Sickle Cell Anemia and Hematological Neoplasias
SEMRA PAYDAS*
Faculty of Medicine, Department of Oncology, Cukurova University, Balcali, Adana, Turkey
(In final form 22 November 2001)
Sickle cell disease (SCD) is a congenital hemolytic anemia with various clinical findings. In some caseshematological neoplasias and some solid tumors may accompany this disease but these have rarely beenreported. Here we report five cases with SCD and accompanying hematological neoplasias includinglymphoblastic lymphoma, multiple myeloma and hairy cell leukemia in four cases with sickle cell traitand one case of Hodgkin’ disease in sickle cell anemia. All of the cases except one had no previouslydiagnosed congenital hemolytic anemia and/or family history. Peripheral blood findings suggestive foran underlying hemolytic anemia were the first step and the most important initial lead in the detection ofSCD. Severe musculoskeletal signs during the first presentation was seen in the lymphoma case,residual renal dysfunction after remission of multiple myeloma, and areas of infarction in the spleen inCT scans in the patient with sickle cell anemia were the most interesting findings in these cases. Astandard therapeutic approach without any additional toxicity was relevant in all cases. Detailed clinicalpresentation and outcome of these five cases are documented here and the literature has been reviewed.
Keywords: Sickle cell anemia; Neoplasia; Hemato-oncological tumors
INTRODUCTION
There are some reports about hemato-oncological
neoplasias occurring in congenital hemolytic anemias
such as sickle cell disease (SCD), thalassemia, congenital
dyserythropoietic anemia and hereditary spherocytosis
[1–9]. Extramedullary hematopoiesis should be con-
sidered as the first diagnostic possibility in cases with a
tumoral mass [10–13], however some hemopoietic
neoplasias and solid tumors including Hodgkin’s disease,
non-Hodgkin’s lymphomas, monoclonal gammopathies,
acute leukemias, hepatocellular carcinoma and renal
medullary carcinoma have been reported as single case
reports in congenital hemolytic disorders including SCD
[1,3,4,6,14,15]. However in most of these cases the
neoplasia has been detected in cases with a known history
of congenital hemolytic anemia.
Although the exact incidence of cancer in patients with
SCD is not known, it seems that there is a higher incidence
of malignancy in these cases in some reports [2]. The
coexistence of two diseases in the same patient may
increase the severity of clinical symptoms of SCD by
precipitating vaso-occlusive crisis. Here, we report five rare
cases with SCD and an associated hemato-oncological
neoplasia including acute leukemia, lymphoma, multiple
myeloma and hairy cell leukemia. The relevant literature is
also reviewed.
CASE REPORTS
Case 1
A 24 year-old-man was admitted with migratory
arthralgia, muscle pain, fever and weight loss. Physical
examination revealed cervical lymphadenopathy, hepato-
megaly and disseminated bone tenderness. He had no
history of previous blood transfusions or similar
arthralgia-muscle pain. Laboratory examination: Hb was
12.9 g/dl, WBC 7:64 £ 109=l; platelets 144 £ 109=l; Hct
was 38.1%. There was aniso-poikilocytosis and rare
sickled cells were seen. White blood cell differentiation
was within normal limits in the peripheral blood smear.
ESR was 104 mm/h. Hemoglobin electrophoresis showed
40.9% Hb S and 59.1% Hb A. Blast infiltration was found
in the bone marrow (BM) aspiration and lymph node
biopsy was reported as lymphoblastic lymphoma-T cell
type. He was diagnosed as lymphoblastic lymphoma-stage
IV together with sickle cell trait and was treated with
combination chemotherapy. A complete response was
ISSN 1042-8194 print/ISSN 1029-2403 online q 2002 Taylor & Francis Ltd
DOI: 10.1080/10428190290033396
*Fax: 322-338-6153. E-mail: [email protected]
Leukemia and Lymphoma, 2002 Vol. 43 (7), pp. 1431–1434
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achieved but 3 months later central nervous system relapse
occurred.
Case 2
A 17 year-old-woman was admitted with the diagnosis of
Hodgkin’s disease (nodular sclerosing type). She had an
history of tonsillectomy–adenoidectomy 8 years earlier
and one unit of blood transfusion was given during this
operation. Physical examination revealed pallor and right
supraclavicular lymphadenopathy. Laboratory examin-
ation: Hb was 7 g/dl, Hct 23%, WBC 12 £ 109=l; platelets
392 £ 109=l. There was aniso-poikilocytosis, sickled cells,
basophilic stipling and normoblasts were seen in the
peripheral blood smear. LDH was 909 IU/l, total/direct
bilirubin levels were 2.52/0.63 mg/dl. Hemoglobin elec-
trophoresis showed Hb SS. CT showed mediastinal and
right hilar lymphadenopathy, hepatomegaly and a
hyperdense spleen with multiple echogenic foci. BM
aspiration showed hypercellularity with erythroid hyper-
plasia and megaloblastic change; there was no evidence of
lymphoma infiltration. Ga scanning confirmed mediastinal
mass (l5 £ l0 cm diameter). BM scanning showed low
activity in the spleen and irregular distribution of
radioactivity. Abdominal US showed functional asplenia.
She was diagnosed as Hodgkin’s disease (nodular
sclerosing type) Stage II associated and sickle cell anemia
and was treated with six courses of ABVD and mediastinal
irradiation. She is under follow up period and active
hemolysis is evident in the peripheral blood smear. Her Hb
level is 6–7 g/dl but she is asymptomatic.
Case 3
A 41 year-old-man was admitted to hospital with fatigue.
He had an history of an operation for ileus 1 year before
and a month’s history of the diagnosis of hairy cell
leukemia which was confirmed by BM biopsy. Physical
examination revealed pallor and the spleen was palpated
near the left costal margin. Hb was 7.4 g/dl, Hct 21.1%,
WBC count 2:92 £ 109=l; platelets were 38 £ 109=l:Aniso-poikilocytosis, polychromasia and striking red
blood cell morphologic findings were evident in the
peripheral blood smear, 60% of the WBC were TRAP (þ)
hairy cells. Due to the RBC morphologic changes and the
relatively small size of the spleen which was less than
expected for hairy cell leukemia, hemoglobin electro-
phoresis was done and this showed 66.3% HbA, 1.5%
HbA2 and 32.2% HbS. He had no prior history of blood
transfusion and no family story of hemoglobinopathy. He
was given therapy with 2-Chlorodeoxyadenosine and
complete remission was achieved.
Case 4
A 40 year-old-man was admitted to the outpatient clinic
with upper quadrant pain. He had a history of blunt trauma
1.5 months ago. He was a recognized HbSAg carrier and
sickle cell trait was diagnosed 6 years before the present
admission. Physical examination revealed pallor and
tender splenomegaly which was palpated 14 cm below
the left costal margin. Laboratory examination revealed
Hb 9 g/dl, WBC l:6 £ 109=l; platelet count 33 £ 109=l:Peripheral blood smear showed aniso-poikilocytosis and
rare sickled cells were evident. Fifty percent of the WBC’s
had cytoplasmic projections compatible with hairy cell
leukemia. BM aspiration was hypocellular but 90% of the
cells had an hairy cell morphology and these were TRAP
(þ) BM biopsy showed hypercellularity with increased
reticulin and infiltration with hairy cells. Upper abdominal
CT showed a possible tear in the spleen with a subcapsular
hematoma. Splenectomy was performed and liver biopsy
was done at the operation. Histopathologic examination of
the liver was reported as having mononuclear cell
infiltration. Hairy cell infiltration and extramedullary
hematopoiesis were found in the spleen. After splenect-
omy the Hct was 29.8%, WBC 6:5 £ 109=l; and the
platelet count 116 £ 109=l: Initially he was treated with
interferon alpha and complete remission was not achieved.
2-Chlorodeoxyadenosine was then given. The last Hct was
40% and WBC 5:8 £ 109=l:
Case 5
A 57 year-old-man was referred to our hospital with a
nephrotic syndrome. Clinical examination revealed edema
and pallor. Laboratory: Hb was 7.9 g/dl, WBC was 4:5 £
109=l; platelet count was 120 £ 109=l:Urinary protein was
found as 9 g/l. BUN was 74 mg/dl, creatinine was
6.3 mg/dl, serum calcium level was 14.5 mg/dl. Aniso-
poikilocytosis, polychromasia and basophilic stipling was
found in the peripheral blood smear. Hemoglobin
electrophoresis showed HbS and alpha thalassemia. Fifty
percent plasma cell infiltration was found in the BM
aspiration. There was no evidence of hypergammaglobu-
linemia. Serum beta-2-microglobulin was 4.7 ng/ml.
Kappa light chain protein was (þ) in the urine. The
patient was diagnosed as having multiple myeloma (Stage
III B). He was admitted to another center for therapy with
VAD and followed by autologous stem cell transplan-
tation. He is currently in CR. Follow up visits showed an
Hb 9–10 g/dl, BUN 30–40 mg/dl and creatinine 2–3 mg/dl.
DISCUSSION
In this report five cases with hemopoietic neoplasia and
SCD are presented. Extramedullary tumors occur in cases
with congenital hemolytic anemias such as SCD,
thalassemia, congenital dyserythropoietic anemia, heredi-
tary spherocytosis and Hemoglobin C disease [10–13] and
because of this, if there is evidence of a tumor in these
cases, extramedullary hematopoiesis should be considered
in the differential diagnosis. However, malignant tumors
may also be seen in these patients. Indeed there are many
reports regarding acute-chronic leukemias, plasma cell
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dyscrasias, Hodgkin’s disease and non-Hodgkin’s lym-
phoma, malignant histiocytosis, breast cancer, renal
medullary cancer and hepatocellular cancer developing in
cases with congenital hemolytic anemias [1–6,14,16–35].
In these reports malignant neoplasias were always detected
in cases with a known diagnosis of congenital hemolytic
anemia. All our cases except for one, had no prior diagnosis
or history of congenital hemolytic anemia and this is the
most interesting point of this respect. Peripheral blood
smear findings were suggestive of a chronic hemolytic
disorder but it is also known that hemolysis particularly
autoimmune type may accompany to lymphoproliferative
disorders and plasma cell dyscrasias. In our cases reported
here however, the RBC morphology was suggestive for an
underlying hemolytic anemia.
There were some diagnostic difficulties and a few
clinical manifestations of interest in these five cases. For
example, in case 1 severe generalized migratory arthralgia
and muscle pains were the most striking symptoms. In this
regard, both SCD and advanced stage lymphomas may be
the cause, but in this case the additive effects of both these
disorders probably caused this severe musculoskeletal
presentation.
In case 2 thoraco-abdominal CT scans performed for
clinical staging had been reported by the radiologist as
Stage III disease because of the presence of space
occupying lesions in the spleen. However, in fact, she had
Stage II disease and the splenic infarctions had in fact
explained been thought to be intrasplenic tumor infiltra-
tions. During chemotherapy and radiation therapy there
was no unexpected toxicity in this case, despite the fact
that she had SS disease. However her hemoglobin level
was generally lower than normal due to repeated
hemolysis. Interestingly, there was no painful crisis and
fatigue was the only presenting symptom of her hemolytic
attacks. In these cases the therapeutic approach to the
anemia may be challenging. Hydroxurea is a valuable
agent in these cases and it succeeds by increasing the
hemoglobin F level, however long term therapy may
induce some additional chromosomal changes and
indirectly cause secondary neoplasias [36–38]. Because
of this a conservative therapeutic approach is probably
better in these cases.
In case 3 the peripheral blood smear suggested SCD but
similar findings are also evident and frequently encoun-
tered in with hairy cell leukemia. In this case however,
careful evaluation of the peripheral blood smear
established the diagnosis SCD. The absence of spleno-
megaly in this patient was found to be interesting for hairy
cell leukemia, but this is probably due to the sickle cell
anemia. In case 4 who had sickle cell trait, blunt
abdominal trauma was the cause of admission and hairy
cell leukemia was indeed a surprise finding with this kind
of presentation. All the above clinical situations are indeed
interesting, however we were unable to find any other
cases with SCD associated with hairy cell leukemia. The
relatively young age of both these patients was unusual for
hairy cell leukemia.
Plasma cell disorders cause hyperviscosity while SCD
also results in decreased red cell deformability and an
increased blood viscosity. Thus severe hyperviscocity may
cause some critical problems in the treatment and follow
up of these patients [35]. Acute and chronic renal findings
and/or failure are common in multiple myeloma as well as
in SCD, thus additive effects may be seen in relation to
renal problems while additional therapeutic problems may
also arise in the management of these renal disorder, as in
case no 5 had sickle cell trait and Stage III B multiple
myeloma. This patient was treated with combined
cytotoxic chemotherapy and successfully transplanted,
but while renal function tests improved, mild-moderate
renal failure persisted. In this case the residual renal
disorder was probably associated with sickle cell
nephropathy, because there was no evidence of multiple
myeloma after successful stem cell transplantation.
In conclusion malignant hematopoietic neoplasias may
occur in patients with sickle cell disorders. Initially
presenting clinical manifestations may suggest the
diagnosis of hemolytic anemia but there are some
diagnostic difficulties because of the SCD additional
signs and/or symptoms due to both disorders being
coexistent. Careful evaluation of peripheral blood smears
is the easiest and most useful step in the diagnosis of these
disorders.
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