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: sepay@mail.cu.edu.tr

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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