# Postirradiation Osteosarcoma of the Maxilla: A Case Report and Current Review of Literature

Authors: Imene Chabchoub; Olfa Gharbi; Sami Remadi; Sami Limem; Amel Trabelsi; Makrem Hochlef; Leila Ben Fatma; Amel Landolsi; Moncef Mokni; Chekib Kraiem; Slim Ben Ahmed
Journal: Journal of Oncology
 (2009)

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## Abstract

Background. Radiation-induced sarcomas are well-known potential late sequelae of radiation therapy. They are of rare occurrence in jaw bones and are even rarer in the maxilla. Case report. We report a case of radiation-induced osteosarcoma involving the maxilla in a patient treated with radiotherapy for nasopharyngeal carcinoma 14 years ago. Despite neoadjuvant chemotherapy, surgical treatment could not be performed, and the patient received palliative chemotherapy. Conclusions. Radiation-induced osteosarcomas are aggressive and often elude early detection and timely intervention, rapidly leading to early demise of afflicted patients. Long-term patient follow-up and a high index of suspicion are crucial for timely intervention.


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## Body

## 1. Background

Radiotherapy
is the standard  treatment for nasopharyngeal carcinoma (NPC) [1].
Unfortunately, it can produce undesirable complications after treatment. When
radiotherapy is used with curative intent, the possibility of late
complications in the irradiated tissues must be considered. The spectrum of
malignant neoplasms secondary to radiation of head and neck tumors is wide. It
includes skin, thyroid, and bone neoplasms. Because radiation fields for NPC may
include the skull base as well as  maxilla, mandible, and pterygoid bones, radiation-induced
osteosarcoma (RIS) can arise from these sites as one of the late complications
of radiotherapy. These tumors are uncommon but aggressive, occurring after a latency
period of five years or more following radiotherapy. Histological proof of sarcoma
is necessary to distinguish it from other radiotherapy changes such as
osteonecrosis.In
view of the large number of
nasopharyngeal carcinoma cases, it is not surprising that
postirradiation maxillary, temporal, and sphenoid malignancies are now being
reported. We present a 49-year-old woman with osteosarcoma of the maxilla occuring
14 years after radiotherapy for NPC with a review of literature.


## 2. Case Report

A
49-year-old woman, treated in 1992 for  NPC (T3N1M0) with radiotherapy (70 Gy over 35
sessions with large lateral opposing faciocervical fields and complementary
anterior facial field), presented
fourteen years later with pain and swelling of the cheek. The swelling was
increasing in size and advancing towards the eye. Examination showed an expansile
mass in the right maxillary region with local paresthesia and proptosis of the
right eye. The overlying skin appeared normal.Computed
tomography (CT) demonstrated a large bony mass in the right maxilla that
extended into temporal bone (Figure1). Histological examination disclosed a
fibroblastic osteosarcoma which produced chondroid substance, and contained
distinct osteoid trabeculae. Immunohistochemistery showed diffuse positivity to
vimentin and S100 protein antibodies (Figure 2). CT of the lung revealed no lung
metastases.Bony mass in the left maxilla and extended to the right temporal bone.Figure 2
Section from the biopsy specimen
showing a chondroblastic osteosarcoma which contains dominating chondroid
substance (right side) and osteoid trabeculae derived from neoplastic cells
(center) (He × 185).After
discussing the unresectability of the tumor with the patient, neoadjuvant
chemotherapy was proposed with high-dose methotrexate. The tumor showed
clinical and radiographic progression after 5 cycles of treatment. The mass
extended into right orbit, right sphenoïd as well as the nasal cavity. A
remedial treatment was started with doxorubicin and cisplatin, though CT
appearances after chemotherapy were unchanged. Twelve months later, the patient
is alive without metastases, and we are pursung palliative chemotherapy with
ifosfamide and etoposide.


## 3. Discussion

The  occurence  of sarcomas in irradiated
tissues is an uncommon but well-documented long-term complication of
radiotherapy. The incidence of radiation-induced tumors is increasing in the
oncology population as a result of increased survival, with improvement in cancer
treatment
[2–4]. In the largest study reported in English literature,
Liu et al. [2] described 15 cases of
RIS as a late complication of NPC. The study included 33.3% osteosarcoma of the
maxilla, 46.7% of the mandible and 20% from a mixture of the nasal cavity and
paranasal sinuses. They estimated the incidence of radiation-induced
osteosarcoma in NPC as approximately 0.037% [2].In
1948, Cahan et al. [5] described 11 cases of sarcomas arising from
irradiated bones. They established four criteria for the diagnosis of
radiation-induced osteosarcoma that are still valid today: (a) the origin of
the neoplasm in the radiation field, (b) the nonmalignant nature of the initial
bone condition (this criteria was modified by Arlen et al. [6] : “the tumors
developed in bone not known to have a primary malignant osteoblastic lesion
when the radiotherapy was given”), (c) the histological diagnosis of the
neoplasm, and (d) a relatively long latency period. Our patient fulfilled the
above-mentioned criteria.The
average standardized incidence of NPC in Tunisia
in 1998 was 3.5 cases per
100 000 males and 1.6 cases per 100 000 females. More than 80 new cases of NPC are
seen annually.The
most effective treatment is radiotherapy. The whole tumor dose delivered is
generally 65 to 75 Gy. The dose targets the primary tumor and regional
lymphatics, inclusive of the whole sphenoid body and  posterior half of maxilla in all cases. Some
other cases may need further intracavitary boost irradiation. In view of the
large number of cases treated for this particular malignancy, it is not
surprising that postirradiation sarcomas are now being reported in this
population.In
general, a radiation dose of at least 30 Gy is required for the development of
radiation-induced sarcoma [5, 7]. Reported radiation doses vary in this
population from 25 to 110 Gy, with a median of 45 Gy [7]. Our patient received
70 Gy.The
latency period between radiotherapy for NPC and the development of temporal
bone tumors ranged from 5 to 30 years with a mean of 12.9 years [8]. Our
patient developed the second tumor 14 years after primary radiation therapy.Although
the pathogenesis is unknown, various predisposing factors have been suggested
[9]. RIS may occur after megavoltage or orthovoltage radiation, but in the latter
case,  the treatment dose is lower and the
period of irradiation is longer [10]. In addition to radiation dose, development
of RIS is probably influenced by other factors: age of the patient at radiation
exposure, association of chemotherapy, and genetic predisposition [11].It is
suggested that the patients who harbor mutations in tumor suppressor genes
likep53 and RB1 are more prone to develop radiation-induced osteosarcoma.
Friend et al. [12] described 8 cases of osteosarcoma with an altered RB allele.
Others have suggested that the lack of RB expression  in osteosarcoma and soft tissue sarcoma may be
common since RB gene transcripts were not detected. Moreover, they consider that
lack of of RB gene expression occurred
only after the tumor develops. Nevertheless, radiation-induced DNA alteration
is well demonstrated, so we could consider that deletion or inactivation of
this tumor suppressor gene may be an important factor for RIS [12] with a
relative risk of RIS 400-fold greater than the general population [13].The Li-Fraumeni syndrome, von Recklinghausen’s
disease, and other hereditary syndromes have also been identified as risk
factors for RIS [14]. In fact, radiotherapy delivered for benign diseases such
as fibrous dysplasia or Paget’s disease in the past may lead to RIS [15].
In fact, some studies have proved that RIS are increased after treatment of
Hodgkin’s lymphoma with radiotherapy. In addition, radiation therapy given
during childhood can also increase the relative risk of RIS to 30 [11]. Leclercq et al. [11] have suggested also that addition of alkylator-based chemotherapy
to radiotherapy will increase the risk of developing RIS threefold.The most common clinical findings of the head and
neck radiation-induced sarcoma are pain and swelling with pathological fracture
also reported. A soft tissue mass and bone destruction due to new bone
formation are the main characteristics on radiography and CT. The degree of new
bone formation on CT is variable.Chondroblastic
osteosarcoma of the head and neck represents 25% of all osteosarcoma of this
region with a low histologic grade encountered in 26% of cases [16]. The
treatment of sarcoma of the maxilla irrespective of etiology includes radical
surgery with adjuvant chemotherapy [16]. For the majority of authors, complete surgical excision with negative
surgical margins is crucial to local control as well as recurrence-free
survival. Some
authors have recommended neoadjuvant chemotherapy before definitive surgery is
undertaken [17]. The majority of authors in the reported cases and series use
the same chemotherapy as used for primary sarcoma with ifosfamide, methorexate,
and doxorubicin, though there are no randomised trials to compare results. Surgery
appears to offer the best chance of cure. However, as osteosarcoma metastasizes
by the hematogenous route, there is rationale for the addition of adjuvant
chemotherapy [4]. There have not been large studies to determine the effectiveness
of various treatments for postirradiation osteosarcoma.Tumor size and
grade are the two most important prognostic factors for soft tissue sarcomas,
including those associated with radiation therapy. The treatment of choice for
RIS is surgical resection with negative margins [18]. The role of adjuvant
therapy in radiation-induced sarcomas is unknown. It seems that there is no survival
benefit for those patients receiving adjuvant chemotherapy or radiotherapy
compared with those treated only with surgery that achieves negative margins [11–18].High-grade
tumors that are larger than 5 cm should be treated with primary chemotherapy followed
by complete surgical excision of residual disease. All low-grade tumors and
high-grade tumors that are 5 cm or smaller should be treated with a margin-negative surgical excision, and
systemic chemotherapy should be considered when a negative margin is not
accomplished [17].Osteosarcomas
of the long bones frequently develop metastatic tumor, especially to the lungs.
In contrast, RIS of the skull does not exhibit this tendency. Moreover, these
tumors have a poor prognosis because of rapid local growth [19].The
prognosis of radiation-induced sarcoma is generally thought to be worse than
primary sarcomas, regardless of site. The cumulative disease-free survival at 5
years for patients with a postirradiation osteosarcoma was 17%, with a median
survival estimate of 1 year [14]. In a review of 78 cases from the Mayo Clinic,
about 30% of the patients with sarcomas of the craniofacial bones survived 5
years without recurrence [20].Most
series report overall survival rates at 5 years in the range of 10% to 30% [14–21].
Several factors predict for this poor survival rate, including
neurosensory symptoms at presentation, increasing  patient age, and surgical
margins less than 5 mm [7–11]. In multivariate analysis of 160 cases of RIS, Brady
et al. [22] demonstrated that three
variables had prognostic significance: the presence of metastatic disease, the
completeness of surgical resection in patients with localized disease, and the
size of the primary tumor in patients who underwent complete resection.
Survival was independent of histologic subtype or site of disease.Often,
there is a delay in diagnosis until an advanced stage of disease because of the
difficult distinction between neoplastic and radiation changes. In addition, RIS
occurs often in anatomic sites (head and neck, pelvic, thorax) where complete
surgical resection is difficult.To
prevent radiation-induced sarcoma, it is important to have meticulous attention
to radiation dosimetry in carefully planned fields. For our case, the current radiation
dose is less than in the past with the addition of chemotherapy in the
treatment of NPC. Furthermore, intensity modulation radiotherapy (IMRT) will
reduce the exposure of normal tissues to radiation.Because
of the aggressive nature of RIS, careful long-term follow-up of irradiated
patients is crucial. A high index of suspicion is needed for early detection
and timely intervention.


## 4. Conclusion

Radiation-induced sarcoma is a potential late sequelae
of radiation therapy. These tumors are very aggressive and often elude early
detection, thereby hindering timely intervention. Although early
detection of radiation-induced tumors is important, it is difficult since changes
seen after radiotherapy have often been attributed to other causes such as
osteonecrosis.
Although
the condition is rare, the possibility of RIS must be considered in any patient
who has received radiation treatment.



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*Source: 876138-2009-05-25.xml*