Abstract
We will review the case of a 71-year-old woman with an atypical presentation of stage IV breast
cancer. She presented with symptomatic normocytic anemia (Hb 85 to 100 g/L) for the past two
years, with a normal extended laboratory evaluation. Due to deterioration of her anemia, a bone
marrow biopsy was done and concluded to myelodysplastic syndrome. Treatment with epoetin
alfa and a trial of lenalidomide didnt improve her hemoglobin and she was still transfusion
dependent. A second bone marrow biopsy revealed breast carcinoma infiltration, which was
initially missed on the first biopsy. The patient was started on letrozole and palbociclib with
good clinical response. Here, we present the clinical evolution, diagnosis and management of
bone marrow micrometastasis due to breast cancer.
Résumé
Nous présentons létude de cas dun cancer du sein de stade IV, chez une femme de 71 ans, ayant
eu une présentation atypique. Elle sest présentée avec une anémie normocytaire (Hb 85 à 100 g/L)
symptomatique depuis deux ans, non explicable par un bilan biochimique approfondi. Suite
à la dégradation de son anémie, une biopsie de moelle osseuse a été effectuée concluant à un
syndrome myélodysplasique. Un traitement à lepoetin alfa ainsi quun essai de lenalidomide ne
permirent pas lamélioration de son hémoglobine et elle est demeurée dépendante aux transfusions.
Une seconde biopsie de moelle osseuse démontra une infiltration par un carcinome mammaire
qui navait pas été constatée lors de la première biopsie. Un traitement avec du letrozole et du
palbociclib a alors été débuté avec une réponse clinique satisfaisante. Nous passons en revue la
présentation clinique, la démarche diagnostique ainsi que la prise en charge des micro métastases
de la moelle osseuse dans le cancer du sein.
Keywords: metastatic breast cancer, bone marrow micrometastasis, cytopenia.
About the Authors
Julie Beaudoin-Maitre is PGY 5 in the Department of Internal Medicine at the University of Sherbrooke, Sherbrooke, QC.
Chantal Vallée is an Assistant Professor, Department of Internal Medicine at the University of Sherbrooke, Sherbrooke, QC and
Chief of Department ofSpecialized Medicine,CISSS de la Montérégie-Centre.
Correspondence to: julie.beaudoin-maitre@usherbrooke.ca
Submitted: December 20, 2017. Accepted: June 6, 2018. Published: February X, 2019. DOI: 10.22374/cjgim.v14i1.261
Metastatic Breast Cancer Presenting as
Refractory Anemia
By Julie Beaudoin-Maitre, MD and Chantal Vallée, MD
Case Study
Canadian Journal of General Internal Medicine
Volume 14, Issue 1, 2019 17
Breast cancer is the most common cancer affecting women in
Canada, with an estimated 25,700 new cases each year. It is the
second most prevalent cause of cancer death in women,
1
particularly
because of distant metastases. Indeed, approximately 15% of
women with operable breast cancer relapses within 15 years.
2
In pooled multicenter analysis, bone marrow micrometastasis
(BMM) was detected in 30% of patients with breast cancer stage I,
II, and III. The presence of micrometastasis was an independent
prognostic factor of poor outcome.
3
While BMM is considered relatively frequent, the development
of cytopenia and bone marrow failure is rare.
4
Here we present a
patient with progressive symptomatic anemia over three years,
who was initially diagnosed with myelodysplastic syndrome but
was later found to be a manifestation of breast cancer metastasis
to the bone marrow.
Case Presentation
A 71-year old female patient was referred to our service for
evaluation of a heterogeneous aspect of the thoracic spine on
a chest computed tomography (CT). Her past medical history
is significant for hypertension, hyperlipidemia, subarachnoid
hemorrhage with a type I Chiari malformation, and a bioprosthetic
aortic valve. The initial skeletal survey and bone scan were negative
for metastasis. Blood tests revealed normocytic anemia, with a
hemoglobin 85 to 100 g/L and a mean corpuscular value of 95 fL
for the past two years. The white cells and platelets were within the
range of normal. The extended laboratory evaluation for anemia
was normal. Bone marrow evaluation was done in the following
months, because of progressively worsening symptomatic anemia.
The bone marrow aspiration was not diagnostic due to a dry
tap, while the biopsy showed an hypercellular bone marrow with
erythroid dysplasia, megakaryocytes and myelofibrosis grade
1 and 2, compatible with myelodysplastic syndrome. Patient
was referred to a hematologist and started on epoetin alfa. Her
hemoglobin improved with higher doses of epoetin, but red cell
transfusions were still needed every four to six weeks to maintain
a hemoglobin above 80 g/L. A trial of lenalidomide was stopped
after one month, because there was no improvement of the
anemia and the patient presented a skin rash. The patient later
developed an iron overload due to the transfusions.
Since the anemia didn’t respond as expected with typical
treatment of myelodysplastic syndrome, a second bone marrow
biopsy was done eight months after the first one and revealed
breast carcinoma infiltration with positive estrogen receptor,
negative HER2 and progesterone receptor. In light of the findings,
the first biopsy was reviewed and showed positive epithelial cells
to cytokeratin AE1/A3, GATA 3 and slightly positive to CD 138,
consistent with a mammary carcinoma infiltration of 10–15%
of the specimen surface. Those cells were probably mistaken on
the first biopsy for granulocytic precursors cells. Based on these
results, a review of the patients gynecological history was taken.
There was no past or familial history of breast or ovarian cancer.
Her mammography’s of the last two years were negative, the last
one done a month prior. The physical exam was within normal
and didnt reveal breast lump or lymphadenopathy. Tumour
marker panel indicated increased serum level of Ca15-3, Ca19-9
and CEA. LDH were normal. The patient underwent a skeletal
scintigraphy, which was remarkable for many bilateral costal
lesions. An abdominal and pelvic CT scan confirmed the presence
of diffuse lytic lesions and right axillary lymphadenopathy, which
has been stable for the past two years. Diffuse metastasis of the
spine was revealed on magnetic resonance imaging (MRI). No
primary breast lesion was found on echography or MRI. After
discussion, with the oncology team, we decided against doing
a positron emission tomography (PET) scan since it wouldnt
change the management of the cancer.
Patient was started on letrozole and palbociclib, an highly
selective inhibitor of CDK 4/6. Cytopenia improved significantly
in the next 6 months, with hemoglobin level of 112 g/L and
normalization of white blood cells and platelets level. A single
dose of palliative radiotherapy was delivered on the left knee to
alleviate the pain from metastasis infiltration.
Discussion
Patients presenting with chronic unexplained cytopenia can be
a clinical challenge and warrant an extensive evaluation. The
Figure 1. Diffuse metastatic infiltration of the spine on magnetic resonance
imaging
Metastatic Breast Cancer Presenting as Refractory Anemia
Canadian Journal of General Internal Medicine
18 Volume 14, Issue 1, 2019
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.
5
In our
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.
6
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.
7
As reported earlier, a third of patients have BMM detected at
the time of breast cancer diagnosis.
3
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.
4
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.
8
Other laboratory
abnormalities include hypoproteinemia and elevated serum
lactate dehydrogenase.
9
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
bone metastasis
4
. Other studies found that 2–8 % of patients
with BMM had no evidence of skeletal involvement.
9
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
(17.9 months)
10
which is consistent with past studies. Risk factors
for BMM include large tumoUr size, poor differentiation, lymph
node metastasis, and negative hormone receptors.
3
There are some
reports of bone marrow involvement as the initial presentation
of breast cancer.
11
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
mammography.
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.
12
Peripheral blood
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
blood.
13
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,
14
with
less than 15% of false-negative results.
8
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%.
14–16
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.
8–18
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.
4–10
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
9
/ L was associated
with a poor prognostic.
8–19
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
respectively.
20
Conclusion
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 dont have bone marrow
failure, but they can present with anemia, thrombocytopenia
or pancytopenia. Further studies are needed to develop more
effective therapies.
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
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