Clinical features and hypoxic marker expression of primary sinonasal and laryngeal small-cell neuroendocrine carcinoma: a small case series
World Journal of Surgical Oncology
Clinical features and hypoxic marker expression of primary sinonasal and laryngeal small-cell neuroendocrine carcinoma: a small case series
Liang Chai 0
Hong-Fang Ying 0
Ting-Ting Wu 0
Shui-Hong Zhou 0
Yang-Yang Bao 0
Hong-Tian Yao 1
Qi-Han You 1
0 Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University , 79 Qingchun Road, Hangzhou City, Zhejiang Province 310003 , China
1 Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University , 79 Qingchun Road, Hangzhou City, Zhejiang Province 310003 , China
Background: Small-cell neuroendocrine carcinoma (SCNEC) of the head and neck is rare. The prognosis of SCNEC in the nasal cavity and larynx is poor. The aim of this study was to investigate the clinicopathological features of nasal and laryngeal SCNEC and to determine the expression of HIF-1, GLUT-1, PI3K, and p-Akt in SCNEC. Methods: Between 2003 and 2012, 10 consecutive patients with histologically demonstrated nasal and laryngeal SCNEC were enrolled. Clinicopathological materials and follow-up data were analyzed retrospectively. Immunohistochemistry was used to detect GLUT-1, HIF-1, PI3K, and p-Akt expression in paraffin wax-embedded tumor specimens. Results: The subjects were eight males and two females with a mean age of 60.8 (range: 53 to 71) years. Tumors were located in the maxillary sinus (n = 3) and larynx (n = 7). At last follow-up, four patients (40.0%) had local recurrence and five patients (50.0%) had developed distant metastases. Six patients died. The mean overall survival was 19.3 2.1 months. Expression of GLUT-1, HIF-1, PI3K, and p-Akt was seen in sinonasal and laryngeal SCNEC in 80 (8 out of 10), 50 (5 out of 10), 40 (4 out of 10), and 40% (4 out of 10) of cases, respectively. Expression of GLUT-1, HIF-1, PI3K, and p-Akt was higher in sinonasal and laryngeal SCNEC than in precancerous lesions. Conclusions: Primary sinonasal and laryngeal SCNEC is rare. This paper presents 10 cases of sinonasal and laryngeal SCNEC with more common local recurrence and distant metastasis. HIF-1, GLUT-1, PI3K, and p-Akt expression was higher in sinonasal and laryngeal SCNEC than in precancerous lesions.
Small-cell neuroendocrine carcinoma; Larynx; Nasal cavity and paranasal sinuses; Hypoxia-inducible factor-1; Glucose transporter-1; PI3K/Akt pathway
Small-cell neuroendocrine carcinoma (SCNEC) of the
head and neck is rare. Approximately 180 cases of the
larynx and 75 cases of nasal and paranasal cavities have
been reported in the English literature ; these were
mostly in males around 50-years-old and heavy smokers
[1-3]. The prognosis of SCNEC in the nasal cavity and
larynx is poor. Extra-pulmonary small-cell carcinoma is
usually a fatal disease, with a 13% five-year survival rate
. In the larynx, the two-year survival rate was 16%
and the five-year rate was only 5% . In the nasal cavity
and sinus, the median survival time was two to three
years . The survival rates are similar to those for
small-cell lung cancer. Unfavorable prognostic factors of
SCNEC in the head and neck show a correlation with an
invasion of the lamina cribrosa , ectopic hormone
syndrome , recurrence, and distant metastasis . However,
tumor size and number of mitoses show no correlation
with recurrence, metastasis, or survival . Conclusive
prognostic factors remain unclear because of the limited
number of SCNEC cases in the head and neck. Thus,
prognostic factors need further study using a greater numbers
of cases of SCNEC in the head and neck.
Some studies have investigated the prognostic factors
for SCNEC, looking at molecular markers, such as
hypoxia-inducible factor-1 (HIF-1).HIF-1has been
studied in neuroendocrine carcinoma (NEC) [9,10].
Hypoxia in solid tumors has been associated with
therapy resistance and poor clinical prognosis [9,10].
HIF1 is upregulated in a wide range of solid tumors in
humans, and over-expression of HIF-1 is associated
with tumor aggressiveness and poor prognosis [9,10].
In small-cell lung cancer, a few studies have revealed
that high levels of HIF-1 is correlation with poor
survival [9,10]. GLUT-1, a major protein of cellular
glucose uptake, has been studied in NEC . Hypoxia
promotes the chemo-radioresistance of carcinomas 
and GLUT-1 is overexpressed in a hypoxic environment
. HIF-1, a transcription factor associated with the
cellular response to hypoxia , upregulates the expression
of several hypoxia response genes, including GLUT-1.
We have previously reported that there is a significant
correlation between GLUT-1 and HIF-1 expression in
laryngeal carcinoma , and there is further evidence
thatthe phosphatidylinositol 3-kinase (PI3K)/protein
kinase B (Akt) pathwaymay regulate HIF-1 and GLUT-1
. To the best of our knowledge, there is no previous
report of these hypoxic markers in NEC.
In the present study, we retrospectively investigated
the clinicopathological features of nasal and laryngeal
SCNEC. We also used immunohistochemistry to
determine the expression of HIF-1, GLUT-1, PI3K, and p-Akt
protein in these SCNEC.
The subjects were 10 consecutive patients at The First
Affiliated Hospital with histologically demonstrated
sinonasal and laryngeal SCNEC between 2003 and 2012, and
15 sinonasal and laryngeal precancerous lesions were
also obtained as a control group. Data were obtained
from the hospital surgical pathology files.
Our study was approved by the Institutional Review
Board of The First Affiliated Hospital, College of Medicine,
Zhejiang University. Written informed consent was
obtained from each patient before inclusion in the study.
Formalin-fixed and paraffin wax-embedded tissue blocks
from primary lesions were cut into 4-m sections, and
representative sections were analyzed using
immunohistochemistry (EliVision Plus IHC kit; Fuzhou Maixin Biotechnology
Development Co., Ltd., Fuzhou, China), using Ki-67 (mouse,
clone MIB 1, DAKO, Glostrup, Denmark) at a dilution of
1:400, a rabbit polyclonal antibody against GLUT-1
(1:50, Santa Cruz Biotechnology, Dallas, USA.), a mouse
monoclonal antibody against HIF-1 (1:100; Santa Cruz
Biotechnology Dallas, USA.), a rabbit monoclonal
antibody against PI3K (1:100, Santa Cruz Biotechnology Dallas,
USA.), and a rabbit polyclonal antibody against p-AKT
(1:50, Santa Cruz Biotechnology, Dallas, USA.). Briefly, the
sections were deparaffinized with xylene and dehydrated
through an ethanol series. Then, antigen retrieval was
performed with a microwave oven over two 10-min cycles.
Endogenous peroxidase activity was blocked by incubating
the slidesin 1.5% hydrogen peroxide in absolute methanol
at room temperature for 10 minutes. Primary antibodies
were applied for 1 hour at room temperature, followed by
50 L of polymer enhancer for 20 minutes and 50 L of
polymerized horseradish peroxidase-anti-mouse
immunoglobulin G (IgG) (DAB Kit; Maixin Biological Company,
FuZhou, City, China) for 30 minutes. The reaction
products were visualized using 3,3-Diaminobenzidine (DAB
Kit; Maixin Biological Company, FuZhou, City, China),
and the sections were counterstained with hematoxylin
and eosin, dehydrated, and examined under a light
microscope. Tris-buffered saline was used in place of the primary
antibody for negative controls.
Ki-67, GLUT-1, HIF-1, PI3K, and p-Akt levels were
evaluated by the same investigator (QH You), who was
blinded tothe clinicaland follow-up data. GLUT-1
expression was considered positive only if distinct
membrane staining was present. HIF-1, PI3K, and p-AKT
proteins were observed in the nucleus and cytoplasm.
Protein analysis was performed in 10 random high-power
fields,with 100 tumor cells counted within each field for
each case and for all antibodies. The percentage of positive
cells was calculated by dividing the number of positive
tumor cells by the total number of tumor cells counted.
A sample was considered negative if less than 25% of
the cells were stained.
The patients were scheduled for follow-up visits every
three months after the initial surgery. Follow-up
consisted of a routine physical examination and a computed
tomography (CT) or magnetic resonance imaging (MRI)
scan of the primary site. Patient follow-up was reported
up to the date they last seen in the clinic.
The SPSS software (version 20 for Windows; SPSS Inc.,
Chicago, Illinois, United States) was used to conduct all
statistical tests. Associations among GLUT-1, HIF-1,
PI3K, and p-Akt protein expression and pretreatment
clinical parameters were analyzed using the chi-squared
and Fishers exact tests. Overall survival (OS), defined as
the time from surgery until death from any cause, was
plotted as a Kaplan-Meier curve. Univariate survival analysis
was performed using a log-rank test, and multivariate
analysis was performed using Cox proportional-hazards
regression analysis. A P value of less than 0.05 was deemed
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to indicate statistical significance. The correlation analysis
was performed using Spearmans rank correlation.
Results and discussion
Clinicopathological findings are shown in Table 1. The
subjects included eight males and two females with a
mean age of 60.8 (range: 53 to71) years. Tumors were
located in the maxillary sinus (n = 3, 30%) and the larynx
(n = 7, 70%). In the larynx, five cases were located in the
supraglottic area and two in the subglottic area. No
patient presented with paraneoplastic endocrine syndrome.
The SCNEC radiological images available varied. CT images
were available for eight patients and showed homogenous
(two cases) and heterogeneous (six cases) soft-tissue masses.
Contrast-enhanced CT images were available for eight
patients: mild enhancement was found in the two cases of
laryngeal SCNEC and strong enhancement in six cases (one
in the nasal cavity, five in the larynx; Figures 1, 2, 3 and 4).
MRI data were available for four patients (two in the
nasal cavity and two in the larynx). In four patients,
the T1-weighted signals and the T2-weighted signals
were hyperintense. Contrast-enhanced T1-weighted MRI
images showed strong enhancement in all four patients.
Diffusion-weighted MRI (DWI) was available for two
patients. The DWI in two patients was high-signal and
the apparent diffusion coefficient (ADC) was 0.793
0.33 103 mm2/s (laryngeal SCNEC) and 1.78 0.16
103 mm2/s, respectively (Figures 5, 6, 7 and 8).
Treatment and follow-up
In nasal SCNEC, two patients received concurrent
chemoradiotherapy (CCRT) and one patient received partial
maxillectomy and postoperative radiotherapy. Three patients
developed local recurrence and two patients developed
distant metastasis. Three patients died at 22, 22, and
20 months after diagnosis. In larynx SCNEC, four
patients underwent horizontal supraglottic laryngectomy
and one patient received bilateral neck dissection
simultaneously. All four patients received postoperative
CCRT. One patient was alive at over 26 months. Two
patients were followed for only 1 and 6 months after surgery.
One patient suffered a local recurrence 14 months after
initial surgery and underwent a total laryngectomy and
bilateral neck dissection and postoperative radiotherapy.
The patient died 18 months after the first surgery due to
distant metastasis. Three patients underwent total
laryngectomies. One patient received bilateral neck dissection
and postoperative CCRT. He died 12 months after
surgery. One received a unilateral neck dissection and died
7 months after diagnosis due to a distant metastasis.
Another patient received 14-Gy postoperative radiotherapy.
However, she did could not tolerate the side effects of
radiotherapy and abandoned it. She was disease-free after
22 months of follow-up. In this small series, the mean
overall survival (OS) was 19.3 2.1 months and the
twoyear survival rate was 25.4%.
The Ki-67 index was 25% in one patient, 30% in two
patients, 45% in three patients and higher than 70% in
four.The cutoff of the Ki-67 for the diagnosis of
smallcell carcinomaswas 50%. Expression of GLUT-1, HIF-1,
PI3K, and p-Akt was seen in sinonasal and laryngeal
SCNEC in 80 (8 out of 10), 50 (5 out of 10), 40 (4 out of
10), and 40% (4 out of 10) of cases, respectively (Table 1,
Figure 9). Expression of GLUT-1, HIF-1, PI3K, and p-Akt
in control precancerous lesions was seen in 6.7 (1 out of
15), 0 (0 out of 15), 0 (0 out of 15), and 0% (0 out of 15)
cases, respectively. The expression of GLUT-1, HIF-1,
Figure 1 CT of the sinonasal small-cell neuroendocrine carcinoma of Case 1. a) Noncontrast axial CT showing a soft-tissue mass in the right
maxillary sinus involving the right nasal cavity, right ethmoid sinus, and sphenoid sinus. b) Contrast-enhanced CT showing that the lesion was
Figure 2 CT of laryngeal small-cell neuroendocrine carcinoma of Case 3. a) Noncontrast axial CT showing a heterogeneous irregular soft-tissue
mass in the right supraglottic region involving the right vocal cord. b) Contrast-enhanced CT showingthat the lesion was heterogeneous enhanced
and the thyroid cartilage was not involved.
PI3K, and p-Akt was higher in sinonasal and laryngeal
SCNEC than in precancerous lesions (P = 0.001, 0.005,
0.017, and 0.017, respectively). Of the five patients who
died, five (100%) were positive for GLUT-1 and two (40%)
were positive for HIF-1, PI3K, and p-Akt.
In this small series, univariate analysis showed that
poor survival was significantly associated with distant
metastasis (2 = 4.97, P = 0.026). Ki-67, GLUT-1,
HIF1, PI3K, and p-Akt expression were not correlated
with survival.In a multivariate analysis,these markers
were not predictors of OS.
Sinonasal and laryngeal SCNEC typically presents
therapeutic challenges, and specific etiological factors and
prognostic factors remain unknown due their extreme
rarity. Nasal and laryngeal SCNEC is the most
aggressive and has a poor prognosis. Unlike other reports of
sinonasal NEC, which is most common in the ethmoid
sinuses , in our series, all three sinonasal tumors
were located in the maxillary sinus. In the larynx, five
cases were located in the supraglottic area and two in
the subglottic area. There was a male predominance,
with a male/female ratio 4:1, and a mean age of 60.8
(range: 53 to 71) years. Seven patients were heavy smokers.
The mean duration of symptoms at presentation was
16.7 months (range: 1 month to 8 years). In another
report of 16 cases of NEC in the head and neck, the
Figure 3 CT of laryngeal small-cell neuroendocrine carcinoma of Case 4. a) Noncontrast axial CT showing a heterogeneous well-defined
softtissue mass in the subglottic regionnot involving the bilateral vocal cord and laryngeal cartilages. b) Contrast-enhanced CT showing that the
lesion was mildly enhanced.
male/female ratio was 1.7:1, and the mean age was
65.8 (range: 43 to 88) years. Of those, 11 (68.8%) had
smoked cigarettes (mean pack-years: 50.5; range: 15 to
CT or MRI imaging of the head and neck are more
useful than conventional radiography when assessing the
extent of the local invasion of the tumor and are better
for the planning of further treatment . In our series,
CT scans showed heterogeneous soft-tissue masses in
most cases and a mass in the right maxillary sinus
extending to the right nasal cavity in one case.
Contrastenhanced CT images showed that the lesions had
differing degrees of enhancement. An MRI scan improves
differentiation between inflammatory reaction, tumor,
and liquid retention. The combination of DWI and ADC
may differentiate malignant tumors from precancerous
lesions and benign tumors . In the present study,
the T1-weighted signals and the T2-weighted signals were
hyperintense. Indeed, contrast-enhanced T1-weighted
MRI images showed a strong enhancement. We first
reported DWI and ADC values in head and neck SCNEC.
We found high DWI and low ADC values in laryngeal
SCNEC compared with our previous findings . Future
studies with larger patient populations are recommended
to further evaluate the role of DWI in head and neck
The treatment of sinonasal and laryngeal SCNEC is
controversial. Surgery, radiotherapy, and chemotherapy
alone, or in combination, have been used for sinonasal
SCNEC . In the present study, two of the three
patients with sinonasal SCNEC received CCRT and one
patient received surgery and postoperative radiotherapy.
Three patients died within two years.In the 1980s,
surgery followed by radiotherapy was the routine
therapeutic strategy for sinonasal SCNEC . Since the late
1990s, a combination of chemotherapy and radiotherapy,
with or without surgery, has been recommended .
Regarding the treatment of laryngeal SCNEC, most authors
Figure 5 MRI of Case 2 showingan abnormal signal in the left maxillary sinus, left nasal cavity, and nasopharynx. a) TheT1-weighted
signals were hypointense, b) the T2-weighted signals were hyperintense, c) and the contrast-enhanced T1-weighted MRI images show
Figure 6 Laryngostroscopy and MRI of Case 7. a) Laryngostroscopy showed that there was a red smooth mass in the right subglottic area. An
MRI scan revealed that there was a mass in the right subglottic area. b) TheT1-weighted signals, c) and the T2-weighted signals were hyperintense,
d) and the contrast-enhanced T1-weighted MRI images show strong enhancement.
generally agree that surgery, alone or in combination
with radiotherapy, does not improve local tumor control
. Baugh et al. found that the combination of primary
radiation therapy and adjuvant chemotherapy resulted in
relative good prognosis through comparison of various
previously reported therapeutic modalities for laryngeal
SCNEC . However, this review was published in 1986
and concerned approximately 50 cases. Since then, there
has been no large series report of laryngeal SCNEC and
there is no review or meta-analysis of the treatment of
laryngeal SCNEC. Thus, no standard therapeutic modality
has yet been determined for laryngeal SCNEC. In the
present study, four patients underwent partial
laryngectomies plus postoperative CCRT and three patients
underwent total laryngectomy. Two patients died of distant
metastases. The other six patients were alive, but the
follow-up duration is insufficient.
Extra-pulmonary small-cell carcinoma has a dismal
prognosis, with a 13% five-year survival rate . The
prognosis of sinonasal and laryngeal SCNEC is poor and
is similar to that of small-cell lung cancer (SCLC). In
larynx SCNEC, the two-year survival rate was 16%, while
the five-year rate was only 5% . In the nasal cavity
and sinus, the five-year overall survival for SCNEC is
below 30% . However, the prognostic factors remain
unclear. Unfavorable prognostic factors of SCNEC in the
head and neck seem to be correlated with an invasion of
the lamina cribrosa , recurrence, and distant
metastasis . In pulmonary SCNEC, ectopic hormone syndrome
may be a predictor of increased mortality due to the
higher risk of cerebral metastasis . Endocrine
syndrome also seems to worsen the prognosis in cases of
head and neck SNEC . Almost 50% of the patients with
laryngeal SCNEC have positive lymph nodes at the initial
diagnosis and 90% of them develop distant metastases (for
example lymph nodes, liver, lung, bones, or bone marrow)
. In the present laryngeal SCNECs, only two patients
(28.6%) had positive lymph nodes at the time of symptom
presentation. At the final follow-up, only one patient
(14.3%) had local recurrence and three patients (42.9%)
developed distant metastases, including in the liver, lung,
and cervical lymph node. Unlike laryngeal SCNEC,
patients with sinonasal SCNEC had low lymph node
metastatic rates at symptom presentation. Babin et al. reported
that only three patients (14.3%) had positive lymph nodes
at the initial diagnosis . In their series, 17 of 21 patients
suffered relapses or metastases within the first two years
. Han et al. reviewed 55 cases of sinonasal SCNEC in
the English literature . They found that the overall local
recurrence rate was 33% and the metastasis rate was 31%
. In 11 patients with head and neck SCNEC, Meacham
et al. found that eight patients had regional lymph node
metastases and another patient had distant metastases. Of
patients with SCNEC in the head and neck, 35.4%
survived to 24 months . In our series, three patients had
no metastatic cervical lymph nodes at initial diagnosis. In
our small series, the mean overall survival was 21.3 months.
A high Ki-67 index is an unfavorable sign in some NECs
. An unfavorable course is observed when the Ki-67
index is higher than 5% . In our study, the Ki-67 index
was higher than 25% in eight patients.However, univariate
analysis showed that poor survival was not associated with
Overexpression of HIF-1is considered to be a
significant poor prognostic factor in SCLC as well as
nonSCLC [9,10]. In SCLC, low expression of HIF-1 may be
a useful predictor of better overall survival . HIF-1
expression had an unfavorable influence on overall
survival in SCLC . HIF-1 upregulates expression of
GLUT-1 via the PI3K/Akt pathway . GLUT-1 was
expressed in approximately half of the pulmonary NEC,
and GLUT-1 expression was associated with an increased
risk of death in pulmonary NEC . Although there was
no significant difference between HIF-1/GLUT-1/PI3K/
Akt expression and sinonasal and laryngeal SCNEC, this
is the first study of HIF-1, GLUT-1, PI3K, and p-Akt
Figure 9 The expression of hypoxic markers in the sinonasal and laryngeal small-cell neuroendocrine carcinoma. The expression of
a) GLUT-1, b) HIF-1, c) PI3K, and d) p-Akt was positive.
expression in head and neck NEC. In this study, we found
that HIF-1, GLUT-1, PI3K, and p-Akt expression was
significant higher in sinonasal and laryngeal SCNEC than
in precancerous lesions. Of the five patients who died, five
(100%) were positive for GLUT-1 and two (40%) were
positive for HIF-1, PI3K, and p-Akt. Because of the small
number of cases in our series (n = 10), it is difficult to reach
any statistically significant conclusions regarding the
prognostic significance of these hypoxic markers. The effect of
the expression of these hypoxic markers on the prognosis
in sinonasal and laryngeal SCNEC requires further
clarification with a larger cohort.
Primary sinonasal and laryngeal SCNEC is rare. In our
case series, laryngeal SCNEC was more common.
Sinonasal and laryngeal SCNEC present with common local
recurrence and distant metastasis. CT and MRI scans may
aid in the diagnosis and assessment of the extent of local
invasion. The mean overall survival was 19.3 months in 10
sinonasal and laryngeal SCNEC cases.The best treatment
of sinonasal and laryngeal SCNEC is still unclear. HIF-1,
GLUT-1, PI3K, and p-Akt expression was significant
higher in sinonasal and laryngeal SCNEC than
insinonasal and laryngeal precancerous lesions. An
examination of a larger series is required to identify prognostic
factors and formulate appropriate therapeutic strategies.
ADC: Apparent diffusion coefficient; CCRT: Concurrent chemo-radiotherapy;
DWI: Diffusion-weighted MRI; EGFR: Epidermal growth factor receptor;
F-FDG: 18 F-2-fluro-2-deoxy-d-glucose; GLUT-1: Glucose transporter-1;
HIF-1: Hypoxia-inducible factor 1; NEC: Neuroendocrine carcinoma;
PI3K/Akt: Phosphatidylinositol 3-kinase/protein kinase B pathway;
SCLC: Small-cell lung cancer; SCNEC: Small-cell neuroendocrine
carcinoma; VEGF: Vascular endothelial growth factor.
The authors declare that they have no competing interests.
LC participated in study design and aided surgeries. S-HZ conceived and
designed the study, performed surgery, participated in data collection, analyzed
the data, and drafted the manuscript. H-TY contributed to the study design
andperformed immunohistochemistry. Q-HY evaluated the results of
immunohistochemistry. H-FY, T-TW and Y-YB collected the materials
and follow-up. All authors read and approved the final manuscript.
The authors acknowledge the National Natural Science Foundation of China
(No. 81172562 and 81372903), Science and Technology Department of
Zhejiang Province, China (No. 2009C33026 and N20120631), and Health
Department of Zhejiang Province (No. 2010KYA062, and 2009B042).
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