Chondroblastic osteosarcoma of maxil­la, a patient with Li- Fraumeni syndrome

Chondroblastický osteosarkom maxily, pa­cientka s Li-Fraumeni syndromem

Osteosarkom čelistních kostí představuje velice vzácný a vysoce zhoubný novotvar, který může být jedním z projevů Li-Fraumeniho syndromu –  dědičného onemocní, charakterizovaného vysokou pravděpodobností časného vzniku širokého spektra maligních nádorů. Incidence osteosarkomů čelistních kostí je asi 0,07/ 100 000. Prognózu pa­cienta nejvíce ovlivňuje stádium tumoru a možnost kompletního radikálního odstranění nádoru. Vzhledem k vzácnosti tohoto onemocnění bývají osteosarkomy čelistí zpočátku často špatně dia­gnostikované, což vede ke zpoždění v zahájení léčby a zhoršení prognózy. V tomto článku prezentujeme případ 32leté pa­cientky s Li-Fraumeni syndromem postižené chondroblastickým osteosarkomem, který také nebyl v úvodu správně dia­gnostikován. Po nekompletní resekci a časné lokální recidivě, která zcela vyplnila defekt po subtotální maxilektomii, bylo chemoradioterapií dosaženo kurativní odpovědi a více než 7letého přežití bez návratu onemocnění. Dále ve sdělení popisujeme příznaky, dia­gnostiku a léčbu tohoto vzácného onemocnění a také se zaměřujeme na Li-Fraumeniho syndrom. Zajímavostí tohoto případu je kurativní odpověď osteosarkomu po podání chemoradioterapie, která je všeobecně pokládaná jen za paliativní léčbu. Nečekaná odpověď ně­kte­rých nádorů na léčbu, stejně jako role mutace genu p53 stále nejsou zcela objasněny a jsou předmětem rozsáhlého výzkumu.

Klíčová slova:

chondroblastický osteosarkom – Li-Fraumeni syndrom – čelist

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Authors: J. Zelinka;  J. Blahák;  Z. Daněk;  O. Bulik
Authors‘ workplace: Faculty of Medicine, Masaryk University, Brno, Czech Republic ;  Department of Oral and Maxillofacial Surgery, University Hospital Brno, Czech Republic
Published in: Cesk Slov Neurol N 2018; 81(Suplementum 1): 47-50
Category: Original Paper


Osteosarcoma of the jaw is a very rare and highly malignant tumor, which could be a manifestation of Li-Fraumeni syndrome –  an inherited cancer syndrome characterized by a high frequency and wide spectrum of early onset neoplasms. Incidence of jaw osteosarcoma is only about 0.07/ 100,000 per year. The tumor’s stage and pos­sibility of complete surgical removal have the biggest impact on patient prognosis. Because rare, osteosarcomas are often misdia­gnosed initial­ly, which delays treatment and worsens the prognosis. We present a 32-year-old female patient with Li– Fraumeni syndrome and initial­ly misdia­gnosed chondroblastic osteosarcoma. After incomplete resection and early local recur­rence, which completely fil­led the defect after subtotal maxil­lectomy, we achieved curative response and more than 7 years dis­ease-free survival with chemo-radiother­apy. Furthermore, we describe symp­toms, dia­gnosis, and treatment of this rare dis­ease, and also focus on Li– Fraumeni syndrome. Outcome of this case report disagrees with the widely held tenet that chemo-radiother­apy of osteosarcoma of the jaw is considered only a pal­liative treatment, unexpected response of some tumors to treatment, and the role of p53 mutations still are not clear and are the object of extensive investigations.

Key words:

chondroblastic osteosarcoma – Li-Fraumeni syndrome – jaw


Osteosarcoma is highly malignant bone tumor in which mesenchymal cel­ls produce osteoid. There are three histological sub-types of osteosarcomas –  osteoblastic, chondroblastic and fibroblastic, depend­­ing on predominance of the neoplastic component. Although they are the secondmost com­mon primary malignant bone tumor after multiple myeloma, they are still very rare [1]. Incidence of osteo­sar­comaof the jaw is about 0.07 case per 100,000 po­-pulation per year [2]. Men develop osteo­sarcoma more often than women (about 60% of patients with jaw osteosarcoma are men) [1,2]. There are some dif­ferences between osteosarcomas of the jaw and those of the long bones, which are more com­mon. The peak incidence for jaw osteosarcoma is in the 3rd–4th decade, while the average age of occur­rence of conventional osteosarcoma is about decade earlier [1,2]. Also, in bio­logical behavior osteosarcoma of jaws dif­fers from conventional osteosarcomas by a lower incidence of metastasis and better prognosis, on the other hand the radical surgical treatment as well as radiother­apy of sarcomas of the bones of the face can change negatively and influence quality of life, due to function deficits and esthetic of the face, especial­ly when heal­­ing complications after radiother­apy occur [1– 4]. The etiology of osteosarcoma of the jaws is not known, it has been as­sociated with radiother­apy, Paget dis­ease, trauma, etc. Osteosarcomas are also characteristic for Li– Fraumeni syndrome (LFS), which is a rare, dominantly inherited cancer syndrome characterized by high frequency of early onset and a wide spectrum of neoplasms. Most com­mon are sarcomas, premenopausal breast carcinomas, carcinomas of the lung, skin, pancreas and adrenal cortex, leukemia, and brain tumors [2,3,5– 8]. Clas­sic LFS was defined as proband, with sarcoma dia­g­nosed under age 45 years, who has a first degree relative with any cancer under 45 years, and another first- or second-degree relative with either any cancer under 45 years or a sarcoma at any age [9].

Case report

A 32-year-old woman was refer­red to the Department of Oral and Maxil­lofacial Surgery, University Hospital Brno, for gradual­ly enlarg­­ing swel­l­­ing on the right side of the hard palate. For about a month her dentist treated the condition as odontogenic infection, by extraction of the second right upper molar, which was not vital. She also complained about pres­sure in the right maxil­la. Intraoral examination demonstrated an extraction socket without any pathology, and painles­s, firm swel­l­­ing of the right hard palate. Patient history reveled a high risk for malignant dis­ease caused by the presence of LFS and p53 mutation in patient’s family. The patient in the past underwent genetic test­­ing and she is a p53 germ-line mutation car­rier. The patient had not informed her dentist about this condition. Panoramic radiography and Water’s view of skull revealed a radiopaque mass in the right maxil­lary sinus. An incisional bio­psy was performed, but microscopic examination showed only chronic inflam­matory infiltration.

Continu­­ing suspicion of a malignant lesion led us to further investigation. Another incisional bio­psy and head CT scan were performed. Histopathological examination of the second specimen established the final dia­gnosis of high grade (G3) chondroblastic osteosarcoma with TP53 mutation in 100% of the tumor cel­ls. The CT image showed a lesion inside the right maxil­lary sinus extend­­ing to the nasal cavity, ethmoidal cel­ls, and pterygopalatine fos­sa. For better anatomic definition, a head MRI was performed (Fig. 1, 2). Bone scintigraphy, chest CT scan, and ultrasonography of neck, abdomen, and pelvis showed no metastatic spread of osteosarcoma. Dur­­ing 2 weeks there was visible local progres­sion of the dis­ease; tumorous spread to the vestibule, and also onto the alveolar ridge. Patient started to complain about nasal obstruction. Patient underwent subtotal maxil­lectomy, but the tumor was too large and not amenable to complete surgical intervention, mainly in the pterygopalatine fos­sa. Local recur­rence began soon after surgery and the tumor mass completely fil­led the defect after previous operation. The oncologists decided to use pal­liative chemother­apy and radiother­apy. After four cycles of chemother­apy (doxorubicin, cisplatina) (the 3rd and 4th cycles of chemother­apy were reduced 25% for poor tolerance and toxicity), and locoregional radiother­apy 57.2 Gy (26 × 2.2 Gy), complete remis­sion of the dis­ease was achieved. Almost 7 years after adjuvant ther­apy, the patient was without recur­rence of the tumor. The defect after subtotal maxil­lectomy was covered with an obturator prosthesis, with good function and esthetic, no impaired wound heal­­ing after chemother­apy and radiother­apy had occur­red and good quality of life was achieved.

1. MRI coronar view – demonstrates large mass in the maxilla extending to the nasal cavity, also causing bulging and destruction of hard palate.
Obr. 1. MR koronární pohled – zobrazuje masivní hmotu v horní čelisti až do nosní dutiny, což také způsobuje deviaci a destrukci tvrdého patra.
MRI coronar view – demonstrates
large mass in the maxilla extending to the
nasal cavity, also causing bulging and destruction
of hard palate.<br>
Obr. 1. MR koronární pohled – zobrazuje
masivní hmotu v horní čelisti až do nosní
dutiny, což také způsobuje deviaci a destrukci
tvrdého patra.

2. MRI transverse view – sarcoma in the right maxilla, obstructing right part of nose, deviating nasal septum and expanding into infratemporal fossa.
Obr. 2. MR příčný/transverzální pohled – sarkom v pravé maxile, obstrukce pravé části nosu, odklonění nosní přepážky a rozšíření do infratemporální fossy.
MRI transverse view – sarcoma in
the right maxilla, obstructing right part of
nose, deviating nasal septum and expanding
into infratemporal fossa.<br>
Obr. 2. MR příčný/transverzální pohled –
sarkom v pravé maxile, obstrukce pravé
části nosu, odklonění nosní přepážky
a rozšíření do infratemporální fossy.


Osteosarcoma is a highly malignant, but rare, tumor. Its incidence is about 1 case per 100,000 persons, with approximately 4% to 8% aris­­ing in the jaw. As a result, with few case reports or retrospective studies available, dia­gnosis, mainly in the early stages, is made more dif­ficult [2,3,10,11]. In August’s review of 30 osteosarcomas of the jaw 13 were initial­ly misdia­gnosed as odontogenic infection, as in the case presented here [3]. Dif­ferential dia­gnosis of chondroblastic osteosarcoma, besides inflam­mation, in­cludes fibrous dysplasia, Paget’s dis­ease, high-grade carcinoma, Ewing’s sarcoma, and chondrosarcoma, which has similar histological features but better prognosis and lower potential for metastasis than chondroblastic osteosarcoma [12– 14].

Symp­toms of osteosarcomas of the jaws are not specific. Most patients complain of a mass or swel­ling, about half of the patients suf­fer pain; other symp­toms are loose teeth or displacement of teeth, paresthesia, toothache, bleeding, and nasal obstruction. Radiological appearance may be a radiolucent, radiopaque, or mixed. In a study of 46 patients with craniofacial osteosarcomas the dominant pattern in mandibular tumors was osteoblastic, while in other craniofacial areas it was osteolytic. Plain films are of limited worth, while CT provides perfect anatomic definition of the tumor, and MRI is even more ef­fective [15]. Histological evaluation of the bio­psy specimen is always neces­sary to confirm dia­gnosis. Also, in the case presented the patient’s report of hard palate swel­l­­ing was initial­ly misdia­gnosed as inflam­mation. The patient was later discovered to have LFS and is a p53 germ-line mutation car­rier. This syndrome is characterized by a high frequency of early onset of various tumors. It is a rare condition, with mutations of p53 identified in 60% to 80% of families with LFS [16,17]. Wu et al. report that men with germ-line p53 mutation have 151-fold higher odds of develop­­ing cancer than those with no mutations; women have even higher odds –  1.075-fold. Lifetime risk of cancer was estimated at about 70% in males, and nearly 100% in females in LFS families [18,19].

There is still ethical controversy about genetic test­­ing of pos­sible p53 mutation car­riers, especial­ly in children. The patient in this case is the mother of two children, 6 and 11 years old, who have not been tested yet. The data show the importance of screen­­ing and fol­low up of individuals with LFS; nevertheles­s, no international consensus on clinical surveil­lance recom­mendations has been established. There are vary­­ing strategies in dif­ferent countries. For example in the United States the National Comprehensive Cancer Network published the fol­low­­ing guidelines: monthly breast self-exam start­­ing at age 18; clinical breast exam every 6 months start­­ing at age 20– 25 or 5– 10 years before the earliest known breast cancer in the family; an­nual mam­mogram or breast MRI start­­ing at age 20– 25; discuss option of risk-reduc­­ing mastectomy; an­nual physical exam, especial­ly focused on skin and neurological as­ses­sment; colonoscopy every 2– 5 years; additional organ-targeted surveil­lance based on family history [20]. The goal of screen­­ing is early establishment of a cor­rect dia­gnosis, and curative treatment of tumors.

One dif­ficulty with dis­ease surveil­lance in LFS patients is that the spectrum of tumors is very wide and may be found in almost every site of the body. So, every doctor tak­­ing care of a patient with LFS, includ­­ing the dentist, should be aware of the high risk of malignant dis­ease to avoid delayed tumor recognition. For osteosarcomas of the jaw that are too large for radical resection the prognosis is very poor. In Clark’s review of 66 patients the recur­rence rate for large tumors was 80% within 24 months, and with recur­rence, the chances for survival were greatly decreased [1].

The presented case is interest­­ing for several reasons, some of them are in disagreement with widely held tenets. First, chemother­apy and radiother­apy alone are general­ly considered to be pal­liative, with mortality estimated to be 100% [3]. In this case, early local recur­rence completely fil­led the postoperative defect before any adjuvant ther­apy was set, but after chemo-radiother­apy complete remis­sion was achieved, with no evidence of recur­rence after almost 7 years. Second, the basis of tumor response to cancer treatment is still poorly understood; accord­­ing to some studies tumor cel­ls with mutations in p53 resist apoptosis, chemother­apy, and radiother­apy [21– 27]. The response to chemother­apy and radiother­apy in the presented case was unexpected, with a curative outcome despite the patient be­­ing a p53 germ-line mutation car­rier. Third, there is controversy about radiother­apy in patients with LFS. p53 germ-line mutation car­riers have abnormal sensitivity to radiogenic carcinogenesis, and there is evidence that radiation-induced tu­mors frequently occur in the radiation field, radiother­apy also car­ries a risk of osteoradionecrosis of the jaw, xerostomia, radiation dermatitis, delayed wound heal­­ing and so on. So, it is believed that, if pos­sible, radiother­apy should be avoided [6,28]. In this case, after very early local relapse, with very poor long-term prognosis, and knowledge that radiation-induced tumors occur­red with latency often longer than 10 years, the oncologists decided to use a combination of radiother­apy and chemother­apy to achieve the best pos­sible control of local spread.

After almost 7 years, patient is without any clinical or radiological sign of recur­rence. Careful long-term fol­low-up of patients with LSF is crucial. Individuals with the p53 mutation are also at very high risk of develop­­ing secondary tumors, and radiation-induced sarcoma as a late sequel of radiation ther­apy. The goal of this article was to present and describe a rare tumor and syndrome with an unexpected curative response to pal­liative treatment.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manu­script met the ICMJE “uniform requirements” for biomedical papers.

Jiří Zelinka, MD

Department of Oral and Maxillofacial Surgery University Hospital Brno

Jihlavská 20

625 00 Brno

Czech Republic


Accepted for review: 13. 7. 2018

Accepted for print: 16. 8. 2018


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