differential diagnosis is large and include nutritional deficiency,
chronic inflammatory reactions, autoimmune diseases (e.g.,
autoimmune hemolytic anemia), chronic renal or hepatic
diseases, infectious disorders, inherited conditions and bone
marrow failure. Several causes of bone marrow failure need
to be considered, such as myelodysplastic syndrome, aplastic
anemia, infiltration of the bone marrow by hematologic or non-
hematologic neoplasm, myelofibrosis or toxic damage.
case, the second bone marrow biopsy was diagnostic for breast
cancer bone marrow infiltration.
While breast cancer is commonly diagnosed in the early
stages of the disease without evidence of distant metastases,
recurrence at distant sites may arise years after the initial
diagnosis and treatment. We now know that breast cancer has
an early spread of tumour cells.
The dissemination of tumour
cells can take two pathways, either lymphatic dissemination or
hematogenous dissemination. The detection of BMM is evidence
of dissemination through the blood circulation.
As reported earlier, a third of patients have BMM detected at
the time of breast cancer diagnosis.
The majority of those patients
have normal blood counts and no specific symptoms. A previous
study (Kopp et al.) reported an incidence of only 0.17% clinically
apparent BMM. The actual incidence may be underestimated,
as stated by the investigators, because the diagnosis may have
been missed and their databased was incomplete.
When BMM is clinically evident, the most common finding is
anemia, present in 40–60% of patients, while 12–25% of patients
have leukopenia and thrombocytopenia.
abnormalities include hypoproteinemia and elevated serum
Symptoms reported are asthenia, anorexia
and bone pain secondary to osteolytic lesions. In a past series of
22 cases, a close association between bone metastasis and bone
marrow involvement was confirmed, with all patients having
. Other studies found that 2–8 % of patients
with BMM had no evidence of skeletal involvement.
Demir et al, reported that the median time to diagnosis of
BMM was of 3 years after the initial diagnosis of breast cancer.
The interval was shorter in hormonal receptor negative tumoUrs
which is consistent with past studies. Risk factors
for BMM include large tumoUr size, poor differentiation, lymph
node metastasis, and negative hormone receptors.
There are some
reports of bone marrow involvement as the initial presentation
of breast cancer.
To our knowledge, there is no other reported
case of evidence of BMM months before the diagnosis of breast
cancer without breast lesion on physical exam and a normal
Non-invasive test for diagnosis of BMM include whole-
body PET, with a sensitivity of 87% with a positive predictive
value of 94%. Since most patients undergo PET scan for the
stating of the disease, PET seems the modality of choice for the
diagnosis of BMM. Whole-body PET with 18F-FDG exploits
the high glycolytic rate of malignant tissue compared with that
of non-malignant cells, which can reveal previously unknow
metastatic disease to the bone marrow.
smear can show signs of marrow infiltration with the presence
of leukoerythroblastosis, if other causes, such as myelodysplastic
syndrome and myeloproliferative syndromes are ruled out.
Leukoerythroblastosis is defined as the presence of nucleated
erythrocytes and immature myeloid cells in the peripheral
Bone marrow evaluation is often needed to confirm
the diagnosis. Past series suggested that bone marrow biopsy is
more useful than aspiration for the diagnosis of BMM,
less than 15% of false-negative results.
There is limited literature regarding the safest and most effective
treatment of patients with BMM. The presence of cytopenia, due to
breast cancer infiltration of the marrow, poses a difficult problem
in the treatment of affected patients. Past reports demonstrated
the need for intensive hematological support in more than 50%
of patients treated with full-dose chemotherapy and a risk of
infection around 20%.
More recently, small studies have
presented benefit, including improvement of cytopenia, with
the use of low-dose chemotherapy with capecitabine, endocrine
therapy, anthracycline or trastuzumab.
More studies are
needed before a standard regimen can be established.
The prognosis of breast cancer patients with BMM, while
variable, is usually poor. The median survival time after the
diagnosis of apparent BMM varied from more than 6 to 19 months,
in past studies.
The extent of bone marrow infiltration may
have prognostic value. In a multivariate analysis of prognostic
factors in patients with breast cancer, a pre-treatment hemoglobin
less than 110 g/L and platelets below 100 × 10
/ L was associated
with a poor prognostic.
BMM may be an indicator of early
recurrence. Cote et al, reported an association between the
presence of micrometastasis in operable breast cancer stage I
and II, and early recurrence. The 2 years’ recurrence rates were
3% and 33% in 49 patients without and with micrometastases
In conclusion, unexplained cytopenia is a strong indicator of
the necessity of bone marrow examination. Bone marrow is
a frequent site of metastasis of breast cancer and other solid
tumours. Patients with BMM usually don’t have bone marrow
failure, but they can present with anemia, thrombocytopenia
or pancytopenia. Further studies are needed to develop more
Canadian Journal of General Internal Medicine
Volume 14, Issue 1, 2019 19
J u l i e B e a u d o i n - M a i t r e e t a l