Clinical Assessment of Anatomic Origin Effect on the Clinical Outcomes in Primary Squamous Cell Carcinomas Affecting Nasoethmoidal Complex.

Background: Sinonasal squamous cell carcinomas (SCCs) present a great challenge in their diagnosis and management owing to their rapid growth, regional recurrence, local recurrence, and aggressive spread locally. Aims: The present clinical trial was conducted to evaluate anatomic subsites' impact on the outcomes concerning SCCs affecting ethmoid sinuses and nasal cavity. Materials and
Methods: Medical records for tumor staging, tumor classification, grading (histologic) clinical features, symptoms, anatomic subsite, p16 results, treatment provided, and the Tumor-related outcomes were obtained for 28 subjects. Following staging and grading, p16 assays were evaluated along with disease-specific survival and disease-free survival. The collected data were subjected to the statistical evaluation and the results were formulated by keeping the level of significance at P < 0.05.
Results: Origin was seen from nasal septum, nasal floor, lateral wall, ethmoid sinus, and edge of naris to mucocutaneous junction in 21.4% (n = 6), 7.14% (n = 2), 35.71% (n = 10), 7.14% (n = 2), and 28.57% (n = 8) subjects, respectively. For tumor staging, Stages I, II, III, and IV tumors were seen in, respectively, 39.28% (n = 11), 21.42% (n = 6), 10.71% (n = 3), and 28.57% (n = 8) study subjects. Node status was N0, N1, N2, and N3 in 78.57% (n = 22), 3.57% (n = 1), 7.14% (n = 2), and 10.71% (n = 3) subjects. Carcinoma arising from nasal septum had statistically significant worse disease-specific survival compared to carcinomas arising from other sites (P < 0.001).
Conclusion: The present study concludes that anatomic subsites largely govern the outcomes and tumor behavior. Also, squamous cell carcinoma affecting the nasal septum is an aggressive tumor with more compromised outcomes and more lymph node involvement. Copyright:

INTRODUCTION

Malignant lesions rarely affect the nose, paranasal sinuses, and the nasal cavity and constitute approximately 3% of the carcinomas seen in the region of the head and neck. The carcinomas of paranasal sinuses and nasal cavity are majorly the squamous cell carcinomas (SCCs). The common symptoms seen in the malignancies of the nasal cavity present early and include pain and/or epistaxis allowing early diagnosis and treatment compared to carcinomas of paranasal sinuses.[1]

Sinonasal squamous cell carcinomas (SCCs) present a great challenge in their diagnosis and management owing to their rapid growth, regional recurrence, local recurrence, and aggressive spread locally. The main conventional treatment modality followed for their management is radical resection of the tumor with adjuvant radiotherapy and/or periodic monitoring. In addition to conventional open surgical approaches like the degloving facial approach and rhinectomy, recently, endoscopic approaches use has increased for treating sinonasal SCCs.[2]

Average 5 years of survival for sinonasal SCCs ranges between 50 and 80% with larger tumor size, advanced tumor stages, and lymph nodes involvement judging the survival rates. Lymph node involvement reduces the mean survival to almost half, worsening the prognosis, whereas regional recurrence can significantly decrease following elective neck surgeries.[3] However, the impact of neck dissection/elective neck treatment in cases with SCCs of the nasoethmoid region is still not fully explained yet. Also, it was depicted recently that human papillomavirus (HPV) infection acts as a favorable factor for prognosis of the survival of sinonasal SCCs.

Sinonasal carcinomas are divided into tumors arising from maxillary sinuses and tumors originating from the ethmoid sinus and nasal cavity. Tumor site and histological differentiation largely govern survival rates and clinical outcomes in sinonasal SCCs.[4] It is established that tumor location and extension to maxillary sinus affect the sinonasal SCCs prognosis, whereas the effect of anatomic subsites on clinical outcomes of these lesions is not well-understood yet. However, assessing anatomic subsites' impact can help to recognize subjects with worse outcomes and increased nodes involvement risks, further allowing initial management and recalls to lead to better outcomes.[5] Hence, the present clinical trial was conducted to evaluate anatomic subsites' impact on the outcomes concerning SCCs affecting ethmoid sinuses and nasal cavity.

MATERIALS AND METHODS

The present retrospective clinical trial was carried out after obtaining the clearance from the concerned ethical committee. The study subjects were recruited from the patients visiting the Outpatient Department, Department of Otolaryngology. The study population comprised 42 subjects with nasoethmoidal carcinoma (SCC). The exclusion criteria for the study were subjects with carcinomas primarily affecting skin, carcinoma of nasal vestibule, and maxillary sinus leaving a final study sample of 28 subjects with the nasal cavity and ethmoid sinus SCC.

The data collected from the previous medical records from the hospital included tumor staging, tumor classification, grading (histologic) clinical features, symptoms, anatomic subsite, p16 results, treatment provided, and the tumor-related outcomes.

Tumor clinical staging was done following the widely accepted TNM staging system. Further, SCCs of nasoethmoidal complex were differentiated based on their origin site (edge of naris to the mucocutaneous junction, ethmoid sinus, nasal septum, nasal wall, and nasal floor) and anatomic subsites. Also, to assess the HPV infection, a p16 assay was considered which was obtained from the medical records of 75% (n = 21) of the study subjects, all were assessed by immunohistochemical staining done in the Department of Pathology of the institution where positive was allotted to samples with cells showing >90% strong p16 expression. The staining was scored to 0, 1, 2, or 3 depicting none, weak, moderate, and strong, respectively, based on the intensity of staining.

The present study assessed disease outcomes on two main parameters: disease-specific survival and disease-free survival. Disease-specific survival was assessed from the surgery date to the last follow-up date or death from SCC of nasoethmoidal complex, whichever was applicable, whereas, disease-free survival was evaluated from the surgery date to the recurrence date or last follow-up day, whichever was applicable. Deaths not related to these carcinomas or deaths from other causes were not considered.

The collected data were subjected to the statistical evaluation using SPSS software version 21.0, 2012, Armonk, NY, ANOVA, and t-test. The results were formulated keeping the level of significance at P < 0.05.

RESULTS

The present clinical trial was conducted to evaluate anatomic subsites' impact on the outcomes concerning squamous cell carcinomas affecting ethmoid sinuses and nasal cavity in 28 subjects. The study included both males and females of 32–78 years, and the mean age of 61.3 ± 13.8 years. The demographic- and tumor-concerning characteristics of the study subjects are summarized in Table 1. The study comprised 35.71% (n = 10) females and 64.28% (n = 18) males. The mean duration of symptoms was 4.7 ± 48.8 months and the stages could be done in all 100% (n = 28) of the subjects with 57.14% (n = 16) having MRI and 82.14% (n = 23) with CT for staging. The symptoms were absent in 14.28% (n = 4) of the subjects, whereas, others presented with symptoms including nasal obstruction, pain, epistaxis, sensation of foreign body, and swelling in 7.14% (n = 2), 28.57% (n = 8), 28.57% (n = 8), 10.71% (n = 3), and 25% (n = 7), respectively. A previous history of malignancies was reported by 25% (n = 7) of the subjects, biopsy reports were available for 85.71% (n = 24) of the subjects, and 35.71% (n = 10) of the subjects had a positive smoking history.

Table 1

Demographic and clinical characteristics in the study subjects

Characteristics	Subgroup	%	n
Mean age (Mean±SD)		61.3±13.8
Age Range (years)		32-78
Gender	Females	35.71	10
	Males	64.28	18
Presenting symptoms duration (Mean±SD) in months		4.7±48.8
Tumor staging		100	28
Staging methods	MRI	57.14	16
	CT	82.14	23
Presenting Symptoms	Present	85.71	24
	Not Present	14.28	4
Symptoms Reported	Nasal Obstruction	7.14	2
	Pain	28.57	8
	Epistaxis	28.57	8
	Sensation of foreign body	10.71	3
	Swelling	25	7
History of other malignancies	Positive	25	7
	Negative	75	21
Biopsy Results Availability	Yes	85.71	24
	No	14.28	4
History of Smoking	Positive	35.71	10
	Negative	64.28	18

On assessing the tumor characteristics, the results showed that concerning anatomic subsites, the origin was seen from nasal septum, nasal floor, lateral wall, ethmoid sinus, and edge of naris to mucocutaneous junction in 21.4% (n = 6), 7.14% (n = 2), 35.71% (n = 10), 7.14% (n = 2), and 28.57% (n = 8) of the subjects, respectively. For tumor staging, Stages I, II, III, and IV tumors were seen in, respectively, 39.28% (n = 11), 21.42% (n = 6), 10.71% (n = 3), and 28.57% (n = 8) of the study subjects, whereas, Grade I (well-differentiated), Grade II (moderately differentiated), and Grade III (poorly differentiated) tumors were seen in 14.28% (n = 4), 60.71% (n = 17), and 25% (n = 7) of the subjects. Concerning TNM staging, T1, T2, T3, and T4 were seen in 46.42% (n = 13), T2 in 28.57% (n = 8), T3 in 10.71% (n = 3), and T4 in 14.28% (n = 4) of the subjects, node status was N0, N1, N2, and N3 in 78.57% (n = 22), 3.57% (n = 1), 7.14% (n = 2), and 10.71% (n = 3) of the subjects, metastasis was seen in 3.57% (n = 1) of the subjects. On assessing p16 marker for HPV was positive in 17.85% (n = 5) and was negative in 57.14% (n = 16) of the subjects as shown in Table 2.

Table 2

Tumor-related characteristics in the study subjects

Characteristics	Subgroup	%	n
Anatomic Subsites	Nasal Septum	21.4	6
	Nasal Floor	7.14	2
	Lateral wall	35.71	10
	Ethmoid sinus	7.14	2
	Edge of naris to the mucocutaneous junction	28.57	8
Tumor Staging	Stage I	39.28	11
	Stage II	21.42	6
	Stage III	10.71	3
	Stage IV	28.57	8
Tumor Grading	Well-differentiated (G1)	14.28	4
	moderately differentiated (G2)	60.71	17
	Poorly differentiated (G3)	25	7
TNM system
T system	T1	46.42	13
	T2	28.57	8
	T3	10.71	3
	T4	14.28	4
N system	N0	78.57	22
	N1	3.57	1
	N2	7.14	2
	N3	10.71	3
M system	M0	96.42	27
	M1	3.57	1
P16 assessment	Positive	17.85	5
	Negative	57.14	16
	Not-known	25	7

The present study also analyzed survival-related outcomes, where disease-specific survival and disease-free survival were assessed at follow-up periods of 6 months, 1 year, and 2 years. The tumor recurrence was seen in a total of 28.57% (n = 8) of the subjects, where 10.71% (n = 3) of the subjects had local recurrence, and recurrence at the distant site was seen in 3.57% (n = 1) of the subjects. Tumor recurrence was not seen in any subject who underwent elective neck dissection, whereas 66.6% (n = 12) of the subjects had recurrence where neck dissection was not performed. However, the difference was statistically insignificant (P = 0.073). The parameters assessed were anatomic subsites, tumor staging, TNM classification, p16 assay, and elective neck dissection. Concerning anatomic subsites, Nasoethmoidal carcinoma arising from the nasal septum had statistically significant worse disease-specific survival compared to carcinomas arising from other sites (P < 0.001). For T, neck dissection and p16 assay showed statistically non-significant results with respective P values of 0.418, 0.267, and 0.605. These P values for disease-free survival for anatomic subsites, tumor stage, T-classification, N-classification, elective neck dissection, and p16 assay were 0.534, 0.626, 0.379, 0.846, 0.073, and 0.067, respectively [Table 3].

Table 3

Analysis of survival outcomes in the study subjects

Parameter	n	Disease-Specific survival				Disease-Free survival
		6 month %(n)	1 year %(n)	2 years %(n)	P	6 months %(n)	1 year %(n)	2 years %(n)	P
Anatomic Subsites	Nasal Septum (6)	83.3 (5)	33.3 (2)	33.3 (2)	0.014	66.6 (4)	66.6 (4)	66.6 (4)	0.534
	Other than nasal septum (22)	95.45 (21)	86.36 (19)	72.72 (16)		68.18 (15)	59 (13)	59 (13)
Tumor Stage	Stage I-II (17)	100 (17)	94.11 (16)	82.35 (14)	0.004	70.58 (12)	64.7 (11)	64.7 (11)	0.626
	Stage III-IV (11)	81.8 (9)	54.5 (6)	36.3 (4)		63.63 (7)	63.63 (7)	63.63 (7)
T-classification	T1-T2 (21)	95.23 (20)	76.19 (16)	71.42 (15)	0.418	76.19 (16)	66.6 (14)	66.6 (14)	0.379
	T3-T4 (7)	85.71 (6)	71.42 (5)	57.14 (4)		57.14 (4)	57.14 (4)	57.14 (4)
N-classification
N-classification	Negative (22)	100 (22)	86.36 (19)	77.27 (16)	˂0.001	68.18 (15)	59.09 (13)	59.09 (13)	0.846
	Positive (6)	66.6 (4)	33.3 (2)	16.6 (1)		66.6 (4)	66.6 (4)	66.6 (4)
Neck dissection (Elective)	Done (6)	100 (6)	83.3 (5)	83.3 (5)	0.073	100 (6)	100 (6)	100 (6)	0.073
	Not Done (18)	100 (18)	88.8 (16)	66.6 (12)		83.3 (15)	66.6 (12)	66.6 (12)
p16 assessment	Positive (5)	100 (5)	100 (5)	60 (3)	0.605	60 (3)	20 (1)	20 (1)	0.067
	Negative (16)	87.5 (14)	75 (12)	68.75 (11)		68.75 (11)	62.5 (10)	62.5 (10)

DISCUSSION

The results of the present study showed that nasoethmoidal squamous cell carcinoma was majorly aroused in the study population from the lateral nasal wall in 35.71% (n = 10) of the subjects followed by from the edge of naris to the mucocutaneous junction in 28.57% (n = 8) concerning other anatomic subsites. The origin was seen from the nasal septum, nasal floor, ethmoid sinus, and the edge of naris to the mucocutaneous junction in 21.4% (n = 6), 7.14% (n = 2), and 7.14% (n = 2), of the subjects, respectively. Node status was N0, N1, N2, and N3 in 78.57% (n = 22), 3.57% (n = 1), 7.14% (n = 2), and 10.71% (n = 3) of the subjects. These findings agreed with the findings of the previous studies by Ahn PH et al.[6] in 2016 and Allen MW et al.[7] in 2008, where similar nodal statuses ranging from 6 to 14% were reported by the authors.

Concerning anatomic subsites, Nasoethmoidal carcinoma arising from nasal septum had statistically significant worse disease-specific survival compared to carcinomas arising from other sites (P < 0.001) with more lymph node involvement and more metastasis. More nodes involvement is associated with more death. These positive nodes show a comparatively poor prognosis for the overall survival as suggested by Unsal AA et al.[8] in 2016.

In the present study, tumor recurrence was not seen in any subject who underwent elective neck dissection, whereas 66.6% (n = 12) of the subjects had recurrence where neck dissection was not performed. However, the difference was statistically insignificant (P = 0.073). Elective neck dissection is also advocated by the previous literature studies by Scurry WC et al.[9] in 2007, where disease-free survival was 100% in the subjects who underwent elective neck dissection.

Previous studies by showed that HPV-positive status is a positive and favorable prognostic factor for the nasoethmoidal SCC. However, in the present study, assessing the p16 marker for HPV was positive in 17.85% (n = 5) and was negative in 57.14% (n = 16) of the subjects. Disease-specific survival and disease-free survival were non-significant in the p16 assay with P values of 0.605 and 0.067, respectively. These findings were in contrast to the previous studies of Ang KK et al.[10] in 2010 and Chowdhury N et al.[11] in 2017, where a positive prognosis in HPV-positive-subjects with SCC of nasoethmoidal complex was reported.

CONCLUSION

Within its limitations, the present study concludes that anatomic subsites largely govern the outcomes and tumor behavior. Also, squamous cell carcinoma affecting the nasal septum is an aggressive tumor with more compromised outcomes and more lymph node involvement. Hence, more intensive treatment and elective neck dissection can benefit these high-risk subjects. However, the present study had a few limitations including smaller size, shorter monitoring period, correlation of neck dissection to better outcomes, geographical area biases, and single-institutional nature. Hence, further longitudinal studies with larger sample size and longer monitoring period are required to reach a definitive conclusion.

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Conflicts of interest

There are no conflicts of interest.