International Journal of Pediatric Otorhinolaryngology 117 (2019) 131–137

Contents lists available at ScienceDirect

International Journal of Pediatric Otorhinolaryngology

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

Squamous cell carcinoma of the head and neck in children T

a a,b,c a d,e
Natasha D. Dombrowski , Nikolaus E. Wolter , Alexandria L. Irace , Caroline D. Robson ,
Antonio R. Perez-Ataydef,g, Jennifer W. Mackh,i, Reza Rahbara,j,∗
a
Department of Otolaryngology & Communication Enhancement, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, United States
b
Otolaryngology – Head and Neck Surgery, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada
c
Otolaryngology – Head and Neck Surgery, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
d
Department of Radiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, United States
e
Department of Radiology, Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, United States
f
Department of Pathology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, United States
g
Department of Pathology, Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, United States
h
Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, United States
i
Department of Pediatrics, Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, United States
j
Department of Otolaryngology, Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, United States

A R T I C LE I N FO A B S T R A C T

This work was presented as a poster at the Objective: To discuss the presentation, evaluation, and management of squamous cell carcinoma of the head and
American Society of Pediatric Otolaryngology neck in the pediatric population.
Annual Meeting, National Harbor, MD, United Methods: Medical records of pediatric (≤20 years) patients treated for squamous cell carcinoma of the head and
States on April 20, 2018. neck between 1996 and 2016 were reviewed. Data pertaining to clinical presentation, diagnostic methods,
Keywords: treatment plan, complications, recurrence, follow-up, or outcome were collected.
Squamous cell carcinoma Results: Eleven patients were diagnosed with squamous cell carcinoma. Seven of these patients had medical
Head and neck histories significant for prior malignancies, immunosuppressant therapy, and/or genetic syndromes. Lesions
Pediatric
were identified in the oral cavity (n = 5, 45.5%), lip/upper lip (n = 3, 27.3%), larynx (n = 2, 18.2%), and nasal
cavity (n = 1, 9.1%). Tumors were most commonly treated with surgical excision alone. Three patients un-
derwent irradiation (2 adjuvant and 1 without surgery) and chemotherapy (1 adjuvant, 1 neoadjuvant, and 1
without surgery). Of these patients, one reported complications of hearing loss, loss of dentition, and laryngeal
stenosis. Two patients developed local recurrence at 1 month and 5 years post-operatively, respectively. One
patient developed an orocutaneous fistula and subsequently died. No other complications were reported. Median
follow-up time was 4.6 years (interquartile range: 2.4–8.4 years). Complications of radiation included: laryngeal
stenosis, wound breakdown, and orocutaneous fistula.
Conclusion: Squamous cell carcinoma is rare in the pediatric population. Most frequently, it is associated with
previous malignancies, immunosuppressant therapy, and/or genetic conditions. Complete surgical excision is
recommended to obviate the need for radiation whenever possible.

1. Introduction HNSCC has delineated a second, younger patient population [7,8];

In adults, squamous cell carcinoma (SCC) is the most frequently
occurring malignant neoplasm of the head and neck [1,2]. Typical risk
factors, such as smoking and alcohol use, require decades to sufficiently
degrade intracellular mechanisms to result in malignancy. As such,
head and neck SCC (HNSCC) is most commonly seen in the sixth or
seventh decades of life but is only rarely seen under the age of 40 years
[3–6]. Elucidation of the role of human papilloma virus (HPV) in
however, HNSCC in the pediatric population (≤20 years) remains rare
and poorly understood [5,9–12]. Most reported cases of these lesions
arising in children occur in the respiratory tract, including the larynx
and trachea; as well as the tongue, lips, and skin [1,13].
The observation that children have not had sufficient time and ex-
posure to accumulate sufficient oncogenic mutations has led some au-
thors to conclude that HNSCC in the pediatric population is a distinct
entity from their adult counterparts [4,5,12]. Between these two

∗
Corresponding author. Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115,
USA.
E-mail address: Reza.rahbar@childrens.harvard.edu (R. Rahbar).

https://doi.org/10.1016/j.ijporl.2018.11.019
Received 27 August 2018; Received in revised form 14 November 2018; Accepted 15 November 2018
Available online 20 November 2018
0165-5876/ © 2018 Elsevier B.V. All rights reserved.
N.D. Dombrowski et al.
Table 1
Description of genetic diseases commonly associated with SCC.
Disease Description
Fanconi Anemia An autosomal recessive aplastic anemia that carries a 50-fold increase for the risk of developing a malignancy.
Bloom syndrome Autosomal recessive – symptoms of short stature, sun-sensitive skin changes, and an increased risk of cancer.
Ataxia telangiectasia Autosomal recessive – symptoms of ataxia and telangiectasia, primarily at risk for leukemia and lymphoma.
Dyskeratosis congenital Symptoms of nail dystrophy, changes in skin pigmentation, and oral leukoplakia. At risk for leukemia, myelodysplastic syndrome, and pulmonary
fibrosis.
Xeroderma pigmentosum Autosomal recessive – defect in the ability to repair damage by ultraviolet (UV) radiation.
Midline carcinomas BRD-NUT transformation t(15;19).
Li-Fraumeni syndrome Autosomal dominant – 25-fold increased risk of malignancy before the age of 50.
groups, lesions differ in origin, ease of diagnosis, and potentially, ag-
gressiveness of disease. Immunocompromise or genetic syndromes
(such as those listed in Table 1) may leave children vulnerable to tu-
morigenesis and may also be contributory [5,6]. Due to the rarity of this
condition, prior research on HNSCC in children has been limited,
mostly being discussed as individual case reports [1,3,12] or systematic
reviews [6]. A multidisciplinary team at Boston Children's Hospital
(BCH) published a case series that described the imaging appearance of
sinonasal and laryngeal carcinoma in children that included 2 patients
in this series [14]. The current study seeks to expand upon the present
literature by presenting a larger series of pediatric patients diagnosed
with HNSCC.
2. Methods
An Institutional Review Board approved retrospective review of all
patients presenting at BCH with a diagnosis of HNSCC between 1996
and 2016 was conducted. In order to best align with the populations of
previous research [4–6] and the World Health Organization's definition
of children [15], patients aged < 20 years were studied. Eleven patients
were included in analysis. Charts were reviewed for clinical presenta-
tion, diagnostic methods, treatment plan, complications, recurrence,
follow-up, and outcome.
Pathologic and imaging reports were reviewed. Pre-operative ima-
ging was available in 8 patients. Pre-operative imaging studies included
computerized tomography (CT) only (n = 3), and both magnetic re-
sonance imaging (MRI) and CT (n = 5). Preoperative whole body 18F
fluorodeoxyglucose (FDG) positron emission tomography (PET) CT was
also obtained in 4 patients. Formalin-fixed paraffin-embedded hema-
toxylin-and-eosin (H&E)-stained sections were examined for histolo-
gical analysis and gross and microscopic pathologic features of the le-
sions were noted. Prompted by concerning histologic findings, three
patients' tumors were tested for HPV. Fluorescent in situ hybridization
(FISH) chromosomal analysis was used in 2 patients.
3. Results
Eleven patients that presented at our institution were diagnosed
with HNSCC (Table 2). Eight patients (72.7%) were male and the re-
maining three patients (27.3%) were female. Median age at diagnosis
was 15.4 (interquartile range [IQR]: 13.9–16.8) years. Median time
from mass onset to presentation was 26.0 days (IQR: 6.3–54.5 days).
Lesions were identified in the oral cavity (n = 5, 45.5%), lip/upper lip
(n = 3, 27.3%), larynx (n = 2, 18.2%), and nasal cavity (n = 1, 9.1%).
Eight (72.7%) tumors were treated with surgery alone. One patient with
retromolar trigone SCC (patient #1) underwent adjuvant chemotherapy
and radiation and one patient with SCC of the nasal cavity (patient #8)
required neoadjuvant chemotherapy and adjuvant radiation. Another
patient with SCC of the supraglottis/larynx (patient #6) required che-
moradiation without surgery. Two patients developed recurrence at 0.7
and 7.6 years. One patient with SCC in the retromolar trigone (patient
#1) died 1.3 years after presentation. Median follow-up time was 4.6
years (IQR: 2.4–8.4 years).
132
International Journal of Pediatric Otorhinolaryngology 117 (2019) 131–137
3.1. Squamous cell carcinoma of the oral cavity
Five patients presented with lesions located within the oral cavity
(Table 2). Median age at diagnosis was 14.7 (IQR: 13.8–17.3) years.
Lesions were located in the retromolar trigone (n = 1, 20%), oral mu-
cosa (n = 1, 20%), palate (n = 1, 20%), and tongue (n = 2, 40%). All
masses presented as ulcerations or “abscesses” in the mouth. Three
patients (#1, #2, and #4) underwent cross-sectional imaging with MRI
and CT and two underwent CT without MRI (patients #3 and #5). FDG-
PET was also obtained in patients #1, #4, and #5. Three patients'
(patients #2, #3, and #5) had lesions that could not be seen on ima-
ging. Pre-operative CT and MRI in one patient (patient #1) revealed a
slightly heterogeneous, moderately enhancing, well-defined lesion of
the retromolar trigone. Imaging of a tongue lesion observed in patient
#4 (Fig. 1A–B) revealed a small, irregular focus of enhancement.
Four patients (80%) had medical histories significant for previous
malignancy. Two patients had undergone multiple radiation and che-
motherapy courses for their malignancies. Patient #2 had Li-Fraumeni
syndrome. Two patients had undergone bone marrow transplantation
(BMT) and immunosuppression prior to HNSCC presentation.
Procedures performed for primary mass treatment included marginal
mandibulectomy with neck dissection, partial maxillectomy with neck
dissection, hemiglossectomy, and wide local excision of the oral mucosa
(Table 2). Patient #1 underwent adjuvant chemoradiation for positive
margins following marginal mandibulectomy. Adjuvant chemoradia-
tion was not necessary in the remaining patients as all other procedures
achieved negative margins.
Pathologic examinations were available for review in four patients
(80%). Findings revealed two patients with moderately-to well-differ-
entiated T1N0M0 lesions, one patient with a T1NXMX lesion, and one
patient with a moderately-differentiated pT2N1M0 lesion with peri-
neural invasion. Two patients' (patients #4 and #5) tumors were tested
for HPV and one (patient #4) was positive for HPV p16 expression.
Median length of follow-up was 3.9 (IQR: 1.0–4.0) years. Patient #1
underwent a marginal mandibulectomy with post-operative radiation
and chemotherapy. She developed an orocutaneous fistula and ulti-
mately a recurrence at 8 months after surgery. She subsequently passed
away due to other medical issues. No other complications were ob-
served.
3.2. Squamous cell carcinoma of the larynx
Two patients presented with lesions of the larynx (Table 2). The
median age of diagnosis was 13.9 years. HNSCC were located in the
supraglottis (n = 1, 50%) and the left vocal cord extending to the ar-
ytenoid cartilage (n = 1, 50%). Presenting symptoms were dyspnea and
hoarse voice. CT and MRI of the supraglottic lesion revealed an irre-
gular, moderately well-defined mass with minimal peripheral en-
hancement. The vocal cord lesion (patient #7) appeared as an asym-
metric thickening of the vocal folds. Neither patient had any significant
medical history.
Pathologic examination of the supraglottic SCC (patient #6) re-
vealed a well-differentiated pT3N2bM0 lesion. This patient was treated
 Table 2
Clinical characteristics in 11 patients with head and neck squamous cell carcinoma.
N.D. Dombrowski et al.

Patient Significant History Tumor Tumor Staging Pre- Initial Procedure at BCH Radiation Chemo-therapy Follow- Outcome Complications and/
Number/Sex/ Location Operative up, years or Further Surgery
Age at Imaging
Diagnosis
(years)

1/F/14.7 Chronic myeloid leukemia, Graft vs. Retromolar pT2N1M0 CT, MRI, Marginal 60 Gy, adjuvant Paclitaxel, 1.0 Deceased Developed
host disease, BMT, trigone FDG-PET mandibulectomy, neck carboplatin, orocutaneous fistula
Immunosuppression dissection (i-iii), Radial adjuvant
forearm free flap
2/M/13.8 Li-Fraumeni syndrome, multiple Oral mucosa Not specified CT, MRI Wide local excision None None 3.7 Disease free None
chemotherapy courses and
radiotherapy for rhabdomyosarcoma
and osteosarcoma
3/M/9.8 Palate T1N0M0 CT Partial maxillectomy, None None 5.3 Disease free None
neck dissection
4/M/17.3 Recurrent ependymoma, multiple Tongue T1N0M0 CT, MRI, Hemiglossectomy, neck None None 4.0 Disease free None
chemotherapy courses and Positive for HPV p16. FDG-PET dissection
radiotherapy
5/M/19.1 Cutaneous basal cell carcinoma and Left side of T1NXMX CT, FDG- Left partial glossectomy None None 0.7 Disease free None
squamous cell carcinoma, Severe tongue Tested negative for HPV PET
Combined Immunodeficiency (SCID),
BMT, Bilateral lung transplant, Graft
vs. host disease, Immunosuppression

133
a
6/F/13.8 Supra-glottis T3N2bM0 CT None 70.2 Gy to larynx Cisplatin 9.7 Disease free Multiple dilation
and 52.2 Gy to procedures,
neck nodes at the arytenoid-ectomy,
time of cisplatin emergent
treatment tracheotomy
7/M/13.9 Vocal cord T1N0M0 CT, MRI, Endoscopic laser excision None None 2.8 Disease free Repeat endoscopic
FISH: no NUT/BRD4 FDG-PET laser excision for
rearrangement positive margin
Positive for HPV p16.
a
8/M/15.4 Nasal cavity T2N0M0 CT, MRI Endoscopic assisted mid- Adjuvant Vincristine, 8.0 Disease free None
FISH: 46,XY, facial degloving approach irradiation Cytoxan,
+der(1)t(1;5)(p12;q11.1), for excision of nasal Doxorubicin,
−5,del(22) tumor Carboplatin;
(q11q13) neoadjuvant
9/M/16.1 Xeroderma pigmentosum, multiple Upper lip T1N0M0 None Wide local excision None None 10.5 Recurrence Repeat wide local
basal cell carcinoma and melanoma excision for
of the face recurrence
10/M/18.0 Immunosuppressant treatment Lip Not specified None Resection of tumor with None None 12.9 Disease free None
mucosa flap
11/F/16.2 Squamous cell carcinoma in situ, Upper lip Not specified None Wide local excision None None 7.0 Disease free None
Immunosuppressant treatment

F=Female, M = Male, BMT=Bone marrow transplantation, HPV=Human papilloma virus, FISH= Fluorescent in situ hybridization, CT = computed tomography, MRI = magnetic resonance imaging,
FDG = fluorodeoxyglucose, PET = positron emission tomography.
a
Patients also presented in prior BCH publications [14].
International Journal of Pediatric Otorhinolaryngology 117 (2019) 131–137
N.D. Dombrowski et al.
with chemotherapy and radiation alone without surgery. Complications
of treatment included hearing loss, loss of dentition, and laryngeal
stenosis. Multiple laryngeal dilation procedures and an ar-
ytenoidectomy were required for the stenosis. This patient's course was
further complicated by emergent tracheotomy for cardiorespiratory
arrest. Pathologic examination of patient #7 revealed an invasive,
T1N0M0 SCC. FISH evaluation of this patient's lesion did not detect any
NUT/BRD4 rearrangement, but assessment for HPV revealed that the
tumor was positive for p16 expression. Positive margins on initial en-
doscopic laser excision prompted a second resection of the mass.
Median length of follow-up was 6.3 years. Neither patient developed
recurrence.
3.3. Squamous cell carcinoma of the nasal cavity
One patient presented with a lesion within the nasal cavity at the
age of 15.4 years (Table 2). The patient presented with nasal obstruc-
tion and was determined to have a nasal mass at an outside institution.
Upon presentation to BCH, a large nasal cavity mass, encompassing the
superior, middle, and inferior turbinates was observed. The patient
underwent MRI and CT for imaging of his lesion. CT demonstrated a left
nasal mass with destruction of the left nasal turbinates and lateral
bowing of the medial wall of the left maxillary antrum. MRI revealed a
large, lobulated, moderately heterogeneously enhancing mass that was
isointense with lymph nodes on T2 weighted images. (Fig. 1C–ID). The
mass extended through the maxillary sinus infundibulum and projected
into the left maxillary sinus. There was tumor extension superiorly into
ethmoid air cells, but there was no intracranial or intraorbital invasion.
Residual mucosal thickening of the right and left maxillary sinuses, left
ethmoid air cells, and left frontal sinus was also observed.
The patient had no significant medical history. He underwent
134
International Journal of Pediatric Otorhinolaryngology 117 (2019) 131–137
Fig. 1. Imaging of HNSCC. A. 17-year-old male
(patient #4) imaged following biopsy of carcinoma
of the tongue. Gadolinium-enhanced fat-suppressed
T1 weighted image reveals a small, irregular focus of
enhancement involving the right side of the tongue.
B. (Same patient). F-18-fluoro-2-deoxyglucose PET
image fused with a CT image shows increased
radiotracer uptake within the lesion. C. 15-year-old
male (patient #8) with left sinonasal squamous cell
carcinoma. Axial fast spin echo inversion recovery
(FSEIR) MR image shows a lobulated tumor that
bows the medial wall of the left maxillary antrum
and deviates the nasal septum. The homogeneous
tumor is of similar signal intensity to lymphoid tissue
unlike the hyperintense secretions trapped within the
left maxillary antrum. D. (Same patient).
Gadolinium-enhanced fat-suppressed T1 weighted
image demonstrates mild, heterogeneous enhance-
ment of the tumor.
neoadjuvant chemotherapy prior to an endoscopic assisted mid-facial
degloving approach for excision of a poorly differentiated T2N0M0
tumor (Fig. 2). FISH testing revealed an abnormal 46,XY, +der(1)t(1;5)
(p12;q11.1), −5,del(22)(q11q13) karyotype. Planned adjuvant radia-
tion was also administered for local control. This patient was followed
for 8 years with no evidence of recurrence. No complications were
observed.
3.4. Squamous cell carcinoma of the lip
Three patients presented with lesions of the lip (Table 2). The
median age at diagnosis was 16.2 (IQR: 16.2–17.1) years. Patients
presented with noticeable lesions located on the upper lip (n = 2,
66.7%) and the inner (wet) lip (n = 1, 33.3%). None of these patients
underwent imaging for diagnosis of their lesions.
One patient (patient #9), who presented with an upper lip SCC, had
a history significant for xeroderma pigmentosum and multiple basal cell
carcinoma and melanoma of the face. This patient had no prior ex-
posure to radiation or chemotherapy. Two remaining patients (patients
#10 and #11) had no prior malignancies but were undergoing im-
munosuppressant therapy for renal transplantation. Surgical treatment
included wide local excision (n = 2, 66.7%) and resection of wet lip
SCC with local mucosa flap reconstruction (n = 1, 33.3%). All proce-
dures achieved negative margins. None of the patients underwent
chemotherapy or radiotherapy for SCC treatment.
Pathologic examination revealed well-differentiated tumors in all
patients. Both upper lip lesions were also described as keratocanthoma.
One upper lip lesion (patient #9) was T1N0M0 staged. This patient had
a recurrence 5.16 years after the initial surgery. Another wide local
excision was performed. Other lesions were 1.5 and 2.5 cm, respec-
tively. Median (IQR) length of follow-up was 8.8 (5.3–11.1) years.
N.D. Dombrowski et al.
Fig. 2. Squamous cell carcinoma of the tongue. A. Infiltrating poorly dif-
ferentiated squamous cell carcinoma of the tongue extensively involving the
submucosa, stained with hematoxylin and eosin. B. At higher magnification,
infiltrating tumor cells have large, pleomorphic nuclei, prominent nucleoli, and
cytoplasmic elongation (arrows), stained with hematoxylin and eosin. C. Tumor
cells show diffuse and strong immunoreactivity for pancytokeratin (between
arrowheads).
4. Discussion
HNSCC, is the sixth most common cancer in the world [16], but it is
rare in the pediatric population making up less than 2% of all pediatric
malignancies [12]. As a result, HNSCC in children is encountered in-
frequently in clinical practice, which could potentially delay diagnosis
and onset of care. HNSCC is frequently associated with tobacco use,
alcohol use, ill-fitting dentures, and betel quid, almost none of which
135
International Journal of Pediatric Otorhinolaryngology 117 (2019) 131–137
are relevant in the pediatric population [4,6]. HPV has emerged as a
risk factor for HNSCC in younger patients [7,8], but its impact in pe-
diatric patients (< 20 years) is unknown. As the risk factors associated
with this disease in adults are not prevalent in the pediatric population,
it is believed that SCC in young patients is etiologically distinct from
SCC in older adults [1,5,12]. Instead, it is predicted that pediatric SCC is
most commonly associated with certain genetic syndromes (Table 1).
Additional risk factors for developing SCC in the pediatric population
include graft-versus-host disease and immunosuppressive states, such as
organ transplant [4–6,9,12]. As such, preventative strategies to reduce
cancer risk are limited mostly to aggressive surveillance in children
prone to cancer.
The rarity of HNSCC in children also limits the ability to define
optimum treatment. Current treatment methods for SCC in the pediatric
population have been extrapolated from adult SCC treatment methods.
Depending on the anatomical location, surgery is typically the standard
treatment for local control, with adjuvant radiotherapy or radio-che-
motherapy administered as indicated [1,4–6]. The most frequently re-
ported sites for these tumors are within the oral cavity, such as the
tongue, palate, gingiva, and lip [1,6]. However, cases of these lesions
appearing elsewhere, such as the skin, nasal airway, or larynx have also
been reported [1,6,9]. Outcome data is also limited by the infrequency
of this disease. Though these lesions grow rapidly and are distinct from
their adult counterparts [3,12], studies have indicated no difference in
survivability between adult and pediatric HNSCC patients [17,18]. A
comparative analysis found that younger patients with SCC of the
tongue had a higher likelihood of locoregional recurrence than older
patients, but no difference in survival rate was observed [17]. A similar
study showed equivalent survival rates for pediatric and adult oral SCC
patients after adjusting for demographics, tumor characteristics, and
treatment [18].
Due to the rarity and differential etiology of SCC in the pediatric
population, it is important to compile experiences in evaluation and
management to adequately treat these patients. There are single case
reports and larger reviews that report on pediatric SCC
[1,3–6,12,17,18], but as oral cavity lesions are more common in the
pediatric population, much of the literature reports on these alone. This
study addresses these gaps in the literature by presenting a relatively
large number of patients that underwent treatment for SCC throughout
the head and neck.
Patterns in age and sex of those patients presenting with SCC were
apparent in this cohort. We reported 8 males and only 3 females and
predilection for males to develop SCC is noted in prior literature as well,
with other case series and systematic reviews reporting sex ratios ran-
ging from 1.7:1 to 11:1 [4,6]. Average age at diagnosis was approxi-
mately 13 years for all patients except for those presenting with lip and
nasal cavity lesions, for which the average age of diagnosis was 16 years
and 15.4 years, respectively. Only one patient (patient #3, 9.1%), who
presented with a tumor of the palate, was under the age of 10 years.
Four patients (36.4%) were between the ages of 10 and 15 and the
remaining 6 (54.6%) were aged 15–18 years. Likewise, this aligns with
previously reported age distributions of SCC in the pediatric population,
with children younger than 10 years even more rarely presenting with
SCC of the head and neck than other pediatric patients [1,3–6].
In our study cohort, masses of the oral cavity were the most
common presentation, followed by the lip, larynx, and nasal cavity. Our
findings align with observations from prior studies, as these studies
found oral, including the upper and lower lip, lesions to be the pre-
vailing SCC diagnoses in children with laryngeal tumors as the next
most common presentation [6]. However, while a patient from our
cohort presented with a nasal cavity lesion, reports of SCC in this region
are uncommon.
Radiological characterization of SCC varied by tumor site in this
cohort. Radiographic assessment of one lesion in the retromolar trigone
revealed a heterogeneously enhancing, ill-defined mass, while three
other oral lesions could not be observed radiologically, likely owing to
N.D. Dombrowski et al.
the anatomic nature of that area and ulcerative or plaque-like lesions.
In contrast, lesions of the larynx and nasal cavity could be easily vi-
sualized in all patients and lip lesions were never radiologically as-
sessed for deeper involvement. CT imaging is critical in these cases to
assess underlying osseous involvement, which impacts surgical plan-
ning. In general, however, the imaging appearance is indistinguishable
from other soft tissue sarcomas as well as undifferentiated and NUT
midline carcinomas.
As the origins of pediatric SCC are frequently associated with pre-
vious malignancies or genetic syndromes, these comorbidities may in-
fluence the tumor site in which the lesions arise. Immunosuppression
from prior treatments and certain genetic syndromes (Table 1) impair
the body's ability to fight disease. Certain infectious agents, such as
HPV, increase the risk of HNSCC formation [8]. In our series, two pa-
tients with tongue and vocal cord lesions stained positive of HPV 16
expression out of three patients who were tested. This is an interesting
finding, as the roll of HPV in pediatric HNSCC is unclear [1]. HPV has
an established roll in oropharyngeal HNSCC in older patients in their
fifth and sixth decade [7,8,19]. Viral infections from Epstein-Barr virus
and HPV are often postulated mechanisms when discussing potential
etiologies for pediatric HNSCC, as children are not usually exposed to
typical causative agents, but its role in patients less than 20 years old is
not known [4,12,20]. Recently a 2-year-old child with HPV-positive
HNSCC of the external auditory canal was reported [21]. Although rare,
taken together with our two patients these reports might suggest a
unique causal relationship, but further investigations are required.
None of the patients in our cohort with nasal or laryngeal lesions had
any relevant comorbidities. However, there were notable patterns in
conditions associated with oral and lip SCC. Two patients with lip le-
sions were undergoing immunosuppressant therapy for renal trans-
plantation. The remaining patient with a lip lesion had xeroderma
pigmentosum and had previously undergone treatment for other skin
malignancies. Three of the 5 patients with oral lesions had undergone
chemotherapy for previous malignancies, with two of the patients also
undergoing radiation therapy. One of these patients had a diagnosis of
Li-Fraumeni syndrome as well. One patient also had Severe Combined
Immunodeficiency and had undergone multiple BMTs and bilateral
lung transplantation. These findings indicate that oral and lip SCC is
more strongly associated with previous malignancies or genetic syn-
dromes, while nasal and laryngeal SCC have less clear etiologies.
Surgical resection was the most common treatment modality and
three patients underwent irradiation and chemotherapy when in-
dicated. The nasal cavity tumor was treated with chemotherapy and
radiation, while none of the tumors observed on the lips required
chemotherapy or radiation. It is important to consider the risk for
radiotherapy-related toxicities in this population, as critical structures
in the head and neck can be affected, such as the larynx (patient #6)
[22]. Radiotherapy administered before craniofacial maturation may
impact craniofacial growth and lead to facial asymmetry later in life
[23]. Acute toxicities, such as mucositis and dermatitis, may require
narcotic administration, hospitalization for symptom management,
treatment breaks, or feeding tube placement [22,24–26]. Dental caries,
xerostomia, craniofacial abnormalities, trismus, endocrine abnormal-
ities, cataracts, or osteoradionecrosis may arise later in disease pro-
gression [22,24–26]. Any area exposed to radiation is likewise at risk
for developing secondary malignancies [22,27]. Of those receiving
chemotherapy and radiation therapy in our patient population, one
reported complications of hearing loss, loss of dentition, and laryngeal
stenosis. One patient developed an orocutaneous fistula after chemor-
adiation. This patient ultimately passed away. Recurrence arose 5 years
post-operatively in one additional patient. There was no tumor site in
which recurrence or complications were more likely.
This study was limited by its retrospective design. Moreover, the
small cohort size and clinical heterogeneity preclude statistical analysis.
However, given the extremely rare nature of SCC in the pediatric po-
pulation, our cohort is relatively broad. While quantitative analysis of
136
International Journal of Pediatric Otorhinolaryngology 117 (2019) 131–137
each tumor site was not possible, the study's overall breadth provides
good insight into the spectrum of the disease. As our institution is a
tertiary care children's hospital that provides care based on referrals,
there is also an associated referral bias that may skew our patient po-
pulation.
5. Conclusion
HNSCC is an extremely rare malignancy in the pediatric population.
The tumors form most commonly in the mouth, larynx, nasal airway,
and lips and can present with variable symptoms based on tumor site.
MRI, CT, and FDG-PET are critical for treatment planning. Treatment
strategies are extrapolated from the adult population, with surgical
excision being recommended whenever possible to obviate the long
term risks of radiation and chemotherapy on the child [22]. Prior
chemo- or radiotherapy, malignancies, immunosuppressant treatment,
and genetic conditions put patients at particular risk for developing
SCC. Patients with any of these comorbidities and respiratory symptoms
indicative of a mass should be vigilant for these lesions in the airway.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors. We have
no conflicts of interest to disclose.
References
[1] V.L. Woo, R.D. Kelsch, L. Su, T. Kim, D.J. Zegarelli, Gingival squamous cell carci-
noma in adolescence, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 107 (1)
(2009) 92–99.
[2] P.J. Carniol, M.P. Fried, Head and neck carcinoma in patients under 40 years of age,
Ann. Otol. Rhinol. Laryngol. 91 (2 Pt 1) (1982) 152–155.
[3] S.A.H. Stolk-Liefferink, A.G. Dumans, E.H. van der Meij, P.P. Knegt, K.G.H. van der
Wal, Oral squamous cell carcinoma in children; review of an unusual entity, Int. J.
Pediatr. Otorhinolaryngol. 72 (1) (2008) 127–131.
[4] V. Bhanuprasad, S. Mallick, S. Bhasker, B.K. Mohanti, Pediatric head and neck
squamous cell carcinoma: report of 12 cases and illustrated review of literature, Int.
J. Pediatr. Otorhinolaryngol. 79 (8) (2015) 1279–1282.
[5] L.T. Morris, S.G. Patel, J.P. Shah, I. Ganly, Squamous cell carcinoma of the oral
tongue in the pediatric age group: a matched-pair analysis of survival, Arch.
Otolaryngol. Head Neck Surg. 136 (7) (2010) 697–701.
[6] V. Bhanu Prasad, S. Mallick, A.D. Upadhyay, G.K. Rath, Systematic review and
individual patient data analysis of pediatric head and neck squamous cell carci-
noma: an analysis of 217 cases, Int. J. Pediatr. Otorhinolaryngol. 92 (2017) 75–81.
[7] D.G. Deschler, J.D. Richmon, S.S. Khariwala, R.L. Ferris, M.B. Wang, The “new”
head and neck cancer patient-young, nonsmoker, nondrinker, and HPV positive:
evaluation, Otolaryngol. Head Neck Surg. 151 (3) (2014) 375–380.
[8] D. Young, C.C. Xiao, B. Murphy, M. Moore, C. Fakhry, T.A. Day, Increase in head
and neck cancer in younger patients due to human papillomavirus (HPV), Oral
Oncol. 51 (8) (2015) 727–730.
[9] M.B. de Carvalho, A. Sobrinho Jde, A. Rapoport, et al., Head and neck squamous
cell carcinoma in childhood, Med. Pediatr. Oncol. 31 (2) (1998) 96–99.
[10] C.D. Llewellyn, N.W. Johnson, K.A. Warnakulasuriya, Risk factors for squamous cell
carcinoma of the oral cavity in young people–a comprehensive literature review,
Oral Oncol. 37 (5) (2001) 401–418.
[11] C.D. Llewellyn, K. Linklater, J. Bell, N.W. Johnson, S. Warnakulasuriya, An analysis
of risk factors for oral cancer in young people: a case-control study, Oral Oncol. 40
(3) (2004) 304–313.
[12] D. Sidell, V. Nabili, C. Lai, G. Cheung, C. Kirsch, E. Abemayor, Pediatric squamous
cell carcinoma: case report and literature review, Laryngoscope 119 (8) (2009)
1538–1541.
[13] A.S. Earle, C.H. Park, C. Vlastou, Oral squamous cell carcinoma in children, Ann.
Plast. Surg. 20 (2) (1988) 148–152.
[14] C.D. Robson, R. Rahbar, S.O. Vargas, et al., Sinonasal and laryngeal carcinoma in
children: correlation of imaging characteristics with clinicopathologic and cytoge-
netic features, AJNR Am. J. Neuroradiol. 31 (2) (2010) 257–261.
[15] HIV/AIDS: Definition of Key Terms, (2018) https://www.who.int/hiv/pub/
guidelines/arv2013/intro/keyterms/en/ , Accessed date: 8 November 2018.
[16] D.M. Parkin, F. Bray, J. Ferlay, P. Pisani, Global cancer statistics, 2002, Ca - Cancer
J. Clin. 55 (2) (2005) 74–108.
[17] P.L. Friedlander, S.P. Schantz, A.R. Shaha, G. Yu, J.P. Shah, Squamous cell carci-
noma of the tongue in young patients: a matched-pair analysis, Head Neck 20 (5)
(1998) 363–368.
[18] L.G. Morris, I. Ganly, Outcomes of oral cavity squamous cell carcinoma in pediatric
patients, Oral Oncol. 46 (4) (2010) 292–296.
[19] S.K. El-Mofty, D.W. Lu, Prevalence of human papillomavirus type 16 DNA in
N.D. Dombrowski et al.
squamous cell carcinoma of the palatine tonsil, and not the oral cavity, in young
patients: a distinct clinicopathologic and molecular disease entity, Am. J. Surg.
Pathol. 27 (11) (2003) 1463–1470.
[20] A. Binahmed, M. Charles, P. Campisi, V. Forte, R.P. Carmichael, G.K. Sandor,
Primary squamous cell carcinoma of the maxillary alveolus in a 10-year-old girl, J.
Can. Dent. Assoc. 73 (8) (2007) 715–718.
[21] M. Snietura, L. Chelmecka-Wiktorczyk, S. Pakulo, et al., Vertically transmitted HPV-
dependent squamous cell carcinoma of the external auditory canal: case report of a
child, Strahlenther. Onkol. 193 (2) (2017) 156–161.
[22] J. Vogel, S. Both, M. Kirk, et al., Proton therapy for pediatric head and neck ma-
lignancies, Pediatr. Blood Canc. 65 (2) (2018).
[23] D. Denys, S.C. Kaste, L.E. Kun, M.A. Chaudhary, L.C. Bowman, K.T. Robbins, The
effects of radiation on craniofacial skeletal growth: a quantitative study, Int. J.
137
International Journal of Pediatric Otorhinolaryngology 117 (2019) 131–137
Pediatr. Otorhinolaryngol. 45 (1) (1998) 7–13.
[24] S.S. Donaldson, J. Meza, J.C. Breneman, et al., Results from the IRS-IV randomized
trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma–a re-
port from the IRSG, Int. J. Radiat. Oncol. Biol. Phys. 51 (3) (2001) 718–728.
[25] N.A. Lockney, D.N. Friedman, L.H. Wexler, C.A. Sklar, D.L. Casey, S.L. Wolden, Late
toxicities of intensity-modulated radiation therapy for head and neck rhabdomyo-
sarcoma, Pediatr. Blood Canc. 63 (9) (2016) 1608–1614.
[26] A.C. Paulino, J.H. Simon, W. Zhen, B.C. Wen, Long-term effects in children treated
with radiotherapy for head and neck rhabdomyosarcoma, Int. J. Radiat. Oncol. Biol.
Phys. 48 (5) (2000) 1489–1495.
[27] J.P. Neglia, D.L. Friedman, Y. Yasui, et al., Second malignant neoplasms in five-year
survivors of childhood cancer: childhood cancer survivor study, J. Natl. Cancer Inst.
93 (8) (2001) 618–629.