this is
associated with poorer outcomes,8,9 high index of
suspicion is therefore primal for early recognition and initiation of
treatment. Our patient presented with acute HF from life-threatening
pericardial effusion, which is a much rare manifestation of
CMML,6,7 Therefore, the diagnosis of CMML as the
primary cause of our patient’s complaints could have been missed were it
not for the attention paid to the pericardial effusion as well as white
blood cell counts. This necessitated further investigations and
exclusion of common potential causes of pericardial effusion in our set
up such as tuberculosis and other bacterial infections. Further, other
causes of reactive monocytosis such as infections, chronic myeloid
leukaemia (CML), essential thrombocythemia, polycythaemia vera and
primary myelofibrosis were excluded by blood culture, PBF, bone marrow
biopsy and flow cytometry. This led to early intervention for the HF and
recognition as well as treatment of CMML in our patient. Consequently,
he clinically improved significantly and was discharged from the
hospital.
CMML diagnosis should therefore be guided by high index of suspicion,
supported by suggestive findings from complete blood count and bone
marrow. According to the 2016 WHO diagnostic criteria, CMML is diagnosed
by: peripheral blood and bone marrow morphological findings of
peripheral monocytosis of >1*109/L, with
monocytes comprising >10% of the total WBC persisting more
than 3 months, <20% blasts in peripheral blood and bone
marrow, and dysplasia affecting ≥1 myeloid cell
lines.5,10,11
Clinical presentation of CMML is quite variable, ranging from being
asymptomatic to constitutional symptoms such as malaise, weight loss and
night sweats, as well as symptoms of specific cytopenias such as
headache among those with anaemia, bleeding tendencies among those with
thrombocytopenia and recurrent infections due to white blood cell
dysfunction 12. On the other hand, polyserositis,
which refers to the inflammation of the serous membranes (pericardium,
pleura and peritoneum) and formation of serous effusions is a rare
presentation of CMML.6,13,14 Fauci et al. reported
that polyserositis affected up to 20% of the cases.15Of the 9,723 cases analysed by Kaur et al., only 0.4% (n =40) had
leukemic involvement of the serous membranes ,with only 1 case being due
to CMML.16 The most common site was pleural cavity
(n=30), followed by peritoneal cavity (n=7), then pericardial cavity
(n=3). Therefore, our patient primarily presenting with
life-threatening pericardial effusion with acute heart failure was a
much rarer case of CMML.
WHO recommends that the diagnosis of CMML be made after the exclusion of
other causes of reactive monocytosis such as chronic myeloid leukaemia
(CML), essential thrombocythemia and polycythaemia vera. Multiparameter
flow cytometry is key in excluding these differentials. The presence of
≥94% of classical human monocytes which express a high positive CD14
and high negative CD16 surface markers in flow cytometry has a
sensitivity and specificity of 91.9% and 94.1% respectively in
distinguishing CMML from the aforementioned differentials.4,11,17 Notably, our patient expressed 94% CD14 in
flow cytometry. Further, he showed 94% CD123 and 83% CD56, which are
also highly suggestive of CMML.4
Further diagnosis of CMML would require elicitation of the absence ofBCR-ABL1 fusion for CML through RT-PCR or FISH. However, we could
not conduct these tests due to resource limitation, although CML would
very rarely present with more than 10% monocytes.5Our patient had 24% monocytes. Additional molecular studies to rule out
genetic rearrangements such as PCM1-JAK2, PDGFRA, PDGFRB, FGFR1for very rare cases which would also have eosinophilia and monocytosis
would be important,3–5 and form part of WHO
diagnostic criteria for CMML. We could however not do these tests in our
set up due to their unavailability. Notwithstanding, the evidence from
our PBF, bone marrow and flow cytometry results was sufficient for the
diagnosis of CMML in our case.
In conclusion, CMML is a rare haematological disorder, with a highly
variable presentation. Its diagnosis requires high index of suspicion
especially in low resource setting where advanced diagnostic tools are
not readily available. Further, pericardial effusion is a rare but a
fatal complication of CMML that clinicians need to be cognisant of.
Noting that CMML has a high propensity to transform to AML with poor
prognosis, early recognition and initiation of treatment would be highly
recommended.