G Model

ANL-2598; No. of Pages 4

Auris Nasus Larynx xxx (2019) xxx–xxx

Contents lists available at ScienceDirect

Auris Nasus Larynx

journal homepage: www.elsevier.com/locate/anl

Squamous cell carcinoma at sites of old maxillary fractures

Masaki Kawabata *, Hiromi Nagano, Hiroyuki Iuchi, Mizuo Umakoshi,
Junichiro Ohori, Yuichi Kurono
Department of Otolaryngology, Head and Neck Surgery, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Malignancies have been reported to occasionally arise in scar tissue following injury. One hypothesis
Received 15 January 2019 involves prolonged overactivation of tissue repair systems due to chronic inflammation and irritation,
Accepted 26 March 2019 although the pathogenesis of cancers occurring in scars is not fully understood. We describe here two
Available online xxx
cases with a history of maxillary fracture at the site where squamous cell carcinoma (SCC) subsequently
developed. The first patient developed SCC 7 years after right maxillary fractures resulting from a
Keywords:
traffic accident. He underwent chemoradiotherapy (70 Gy in 35 fractions) and maintained complete
Maxillary fracture
Squamous cell carcinoma
response (CR) for 10 months. The second patient developed SCC 3 years after sustaining right
Trauma maxillary fractures in an ice hockey game. Radiotherapy and total maxillectomy were performed, but
Scar local recurrence arose and he has since been receiving chemotherapy.
© 2019 Elsevier B.V. All rights reserved.

1. Introduction 2. Case reports

Malignant changes occasionally arise in the scar tissue that
forms following injury. These changes are frequently detected
on previously traumatized skin defined as Marjolin ulcers, most
commonly appearing as squamous cell carcinoma (SCC)
developing in burn scars [1]. However, few reports have
described malignancies other than skin cancers developing in
the head and neck area [2]. Here, we report two cases with
histories of maxillary fractures at the site of subsequent
squamous cell carcinoma (SCC) development. To the best of
our knowledge, this represents the first report of SCC at the site
of maxillary fractures.
* Corresponding author at: Department of Otolaryngology, Head and Neck
Surgery, Kagoshima University Graduate School of Medical and Dental
Sciences, 8-35-1, Kagoshima 890-8520, Japan.
E-mail address: supercar0107@gmail.com (M. Kawabata).
https://doi.org/10.1016/j.anl.2019.03.008
0385-8146/© 2019 Elsevier B.V. All rights reserved.
2.1. Case 1
A 42-year-old man visited our department complaining of a
mass on the hard palate that was first noticed 2 months
previously. He had right maxillary fractures resulting from a
traffic accident (Fig. 1A) and underwent reduction surgery
7 years earlier. Physical examination revealed a rough-surfaced,
17-mm hard mass on the hard palate. Biopsy of the mass on the
hard palate revealed squamous cell carcinoma (SCC) (Fig. 2).
Computed tomography (CT) and magnetic resonance imaging
(MRI) revealed an enhanced tumor at the site of the old
maxillary fractures (Fig. 1B). Positron-emission tomography
(PET)-CT showed focal uptake of fluorodeoxyglucose in the
primary tumor, with no evidence of metastasis. Based on these
findings, the tumor was diagnosed as maxillary sinus carcinoma
(T2N0M0). Concurrent chemoradiotherapy (CCRT) was
selected (70 Gy in 35 fractions, 100 mg/ml of cisplatin on
days 1 and 22) as the initial treatment because the extent of the
lesion was unclear due to the previous maxillary fracture. The

Please cite this article in press as: Kawabata M, et al. Squamous cell carcinoma at sites of old maxillary fractures. Auris Nasus Larynx (2019),
https://doi.org/10.1016/j.anl.2019.03.008
G Model
ANL-2598; No. of Pages 4
2 M. Kawabata et al. / Auris Nasus Larynx xxx (2019) xxx–xxx
Fig. 1. CT scan images in case 1. (A) CT scan taken before reduction surgery shows fractures of the maxilla bilaterally and the right zygomatic bone. (B) CT images
reveal a tumor infiltrating the deep part of the maxilla.
Fig. 2. Histopathological findings in case 1. Histopathological findings from a
biopsy specimen obtained from the lesion (hematoxylin and eosin stain, original
magnification 200) show diffuse proliferation of tumor cells, which exhibit
hyperchromatic round nuclei with prominent nucleoli and scanty keratinization.
primary lesion showed a complete response. The patient is
currently alive with no evidence of disease as of 10 months after
completing treatment.
2.2. Case 2
The patient was a 37-year-old man with diagnosis of
maxillary carcinoma. He was referred to our department for
further examination and treatment of an oroantral fistula when
he was 24 years old. He had been treated for right refractory
oroantral fistula with occasional inflammation after sustaining
maxillary fractures in an ice hockey game at 21 years old.
Physical examination revealed an oroantral fistula with marked
erosions and sequestrum around the maxillary first molar.
Histopathological analysis of the biopsy specimen from the
mucosa around the fistula yielded a diagnosis of SCC (Fig. 3A).
CT and MRI revealed an enhanced tumor around the fistula
(Fig. 3B). PET-CT showed no evidence of metastasis. Based on
these findings, the patient was diagnosed with maxillary sinus
Please cite this article in press as: Kawabata M, et al. Squamous cell carcinoma at sites of old maxillary fractures. Auris Nasus Larynx (2019),
https://doi.org/10.1016/j.anl.2019.03.008
carcinoma (T2N0M0). He rejected surgical treatment since the
use of a denture will be required after the surgery. So that he
received RT (70 Gy in 35 fractions). The primary lesion showed
a complete response. However, 10 years post-treatment, he
presented with a mass in right cheek. Histological examination
revealed well-differentiated SCC, which was very similar to
that of the previous tumor. From these findings, we diagnosed
with the recurrence of maxillary sinus carcinoma, although the
possibility of radiation-induced carcinoma cannot be complete-
ly denied. Although the patient underwent total maxillectomy,
local recurrence was occurred 2 years after the operation.
Histological examination of the recurrence was also very
similar to histological findings of the pat tumors. He has since
been receiving chemotherapy comprising cetuximab,
5-fluorouracil and cisplatin.
3. Discussion
Malignancies have been confirmed to be caused by chronic
physical or physiological stimuli to scar tissue in experimental
models [3]. Tumor suppressor genes that are inactivated in
cancer cells have been shown to be inactive in the wound
healing process, while many oncogenes found in cancer cells
are active in the wound-healing process to proliferate repair
cells [4]. Continuous wound-healing processes due to various
events such as infection and inflammation will induce
cancerization, leading to a clinical cancer mass [5]. As an
example of infection, Johnsonella ignava, a known causative
agent of oral gingivitis and periodontitis, has been suggested to
play roles in oral inflammation and oral tumorization [5].
Irrespective of infection, inflammatory responses usually occur
during wounding and healing processes. Reactive oxygen and
nitrogen species are reportedly released from inflammatory
cells during these processes, causing DNA damage and
mutagenic assault and leading to malignancy [6].
It is conceivable that several cytokines and growth factors,
which play an important role in the healing process, are also
associated with the development of malignancy. For example,
G Model
ANL-2598; No. of Pages 4

M. Kawabata et al. / Auris Nasus Larynx xxx (2019) xxx–xxx 3

Fig. 3. Histopathological findings and MRI images in case 2. (A) Histopathological findings of a biopsy specimen obtained from the lesion (hematoxylin and eosin
stain, original magnification 200) show invasive proliferation of well-differentiated tumor cells with keratin pearl formation. (B) MRI images reveal a tumor at the
site of the fistula around the right first molar of the upper jaw.

an imbalance of interleukin 6, basic fibroblast growth factor
(bFGF) and epidermal growth factor (EGF) could also be
involved in tumor development and progression [7]. In addition,
fracture-induced vascular endothelial growth factor (VEGF)
and bFGF, which stimulate bone repair by activating osteoclasts
and osteoblasts [8], could also contribute to the development of
cancer. Furthermore, matrix metalloproteinases, which play an
important role in all stages of bone repair, could conceivably act
on the extracellular matrix in the presence of molecular
mediators, such as VEGF and transforming growth factor-beta,
leading to advantageous modifications of the microenviron-
ment for cancer development and growth [9].
The effect of fractures on the development and growth of
malignant tumors is unclear. However, malignant tumors are
reportedly induced earlier by carcinogens at the site of fractures in
mouse experiments [10]. In addition, it has been reported that
several cases of malignant tumors occurred at fracture sites such
as femur and tibia [11–13]. Furthermore, cancer metastasis has
occasionally been reported to develop early after fracture [14].
Such findings indicate the possibility that fracture may predispose
toward the development and growth of cancer. Recently, cancer
cells have been shown to induce pro-tumoral neutrophils that can
promote cancer progression around the cancer tissue via
activation of osteoblasts in bones [15]. These findings suggest
that the bone itself is involved in the development of cancers.
To the best of our knowledge, there are only seven reported
cases of malignancies other than skin cancers associated with
trauma in the head and neck area including our cases [2]. All
but our 2 cases were sarcomas (Table 1). In Case 1, a
radiolucent shadow was observed in the maxilla at 6 months
after reduction surgery, and the shadow was further expanded
at his visit to our department (Fig. 1B). From the imaging
findings, some chronic inflammation leading to the develop-
ment of cancer seems to have occurred during the healing
process of the fracture, although the patient did not complain
of any subjective symptoms. In Case 2, continuous wound
healing caused by repeated infections was presumed to be
involved in the development of cancer. It is reported that about
30 years is required for cancer to develop from scar tissue as a
result of injury [1]. However, in the present two cases, cancer
developed within the relatively short periods of 3 and 7 years
after the injuries. From these findings, it is assumed that
inflammation or infections after bone fracture might be
associated with the malignant change. Based on these findings,
we insist that, especially in cases involving chronic
inflammation or infections after maxillary fracture, long-term
follow-up is crucial for early diagnosis of malignant change,
though it is difficult to prove sufficiently the relation between
tumors and fractures in the present 2 cases and the relation
might be a speculation.

Table 1
Malignant tumor cases occurred at traumatized sites in the head and neck area. There are only seven reported cases of malignancies other than skin cancers associated
with trauma in the head and neck area including our cases All but our 2 cases were sarcomas.

Subject [Ref.] Age/sex Site Latency period (years) Histology

1 (Case 1) 37/Male Maxillary sinus 3 Squamous cell carcinoma
2 (Case 2) 42/Male Maxillary sinus 7 Squamous cell carcinoma
3 [2] 58/Male Maxilla 29 Leiomyosarcoma
4 [2] 70/Male Neck 30 Angiosarcoma
5 [2] 62/Male Nose 40 Leiomyosarcoma
6 [2] 46/Male Neck 8 Sclerosing sarcoma
7 [2] 58/Male Neck 11 Pleomorphic sarcoma

Please cite this article in press as: Kawabata M, et al. Squamous cell carcinoma at sites of old maxillary fractures. Auris Nasus Larynx (2019),
https://doi.org/10.1016/j.anl.2019.03.008
G Model
ANL-2598; No. of Pages 4

4 M. Kawabata et al. / Auris Nasus Larynx xxx (2019) xxx–xxx

4. Conclusion [4] Meng X, Zhong J, Liu S, Murray M, Gonzalez-Angulo AM. A new

We encountered two cases of SCC at the sites of old
maxillary bone fractures. Long-term follow-up is necessary
after maxillary fracture, since a malignant tumor can develop at
the fracture site.
Ethical statement
We have obtained written informed consent for publication
from both patients.
Disclosure statement
All the authors declare no conflicts of interest in association
with the present study.
References
[1] Bazali
nski D, Przybek-Mita J, Baranska B, Wie?ch P. Marjolin’s ulcer
in chronic wounds—review of available literature. Contemp Oncol
(Pozn) 2017;21:197–202.
[2] Dijkstra MD, Balm AJ, Gregor RT, Hilgers FJ, Loftus BM. Soft tissue
sarcomas of the head and neck associated with surgical trauma. J
Laryngol Otol 1995;109:126–9.
[3] Arons MS, Lynch JB, Lewis SR. Scar tissue carcinoma part II: an
experimental study with special reference to burn scar carcinoma. Ann
Surg 1966;163:445–60.
hypothesis for the cancer mechanism. Cancer Metastasis Rev
2012;31:247–68.
[5] Pushalkar S, Ji X, Li Y, Estilo C, Yegnanarayana R, Singh B, et al.
Comparison of oral microbiota in tumour and non-tumour tissues of
patients with oral squamous cell carcinoma. BMC Microbiol
2012;12:144.
[6] Coussens LM, Werb Z. Inflammation and cancer. Nature
2002;420:860–7.
[7] Muelller MM. Inflammation in epithelial skin tumours: old stories and
new ideas. Eur J Cancer 2006;42:735–44.
[8] Street J, Bao M, deGuzman L, Bunting S, Peale Jr FV, Ferrara N, et al.
Vascular endothelial growth factor stimulates bone repair by promoting
angiogenesis and bone turnover. Proc Natl Acad Sci U S A
2002;99:9656–61.
[9] De Simone P, Carrai P, Morelli L, Coletti L, Petruccelli S, Filippon F,
et al. Posttransplant hepatocellular carcinoma metastasis at a skull
trauma site. Transplantation 2005;80:1358–9.
[10] Ohmori T, Uraga N, Komi K, Tabei R, Shibata T. The role of bone
fracture at the site of carcinogen exposure on nickel carcinogenesis in
the soft tissue. Jpn J Cancer Res 1990;81:1247–52.
[11] Muller HR. Traumatic rhabdomyosarcoma following successive frac-
tures of the femur. Cancer Res 1917;2:393–9.
[12] Dreyfuss UY, Auslander L, Bialik V, Fishman J. Ewing’s sarcoma of the
hand following recurrent trauma; a case report. Hand 1980;12:300–3.
[13] Akoh CC, Chang J, Buckwalter J. Marjolin’s ulcer of the tibia with
pelvic lymph node metastasis. Iowa Orthop J 2017;37:133–8.
[14] Fukushima M, Katagiri A, Mori T, Watanabe T, Katayama Y. A case of
skull metastasis from hepatocellular carcinoma at the site of skull
fracture. No Shinkei Geka 2010;38:371–7 [in Japanese].
[15] Soukup K, Joyce JA. A long-distance relationship between tumor and
bone. Immunity 2018;48:13–6.

Please cite this article in press as: Kawabata M, et al. Squamous cell carcinoma at sites of old maxillary fractures. Auris Nasus Larynx (2019),
https://doi.org/10.1016/j.anl.2019.03.008