The Clinical Respiratory Journal ORIGINAL ARTICLE

Pathological complete response to gefitinib in a 10-year-old boy

with EGFR-negative pulmonary mucoepidermoid carcinoma: a
case report and literature review
Shaomei Li1*, Zhe Zhang1*, Hong Tang1, Zhen He1, Yun Gao2, Weiguo Ma2, Yuxi Chang3,
Bing Wei3, Jie Ma3, Kangdong Liu4,5, Zhiyong Ma1 and Qiming Wang1
1 Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, China
2 Clinical Laboratory, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, China
3 Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, China
4 Research Service Office, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, China
5 Department of Pathophysiology, School of Basic Medical Science, Zhengzhou University, Zhengzhou 450001, China

Abstract Key words

Background and Aims: Pulmonary Mucoepidermoid carcinoma (MEC) accounts CRTC1-MAML2 EGFR-TKI lung cancer
mucoepidermoid carcinoma pediatric
for 0.1-0.2% of all lung cancer. It occurred in the 3-78 years old, and 50% patients
younger than 30. MEC has no standard treatment, but recently reports indicated
Correspondence
MEC without epidermal growth factor receptor (EGFR) mutations sensitive to Qiming Wang, MD, Department of Internal
gefitinib. Medicine, Affiliated Cancer Hospital of
Objectives: To explore a new standard treatment strategy for MEC, after Zhengzhou University, Henan Cancer Hospital,
reviewed literature related to MEC, we used Gefitinib to treatment a patient No. 127 Dongming Road, Zhengzhou 450008,
with EGFR-negative MEC, and observe its effects. China.
Methods: 10-year-old boy was diagnosed with low-grade MEC by bronchial lung Tel: 186 13783590691
Fax: 0086 0371 65588134
biopsy, EGFR gene mutation test was negative. Gefitinib was administered as neo-
email: qimingwang1006@gmail.com
adjuvant therapy at 125 mg daily.
Results: The patient underwent right middle lobe, lower lobe resection and media- Received: 21 October 2014
stinal lymph node dissection. After surgery, the patient had gained weight (5 kg) Revision requested: 05 April 2015
after 18 days of gefitinib therapy. A CT scan of the chest 1 month after surgical Accepted: 29 June 2015
resection showed no recurrence, and followed for 22 months after treatment with-
out tumour recurrence, suggesting that the patient was completely cured. DOI:10.1111/crj.12343

Conclusion: Gefitinib has potential to become a standard treatment for pulmonary

Authorship and contributorship
MEC patients, including pediatric patients. However, the mechanisms need further QW conceived the research and took overall
investigation. supervision in the study. HT, ZH, SL, ZZ and
YG performed experiments. WM, YC, JM and
Please cite this paper as: Li S, Zhang Z, Tang H, He Z, Gao Y, Ma W, Chang Y, Wei BW performed data analysis. SL and ZZ wrote
B, Ma J, Liu K, Ma Z and Wang Q. Pathological complete response to gefitinib in a the manuscript. QW, KL, ZM and HT
10-year-old boy with EGFR-negative pulmonary mucoepidermoid carcinoma: a case contributed to the discussion of results and to
the review of the manuscript. All authors read
report and literature review. Clin Respir J 2015; 00: 000000. DOI:10.1111/crj.12343.
and approved the final manuscript.

Ethics
The Affiliated Cancer Hospital of Zhengzhou
Conflict of interest *Shaomei Li and Zhe Zhang contributed
University Ethics Committee approved the
All authors declare that there are no equally to this work.
study, with the patients guardian giving
potential conflicts. written informed consent.

Introduction (reportedly, 378 years), but nearly 50% of patients are

less than 30 years old (25). MECs usually originate
Mucoepidermoid carcinoma (MEC) of the lung is a from the parotid or submandibular salivary glands;
rare form of cancer, accounting for 0.1% to 0.2% of all most pulmonary MECs arise in the proximal bronchi
pulmonary tumours (1). It can occur at any age (6). In 38% to 81% of pulmonary MECs, a recurring

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Pathological complete response to gefitinib Li et al.

Figure 1. Initial characterisation of the tumour. (A) PET/CT demonstrated partial right middle lobe and right lower lobe
atelectasis and enlarged slightly metabolically active mediastinal nodes at levels 4 and 7. (B, C) The chest CT scan and airway
revascularisation showed right middle lobe pneumonia, consolidation, atelectasis and a small amount of pleural effusion on
the right side, and right middle bronchial discontinuity. (D) HE staining of biopsy tissue revealed mucoepidermoid carcinoma
cells (2003).

t(11;19) translocation with the associated fusion
oncogene CRTC1-MAML2 (CREB-regulated transcrip-
tion coactivator 1-mastermind-like 2 [Drosophila]) is
present (7, 8). The CRTC1-MAML2 oncogene acts as a
transcription factor on the Notch and CREB (i.e. camp
response element binding protein) signaling pathways,
disrupting the normal cell-cycle and cell differentia-
tion, and contributing to tumour development (7).
In vitro and clinical data indicate that pulmonary
MECs are responsive to gefitinib, the inhibitor of the
tyrosine kinase domain of the epidermal growth factor
receptor (EGFR). Sensitising EGFR mutations (exon
19 deletions or exon 21[L858R] mutations) impor-
tantly affect the therapeutic response to tyrosine kinase
inhibitors (TKIs) and the selection of patients for
treatment (15). However, several studies have reported
a clinical response to gefitinib in MECs lacking sensi-
tising EGFR mutations (9, 10). One explanation for
the observed sensitivity to gefitinib in these cases may
be upregulation of the EGFR ligand amphiregulin
(AREG) by CRTC1-MAML2 (11). These data suggest
that MECs carrying t(11;19) and the associated
CRTC1-MAML2 oncogene are targets for TKI therapy.
Case report
In December 2012, a 10-year-old boy was admitted to
our hospital due to night sweats, mild sputum, cough,
intermittent fever (maximum, 39.78C), and growth
retardation. He was a student, non-smoker, and had
no family history of cancer. Computerised tomography
(CT) of the chest and airway revascularisation (Fig. 1A
and 1B) showed right middle lobe pneumonia, consol-
idation, atelectasis, a small amount of pleural effusion
on the right side, and right middle bronchial disconti-
nuity. Bronchoscopy to remove a foreign body from
the lung found a smooth, well-defined tumour at the
right bronchus that blocked the airway. Pathology
revealed a low-grade MEC (Fig. 1C). Immunohisto-
chemistry was positive for p63, Alcian blue and
periodic acid-Schiff stain, and carcinoembryonic anti-
gen. Positron emission tomography/CT indicated ate-
lectasis of the partial right-middle lobe and right lower
lobe, and enlarged mediastinal lymph nodes at levels 4
and 7 (Fig. 1D). Tumour markers found in serum
included carcinoembryonic antigen (1.49 ng/mL), cir-
culating cytokeratin 19 fragments (CYFRA 21-1; 1.11
ng/mL), and neuron-specific enolase (NSE; 32.69 ng/
mL). Molecular analyses of exons 18, 19, 20, and 21 of
EGFR revealed an absence of mutations. Also absent
were the KRAS (Kirsten rat sarcoma viral oncogene
homolog) mutation, the anaplastic lymphoma kinase
(ALK) protein, and B-raf mutation.
The patient was diagnosed with clinical stage IIIa pul-
monary MEC and mediastinal lymph node metastases.

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Li et al. Pathological complete response to gefitinib

Figure 2. CT scan 18 days after the initial treatment with gefitinib. (A) The tumour was completely suppressed. (B) Tracheal
reconstruction showed the right bronchus was unblocked, and the lung lobe had re-expanded.

Chemotherapy, radiation, and surgical procedures were
considered inappropriate. Because we knew that MECs
lacking sensitising EGFR mutations are clinically respon-
sive to TKI therapy (9, 10), the patient was prescribed
gefitinib. However, clinical data on the effectiveness of
gefitinib in pediatric patients is lacking and the patient
was a minor; consultations were conducted with the
patients family and the Ethics Committee of Affiliated
Cancer Hospital of Zhengzhou University. Gefitinib was
applied in accordance with international guidelines at
125 mg daily, which is half the adult dose.
After 1 day, the patient experienced a rash on the
neck, which disappeared after 2 days. His cough, spu-
tum (streaked with blood), and intermittent fever
(maximum temperature, 388C) persisted. Physical
examination showed adventitious breath sounds and
crepitation, but no other abnormality. Blood, liver, and
kidney function were normal. Microscopic evaluation
revealed malignant cells in the sputum. The patient
received one week of symptomatic treatment. Eighteen
days after initiation of gefitinib, a CT scan of the chest
showed no sign of the tumour (Fig. 2A). Tracheal
reconstruction (Fig. 2B) indicated that the right bron-
chus was no longer blocked.
The patient underwent right-middle and lower lobe
resection and mediastinal lymph node dissection.

Figure 3. CT scan one month after the surgical resection. There was no tumour recurrence.

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Pathological complete response to gefitinib
Pathological examination of the lower lobe of the right
lung showed fibrosis, congestion, inflammatory exu-
dates in the lung tissue, no tumour tissue, and no
evidence of lymph node metastases. The patient had
gained weight (5 kg) after 18 days of gefitinib therapy.
A CT scan of the chest 1 month after surgical resection
showed no recurrence of the tumour (Fig. 3). The
tumour response was evaluated as complete, based on
the RECIST (Response Evaluation Criteria in Solid
Tumors) guidelines (v.1.1). Thus far, the patient has
been followed for 22 months without tumour recur-
rence since the surgery (The last follow-up date was 28
March 2015). These observations suggest that gefitinib
had antitumour activity with no observable toxicity in
this pediatric patient.
Discussion
Pulmonary MEC is a rare form of lung cancer that
is classified as low grade or high grade, based on
histopathological findings. Symptoms include cough,
recurrent pneumonia, and hemoptysis (6). Investiga-
tions of the association between an MECs histological
features, clinical behaviour, and patients prognosis
show that the proportion of squamous cells on tumour
histology may be an indicator of the level of tumour
malignancy, and tumour-node-metastasis staging is an
important determinant of prognosis (12). Surgical
resection is the primary treatment for low-grade MEC,
with excellent outcomes, while high-grade MEC is a
more aggressive malignancy (13). In fact, patients with
low-grade tumours can be cured by complete resection.
However, in cases of high-grade malignant neoplasms,
surgery results in a significantly worse prognosis (14).
Advanced or metastatic MECs are generally treated
as non-small cell lung carcinomas (NSCLCs). The
National Comprehensive Cancer Network guidelines
recommend EGFR-TKIs as first-line, second-line, and
maintenance therapy for NSCLCs (15). Accordingly, we
treated a patient with unresectable IIIA (N2) NSCLC
who was intolerant to combined gemcitabine and cis-
platin chemotherapy with perioperative EGFR-TKI
erlotinib, which allowed successful surgical resection of
the lung tumour and mediastinal lymph nodes (16).
The CRTC1MAML2 fusion oncogene, encoded by
the recurring chromosomal translocation t(11;19)
between exon 1 of the CTRC1 gene on chromosome
19p13 and exons 25 of the MAML2 gene on chromo-
some 11q21 in human MEC (17), is a frequent genetic
alteration in >50% of MECs (11, 18). MAML2 belongs
to a family of mastermind-like, nuclear proteins that
function as coactivators for Notch receptors, whereas
CRTC1 belongs to a family of highly conserved CREB
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Li et al.
coactivators. The CRTC1-MAML2 fusion encodes a
chimeric protein consisting of the CREB-binding
domain of CRTC1 linked to the transactivation
domain of MAML2. The fusion protein activates tran-
scription of, in particular, the target gene of cAMP/
CREB, leading to disruption of normal cellular growth
and differentiation that contributes to tumour devel-
opment (11, 1924). Fusion oncogenes have been suc-
cessfully targeted for treatment in other malignancies,
such as chronic myelocytic leukemia, leading to
changes in the therapeutic approach. Therefore, pul-
monary MECs carrying t(11:19) and the associated
CRTC1-MAML2 oncogene may be valid targets for
EGFR-TKI therapy.
AREG, an EGFR ligand and previously published
cAMP/CREB target gene (25, 26), was induced more
than 20-fold by ectopic CRTC1-MAML2 protein
expression (11). Han et al. (9) reported that the EGFR
wild type H-292 lung MEC cell line is highly sensitive
to the EGFR-TKI, gefitinib (9, 27). This cell line carries
t(11;19) and CRTC1-MAML2, indicating that MECs
have gefitinib-sensitising mechanisms other than EGFR
mutations (9). Furthermore, in vivo observations show
that gefitinib has clinically meaningful anti-tumour
activity in patients with pulmonary MECs that lack sen-
sitising EGFR mutations (9, 10). Evidence suggests that
sensitivity to gefitinib is due to the upregulation of the
EGFR ligand AREG by CRTC1-MAML2 (11). In sup-
port of these data, other reports indicate that a wide
array of wild-type NSCLC cell lines have shown AREG-
dependent sensitivity to gefitinib (28).
The choice of treatment for pediatric MEC patients
must account for toxic effects on growth and develop-
ment. Herein, we report a 10-year-old boy with a stage
IIIa MEC that lacked sensitising EGFR mutations.
Patients with a clinical diagnosis of stage IIIA have a
poor prognosis after conventional management strat-
egies (14, 29, 30). Therefore, we administered gefitinib
to our pediatric patient. As there are no existing guide-
lines to direct the dosage of gefitinib in children, we
referred to standard pediatric-dose conversion formu-
las, and selected half the adult dose. The patient experi-
enced a scattered rash on his neck, which resolved
within 48 h. Therefore, we do not consider that it was
a drug-related adverse event. During gefitinib therapy,
the patient suffered from cough and sputum (blood-
streaked), which was easily managed. After 18 days of
therapy, a CT scan of the chest showed complete sup-
pression of the tumour, and the patient had gained a
significant amount of weight. These data suggest that
the application of gefitinib controlled tumour progres-
sion with safety. Subsequent surgery and pathology
fully confirmed the efficacy of gefitinib therapy in this
VC 2015 John Wiley & Sons Ltd
Li et al.
pediatric patient, suggesting that the patient was com-
pletely cured.
To the best of our knowledge, this is the first report
of a complete response to gefitinib as neoadjuvant
therapy in a pediatric patient diagnosed with low-
grade pulmonary MEC.
Conclusions
Pulmonary MEC is a rare lung cancer with no stand-
ard treatment. Studies have reported that the clinical
response of MECs to gefitinib that lack sensitising
EGFR mutations may be due to upregulation by
CRTC1-MAML2 of the EGFR ligand AREG (911).We
are now ready to test whether this patient carries the
t(11;19) translocation and the CRTC1-MAML2 onco-
gene. Although the mechanisms responsible for this
phenomenon are not completely clear, gefitinib may
have the potential to become a standard treatment for
pulmonary MEC patients, including pediatric patients.
Because MEC is the most common type of salivary
gland malignancy in adults (8), an understanding of
the pathological and therapeutic mechanisms of this
disease may have broad applications.
Acknowledgements
This study was supported in part by the National Nat-
ural Science Foundation of China (No. 81272600), the
National Basic Research Program of China (No.
2012CB933304), Henan Provincial Training Abroad
Foundation for Leaders of Medical Science (No.
201082), Henan Provincial Special Funds for
Health and Technological Innovative Talents (No.
2011020155), Henan Provincial Research Program of
Application Foundation and Advanced Technology
(No. 112300410033), and the Henan Sciences Founda-
tion (No. 112106000039). The funders had no role in
the study design, data collection and analysis, decision
to publish, or preparation of the manuscript.
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