Secondary osteosarcoma arising after treatment for childhood hematologic malignancies.
ABSTRACT Secondary osteosarcoma arising after the treatment of hematologic malignancies other than Hodgkin's lymphoma is rare. We report two cases of secondary osteosarcoma arising after treatment for childhood hematologic malignancies (non-Hodgkin's lymphoma and lymphoblastic leukemia). A 10-year-old boy, at the age of 3, was diagnosed with non-Hodgkin's lymphoma. He received chemotherapy, radiation, and bone-marrow transplantation and then was in complete remission. At 6 years, he complained of increasing pain of the right thigh and was diagnosed with osteoblastic osteosarcoma. A 26-year-old man, at the age of 6, was diagnosed as having acute lymphoblastic leukemia (ALL). He received chemotherapy, radiation, and peripheral blood stem cell transplantation (PBSCT). At 11 years after PBSCT, he visited with the complaint of left lumbar swelling. He was diagnosed with chondroblastic osteosarcoma. In both cases alkaline phosphatase (ALP) had already increased prior to the onset of the symptom. We should rule out secondary osteosarcoma at the abnormal elevation of ALP during clinical follow-up of patients after treatment of childhood hematologic malignancies.
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ABSTRACT: To assess the relative risk of developing a second malignant neoplasm in people with a diagnosis of cancer in childhood and adolescence. Register based follow up study. Populations of Nordic countries. 30,880 people under the age of 20 with a first malignant neoplasm diagnosed during the period 1943-87. Relative and attributable risks of second malignant neoplasms by type of first cancer, age at first diagnosis, calendar period, sex, and country. Expected figures were based on the appropriate national incidence rates for cancer. 247 cases of second malignant neoplasms were observed in 238 patients, yielding a relative risk for cancer of 3.6 (95% confidence interval 3.1 to 4.1). The risk changed significantly from 2.6 in people first diagnosed during the 1940s and 1950s to 6.9 among cohort members included in the late 1970s and 1980s. Increases were observed for most types of cancer. Highest levels of the relative risk were seen during the 10 years immediately after first malignant diagnosis. The incidence of second malignant neoplasms attributable to the first cancer and associated treatments, however, showed a consistent rise throughout the 45 years of follow up. The estimated risks for a second malignant neoplasm were significantly lower than those found in most large hospital based studies but compatible with the results from a similar population based study in the United Kingdom. Extent of risk and cancer pattern were similar among the Nordic countries and are believed to be representative for a large part of the European population.BMJ Clinical Research 11/1993; 307(6911):1030-6. · 14.09 Impact Factor
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ABSTRACT: Osteosarcoma is the most frequent second primary cancer occurring during the first 20 years following treatment for a solid cancer in childhood. Using a cohort study of children treated for a solid cancer, we investigated the incidence and etiology of osteosarcoma as a second malignant neoplasm after childhood cancer in a cohort and a case-control study. We analysed the relationship between the local dose of radiation and the risk of osteosarcoma, taking into account chemotherapy received. A cohort study of 4,400 3-year survivors of a first solid cancer during childhood diagnosed in France or the United Kingdom, between 1942 and 1986, revealed 32 subsequent osteosarcomas. In a nested case-control study, we matched 32 cases and 160 controls for sex, type of first cancer, age at first cancer and the duration of follow-up. Parameters studied were the incidence of osteosarcoma, the cumulative local dose of irradiation and the cumulative dose of chemotherapy received by cases and controls. The risk of a osteosarcoma was found to be a linear function of the local dose of radiation (excess relative risk per gray=1.8), and was found to increase with the number of moles of electrophilic agents per square meter but not with other drugs. No interaction was noted between radiotherapy and chemotherapy. Bilateral retinoblastoma, Ewing's sarcoma and soft tissue sarcoma were found to render patients susceptible to a higher risk of developing an osteosarcoma as a second malignant neoplasm. We recommend long-term surveillance of patients who were treated during childhood for bilateral retinoblastoma, Ewing's sarcoma, soft tissue sarcoma, as well as other first cancer treated with radiotherapy plus high doses of chemotherapy, without focusing exclusively on the radiation field.International Journal of Cancer 08/1998; 77(3):370-7. · 6.20 Impact Factor
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ABSTRACT: This study explores the relationship between histologic variants of bone sarcomas and previous therapy in patients in whom an unrelated malignant neoplasm had been diagnosed during childhood. Sarcomas of bone were the most common second malignant neoplasm (SMN) reported to the Late Effects Study Group, a 13-institution consortium consisting of pediatric oncology centers from western Europe, Canada, and the United States. The authors attempted to relate the histologic subtypes of the 91 bone tumors to clinical factors such as previous therapy and genetic predisposition because morphologic variants have been shown to have biologic significance in other tumors and may have etiologic import. The literature concerning the subtypes of bone tumors, clinical and experimental, is also reviewed. The authors also investigated the effect of several factors on the time interval from the first diagnosis to the SMN (i.e., the bone sarcoma). Anthracyclines significantly shortened the interval by about 3 years. The primary diagnosis also significantly affected the interval, with leukemia/lymphomas having the shortest interval and retinoblastoma the longest. The authors could not demonstrate any significant relationship between morphologic characteristics of the osteosarcoma and predisposing conditions. However, lesions diagnosed as chondrosarcoma and malignant fibrous histiocytoma occurred almost exclusively in patients who had received radiation therapy to the site in which the SMN developed.Cancer 02/1991; 67(1):193-201. · 5.20 Impact Factor
Upsala Journal of Medical Sciences. 2009; 114: 249–255
Secondary osteosarcoma arising after treatment for childhood
ATSUSHI OKADA1,2, MASAHITO HATORI1, MASAMI HOSAKA1,
MUNENORI WATANUKI1& EIJI ITOI1
1Department of Orthopaedic Surgery, Tohoku University School of Medicine, Japan, and2Department of Orthopaedic
Surgery, South Miyagi Medical Center, Japan
Secondary osteosarcoma arising after the treatment of hematologic malignancies other than Hodgkin’s lymphoma is rare. We
report two cases of secondary osteosarcoma arising after treatment for childhood hematologic malignancies (non-Hodgkin’s
lymphoma and lymphoblastic leukemia). A 10-year-old boy, at the age of 3, was diagnosed with non-Hodgkin’s lymphoma. He
received chemotherapy, radiation, and bone-marrow transplantation and then was in complete remission. At 6 years, he
complained of increasing pain of the right thigh and was diagnosed with osteoblastic osteosarcoma. A 26-year-old man, at the
age of 6, was diagnosed as having acute lymphoblastic leukemia (ALL). He received chemotherapy, radiation, and peripheral
blood stem cell transplantation (PBSCT). At 11 years after PBSCT, he visited with the complaint of left lumbar swelling. He
was diagnosed with chondroblastic osteosarcoma. In both cases alkaline phosphatase (ALP) had already increased prior to the
onset of the symptom. We should rule out secondary osteosarcoma at the abnormal elevation of ALP during clinical follow-up
of patients after treatment of childhood hematologic malignancies.
Key words: Acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, osteosarcoma, secondary cancer
Osteosarcoma is one of the most common secondary
malignant neoplasias following childhood malignan-
cies (1). Ewing’s sarcoma, retinoblastoma, rhabdo-
myosarcoma, and Hodgkin’s lymphoma are the most
frequent primary malignancies causing secondary oste-
osarcoma (2,3). However, secondary osteosarcoma
arising after the treatment of hematologic malignancies
other than Hodgkin’s lymphoma is rare (4). We report
two cases of secondary osteosarcoma following treat-
ment of childhood hematologic malignancies.
While previous reports mostly focused on the pri-
mary malignancies during childhood followed by sec-
ondary osteosarcoma, or on the possible causing
agent related to this entity, there have been no reports
concerning early detection of secondary osteosar-
coma. Alkaline phosphatase (ALP) is considered to
be involved in calcification of the bone matrix and
protein synthesis associated with bone matrix produc-
tion (5). There is fairly positive correlation between
the activity of plasma total ALP and the osteoblastic
activity in primary osteosarcoma patients (6–8). The
clinical value of this marker in secondary osteosarco-
mas, however, has not been reported. In this study, we
examined the time course of serum ALP expression in
two patients with secondary osteosarcoma following
childhood hematologic malignancies.
A 10-year old boy, at the age of 3, was diagnosed
with non-Hodgkin’s lymphoma (gamma/delta T cell
lymphoma). Chemotherapy was initiated accord-
ing to Tohoku Childhood Leukemia Protocol. This
Correspondence: Masahito Hatori, Associate Professor, Tohoku University School of Medicine, Department of Orthopaedic Surgery, 1-1 Seiryomachi Sendai
Miyagi 980-8574, Japan. Fax: +81-22-717-7248. E-mail: firstname.lastname@example.org
(Received 29 April 2009; accepted 9 July 2009)
ISSN 0300-9734 print/ISSN 1502-4725 online ? 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)
consisted of induction with vincristine, methotrexate,
and daunorubicin, followed by three courses of high-
dose methotrexate and high-dose cytarabine. After the
confirmation of remission by bone-marrow aspiration,
he underwent allogeneic bone-marrow transplanta-
tion from his (Human Leukocyte Antigen)-identical
brother. Since then he was in complete remission. At
6 years after the transplantation, the patient com-
plainedofincreasingpainofthe right thigh.Laboratory
data showed that his ALP was 2802 IU/L (normal:
200–620). At 2 months prior to the onset of the
symptom, serum ALP level had already elevated to
an abnormally high level of 1604 IU/L. Plain radio-
grams of the proximal femur revealed a mixed sclerotic
and lytic intramedullary lesion with extensive perio-
steal reaction (Figure 1). Magnetic resonance imag-
ing (MRI) revealed an isointense lesion within the
quadriceps femoris muscle on T1-weighted images.
The lesion was enhanced heterogeneously on fat-
suppressed T1-weighted images after gadolinium
injection. T2-weighted images also showed a hetero-
geneous hyperintense lesion (Figure 2). Histological
appearance of the biopsied specimen demonstrated
spindle or polygonal cells with atypical nuclei, eosin-
ophilic amorphous osteoid, and matured bone tissue
(Figure 3). Histological diagnosis was osteoblastic
osteosarcoma. Chemotherapy with Rosen T-20 was
administered to the patient. After preoperative che-
motherapy, wide excision of the tumor was per-
formed. Postoperative chemotherapy was performed
uneventfully, but the patient developed local recur-
rence and lung metastasis 15 months after the oper-
ation. Despite the irradiation to the thigh and
chemotherapy, the recurrent tumor continued to grow.
The patient died of respiratory failure 24 months
after the operation.
Figure 1. Case1. Plain radiograms of the proximal femur revealed a mixed sclerotic and lytic intramedullary lesion with the periosteal
perpendicular spiculation with extensive periosteal reaction and “Codman’s triangle” reaction.
A. Okada et al.
A 26 year-old-male, at the age of 6, was diagnosed
as having acute lymphoblastic leukemia (ALL).
Chemotherapy was initiated according to Tohoku
of 6-mercaptopurine, methotrexate, adriamycin, vin-
cristine, and cyclophosphamide. After 5 years of
chemotherapy, complete remission was achieved.
Ten months later, at the age of 12, he noticed that
Leukemia 83Bprotocol consisting
Figure 2. Case1. (A) MRI revealed an isointense lesion within the quadriceps femoris muscle on T1-weighed images. (B) T2-weighed images
showed a heterogenous hyperintense lesion. (C) The lesion was enhanced heterogeneously on fat-suppressed T1-weighed images after
Figure 3. Case1. Histological appearances of the biopsied specimen demonstrated spindle or polygonal cells with atypical nuclei, eosinophilic
amorphous osteoid and matured bone tissue.
Secondary osteosarcoma after childhood hematologic malignancies
his right testis was swollen. Biopsied specimen
showed leukemic infiltration. After chemotherapy
(prednisolone, vincristine, adriamycin, and asparagi-
nase) for 3 years, irradiation to bilateral testis (total
26 Gy), total body irradiation (total 12 Gy), and
peripheral blood stem cell transplantation (PBSCT),
complete remission was obtained. At 11 years after
PBSCT, he visited our department with the complaint
of left lumbar swelling. Laboratory data showed ALP
was 674 IU/L (normal: 112–330). At 3 months prior
to the onset of the symptom, serum ALP level
was already elevated to an abnormally high level of
559 IU/L. On plain computed tomography (CT), a
lytic lesion in the posterior superior iliac spine was
apparent (Figure 4). MRI showed a low-intensity
lesion around the left sacroiliac joint on T1-weighted
images. The lesion was enhanced on fat-suppressed
T1-weighted images. T2-weighted images confirmed
a heterogeneous hyperintense lesion (Figure 5).
Needle biopsy of the left iliac spine showed polygonal
of chondroid and osteoid tissues. Pathological diag-
nosis was chondroblastic osteosarcoma (Figure 6). At
2 weeks after the biopsy, the patient felt left leg pain.
Abdominal CT showed loss of pooling of contrast
medium in the left inferior vena cava, which suggested
a thrombus. The patient died of pulmonary embolism
4 weeks after the biopsy.
The occurrence of a secondary malignant neoplasm in
a child after or during treatment of a primary malig-
nancy is the most ominous effect of the treatment (4).
Osteosarcoma is one of the most common secondary
malignant neoplasms following cancer treatment (4).
An increased risk for developing osteosarcoma is
associated with prior tumors such as retinoblastomas
(9), Ewing’s sarcomas (9,10), rhabdomyosarcomas
Figure 4. Case 2. Plain CT showed a lytic lesion in the posterior superior iliac spine (arrow).
A. Okada et al.
(2,11), and Hodgkin’s lymphomas (2,3,12). Osteo-
sarcomas following hematologic malignancies other
than Hodgkin’s lymphoma, on the other hand, are
rare (13–16). Newton et al. reported 52 cases of
secondary osteosarcoma, which included 5 cases of
Hodgkin’s lymphoma as a primary cancer. Other
malignancies were retinoblastomas (16 cases), Ewing’s
sarcoma (13 cases), rhabdomyosarcomas (5 cases),
Wilms tumors (4 cases), and others (7 cases) (3).
Le Vu et al. reported 32 cases of secondary osteo-
sarcoma including 2 cases of Hodgkin’s lymphoma
and 2 cases of non-Hodgkin’s lymphoma as pri-
mary malignancies. Others were Ewing’s sarcoma
(8 cases), rhabdomyosarcoma (6 cases), retinoblas-
toma (5 cases), neuroblastoma (2 cases), tumors of
central nerve systems (2 cases), and others (5 cases)
(2). Nygaard et al. reported that no osteosarcomas
were detected in a population-based series of 8 second
Figure 5. Case 2. (A) MRI showed a low-intense lesion around the left sacroiliac joint on T1-weighted images. (B) T2-weighed images
confirmed a heterogenous hyperintense lesion. (C) The lesion was enhanced on fat-suppressed T1-weighed images.
Figure 6. Case 2. Needle biopsy of the left iliac spine showed polygonal cells with hyperchromatic nuclei. The stroma consisted of chondroid
and osteoid tissues.
Secondary osteosarcoma after childhood hematologic malignancies
malignancies in 895 childhood ALL (13). None were
detected among 43 second neoplasms in 9720 chil-
dren with ALL in a study by Children’s Cancer Study
Group, no osteosarcomas among 16 second malig-
nancies in 497 patients with non-Hodgkin’s lym-
phoma, and only 1 out of 52 second neoplasms
among 5006 ALL patients (14–16).
As for the treatment of secondary osteosarcoma,
numerous studies have demonstrated the increased
aggressiveness of, and the increased rate of mortality
associated with, post-irradiation osteosarcoma com-
pared with its naturally occurring counterpart (17).
Sim et al. reported that the average duration of
survival was 1.1 years after the diagnosis of post-
radiation bone sarcoma in 55 patients at the Mayo
Clinic. The poorer outcome for these patients may be
due to a delay in the diagnosis, because many symp-
toms are thought to be related to primary diseases or
radiation osteitis (18). Bechler et al. reported that of
nine casesof secondary osteosarcomaonly one patient
had survived free of disease for 5 years. Most of the
secondary tumors developed in the axial skeleton,
were not amenable to complete operative excision,
and were associated with pulmonary metastasis. They
found that radiation and various chemotherapeutic
agents had only palliative effects and did not affect the
course of the disease appreciably (11). Our two cases
were characterized by a poor outcome. In Case 1,
despite chemotherapy and irradiation, the patient
developed local recurrence and lung metastasis and
died of respiratory failure. In Case 2, the patient died
of thrombosis suddenly, probably due to tumor
Several agents have been proposed as a cause for
many secondary cancers (19). The role of radiation
therapy in carcinogenesis of secondary malignant
neoplasm is well known (3,12,20–22). Le Vu et al.
reported that the risk of osteosarcoma was found
to be a linear function of the local dose of radia-
tion (2). Radiation-associated osteosarcoma has
historically been associated with a poor prognosis,
because they are typically locally invasive and high-
Several studies have found an association between
prior alkylating agent and anthracycline therapy and
osteosarcoma (2,3). However, a causal relationship
between chemotherapy alone and the development
of a second malignant neoplasm in children has
not been established (11). Bone-marrow transplan-
tation, which commonly combines treatment with
high-dose alkylating agents and total body irradia-
tion, may be associated with second malignant neo-
plasms. Asai et al. reported a case of osteosarcoma
3 years after allogeneic bone-marrow transplanta-
tion (24). Bielack et al. also reported four cases of
osteosarcoma following hematopoietic stem cell
Both of our two cases were treated with chemo-
therapy including either anthracycline (daunorubicin)
or alkylating agent (cyclophosphamide) and total
body irradiation ahead of stem cell transplantation.
Although prior reports mostly focused on the
primary malignancies during childhood associated
with secondary osteosarcoma, or on the possible
causing agents related to secondary osteosarcoma,
there have been no reports regarding the early detec-
tion of the secondary osteosarcoma. Previous studies
have shown that plasma total ALP activity raised to
an abnormal level at the time of recurrence or
metastasis in patients with osteosarcoma (6,26,27).
Liu et al. reported that plasma bone-specific ALP
levels of osteosarcoma patients at the time of recur-
rence were significantly higher than those of the
patients without recurrence (28). Bramer et al. com-
pared pre-chemotherapy ALP levels with those of
post-chemotherapy levels in 89 cases of non-
metastatic high-grade sarcoma and concluded that
a pre-chemotherapy ALP above twice the normal
level correlated with worse survival and that post-
chemotherapy ALP correlated with survival and
response to chemotherapy (29). Here in this report,
we found that the elevation of the plasma level of
ALP preceded the aggravation of the symptom. We
should rule out secondary osteosarcomas at the
elevation of ALP during clinical follow-up after
treatment of malignancies.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
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