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| (2021) 11:723 | www.nature.com/scientificreports Li globalcancer incidence1 over40 yearsofage,withaslightlyyounger trend 2 3 .Forexample, thetumor 4 prognosisofpatientswithlaryngealcancer. cancer,includingendometrial cancer5 ,ovarian cancer 6 ,glioblastoma multiforme 7 ,chondrosarcoma 8 andmale breastcancer 9 nosedbetween2004and2010.?eexactscreeningprocessisshowninFig. 1.?ebaselinecharacteristicsof eligiblepatientsandtherelationshipbetweenmaritalstatusandvariablesareshowninTable 1.Amongthese,

54.5%(n

(n P

0.001). However,

Department of Otolaryngology, The First

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| (2021) 11:723 | www.nature.com/scientificreports/

there were no signicant dierences in histological types between the married group and the other three groups

P

0.950).

e widowed group had the highest proportion of women, the highest number of elderly patients (

65years),

the highest number of AJCC II/III tumors, and the highest proportion of untreated patients (surgery, radio

therapy, and chemotherapy), which was signicantly dierent from the other marital status groups (

P < 0.001).

Compared with patients who were widowed (33.0%), single (39.1%), or divorced/separated (37.1%), married

(41.5%) patients were more likely to have surgery (

P < 0.001).

Kaplan-Meier survival analysis showed signicant dierences in OS results between the various mari tal status ( P

0.001, Fig.2A). e married group had the highest 5-year OS (58.6%) compared to the other

groups. e 5-year OS of patients with laryngeal cancer in the widowed group was the lowest (32.3%). Aer

the univariate log-rank test, all dierences were signicant except for sex ( P

0.001), Table2. Multivariate Cox

regression indicated that age, race, grade, histological type, surgery, AJCC stage, chemotherapy, and marital sta

tus were independent prognostic factors aecting survival. However, radiotherapy was not an independent prog

nostic factor aecting survival (Table2). Cox regression analysis showed that, compared with married patients,

the risk of widowed, single (HR: 1.34, 95% CI: 1.24-1.44), divorced/separated (HR: 1.36, 95% CI: 1.27-1.47) was

higher, and widowed patients (HR: 1.62, 95% CI: 1.49-1.77) had the highest risk of death.

To explore the correlation

between marital status and CSS, we performed Kaplan-Meier survival analysis on patients in the dataset. Fig

ure2B shows a signicant dierence in CSS among laryngeal cancer patients with various marital statuses.

Male sex (

P

0.004), age

65years (

P

0.001), race (

P < 0.001), grade I (P < 0.001), squamous cell carcinoma P

< 0.001), yes for surgery (P < 0.001), AJCC Stage I (P < 0.001), yes for radiotherapy (P = 0.001), no or unknown

for chemotherapy ( P = 0.001), and married state (P < 0.001) were associated with a higher 5-year CSS. (Table3).

To prevent possible interference between the variables, we used multivariate Cox regression analysis. As with the

OS results, radiotherapy was not an independent predictor of CSS in patients with laryngeal cancer. In terms of

marital status, married state remains a protective factor for the prognosis of laryngeal cancer. We further evaluated the impact of marital status on OS and CSS

of each AJCC stage. Interestingly, we obtained similar results in the various AJCC stage subgroups (Tables4, 5,

Fig.3). First, marital status was an independent factor aecting the OS and CSS of each AJCC stage in univari-

Figure1.

Flow chart for screening eligible patients.

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| (2021) 11:723 | www.nature.com/scientificreports/ ate and multivariate analyses ( P < 0.001). Second, the 5-year OS and CSS of patients in the widowed group were

consistently lower than those of the other marital groups (Fig.3). In terms of OS, among all AJCC stages, the

survival rate of widowed patients in the AJCC stage II group was signicantly lower than that of married patients

(32.6% vs. 63.7%, P < 0.001; HR 2.06, 95% CI 1.70. 2.50, P < 0.001, Table4). In the analysis of CSS, the most sig-

nicant dierence was between widowed patients and married patients in the AJCC stage III subgroup (32.3%

vs. 58.6%, P < 0.001; HR 1.28, 95% CI 1.00.1.64, P = 0.042, Table5). is phenomenon also occurred in the AJCC

stage III subgroup. e risk of death was higher in the divorced/separated group than in the married group (HR

1.19; 95% CI, 0.97. 1.46), although the dierence was not signicant (

P

0.092, Table

5 Subsequently, we analyzed the inuence of marital status on OS and CSS rates

for each sex. Figures4 shows the Kaplan-Meier curve of OS and CSS rates among the sexes. Regardless of the

sex, the OS and CSS of the widowed group were lower than those of the other groups. Compared with mar-

ried patients in the male group, the 5-year OS and CSS of widowed patients were reduced by 26.9% and 19.5%,

respectively (58.50% vs. 31.60%, P < 0.001, 70.80% vs. 51.30%, P < 0.001, Tables6, 7). Compared with married patients in the subgroup, the reduction was 25.9% and 23.0%, respectively (59.00% vs. 33.10%, P

0.001; 68.60%

Table 1. Baseline clinicopathological characteristics of patients. Other 1 (Asian or Pacic Islander, American

Indian/Alaska Native). Other

2 (Neoplasm, malignant; Carcinoma, NOS; Carcinoma, undierentiated, NOS; Large cell carcinoma, NOS; Large cell neuroendocrine carcinoma; Spindle cell carcinoma, NOS; Pseudosarcomatous carcinoma; Carcinoma, anaplastic, NOS; Non-small cell carcinoma; Small cell carcinoma, NOS; Papillary squamous cell carcinoma; Verrucous carcinoma, NOS; Combined small cell carcinoma; Papillary carcinoma, NOS; Basaloid squamous cell carcinoma; Lymphoepithelial carcinoma; Basaloid carcinoma; Adenocarcinoma, NOS; Scirrhous adenocarcinoma; Adenoid cystic carcinoma; Neuroendocrine carcinoma, NOS; Mucoepidermoid carcinoma; Papillary carcinoma, follicular variant; Adenosquamous carcinoma; Adenocarcinoma with cartilaginous and osseous metaplasia; Adenocarcinoma with neuroendocrine dierentiation; Carcinoma in pleomorphic adenoma).

P valueN = 8834N = 4817N = 894N = 1732N = 1391

Sex < 0.001

Male(%)71664151 (86.2)494(55.3)1417(81.8)1104 (79.4) Female(%)1668666 (13.8)400 (44.7)315(18.2)287 (20.6)

Age < 0.001

65(%)50052580 (53.6)201(22.5)1298(74.9)926 (66.6)

65(%)38292237 (46.4)693(77.5)434(25.1)465 (33.4)

Race < 0.001

White(%)71324103 (85.2)717(80.2)1176(67.9)1136(81.7)

Black(%)1378474 (9.8)153(17.1)521(30.1)230(16.5)

Other 1 (%)324240 (5.0)24(2.7)35(2.1)25(1.8)

Grade < 0.001

Grade I(%)1490911 (18.9)120(13.4)247(14.3)212(15.2) Grade II(%)51552827 (58.7)524(58.6)1025(59.2)779(56.0) Grade III/ Grade IV(%)21891079 (22.4)250(28.0)460(26.5)400(28.8)

Histological type0.95

Squamous cell carcinoma(%)85634669 (96.9)869(97.2)1679(96.9)1346(96.8) Othe r2 (%)271148 (3.1)25(2.8)53(3.1)45(3.2)

Surgery < 0.001

No (%)53452816 (58.5)599(67.0)1055(60.9)875(62.9)

Yes (%)34892001 (41.5)295(33.0)677(39.1)516(37.1)

AJCC stage < 0.001

I (%)28851906 (39.6)249(27.9)394(22.7)336(24.2)

II (%)1497861(17.9)178(19.9)232(13.4)226(16.2)

III (%)1657832 (17.3)189(21.1)343(19.8)293(21.0)

IV (%)27951218 (25.2)278(31.1)763(44.1)536(38.5)

Radiotherapy < 0.001

Yes (%)25661474 (30.6)213(23.8)494(28.5)385(27.7)

No/unknown (%)62683343(69.4)681(76.2)1238(71.5)1006(72.3)

Chemotherapy < 0.001

Yes (%)31961562 (32.4)279(31.2)747(43.1)608(43.7)

No/unknown (%)56383255(67.6)615(68.8)985(56.9)783(56.3)

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| (2021) 11:723 | www.nature.com/scientificreports/ vs. 45.60%, P

0.001, Tables6 and 7). In line with the previous results, widowed patients were at the highest risk

for death when comparing the OS and CSS among all the groups. (Tables 6 and 7 To minimize the eect of possible confounding factors on

the baseline features of the marriage subgroups and to verify the reliability of our results, we implemented a 1:1

matching cohort utilizing propensity score-matching (PSM) methods. We obtained three 1:1 matched cohorts,

including a single and married cohort, a widowed and married cohort, and a divorced/separated and mar-

ried cohort. e demographic and clinicopathological features of the matched cohort are presented in Table8.

As expected, the clinicopathological parameters were well balanced between the groups aer PSM. Widowed

patients showed worse OS and CSS in the divorce/separated-married cohort (Fig.5A,B), the single-married

cohort (Fig. 5

C,D), and the widowed-married cohort (Fig.

5 E,F).

For the rst time, a population analysis based on the SEER database was performed to assess the prognostic

impact of marital status on the survival rate of patients with laryngeal cancer. is study found that marital status

is an independent factor aecting the prognosis of laryngeal cancer. More specically, married patients have the

lowest risk of death, while widowed patients have the highest risk of death. is is like many previous research

results 10 12 . We further conrmed aer PSM that widowed patients had better OS and CSS than divorced, single, or married patients. In 1977, Engel proposed a new model of biological psychological medicine 13 . He believed that biological fac tors, psychological elements, and social factors inuenced disease progression and outcome 14 . Since then, exten sive research has been conducted on the relationship between biological psychological factors and disease 15 -17 e role of biopsychosocial factors in cancer patients has also gradually gained attention 18 19 . A study of women"s

marital status and mortality rates showed that single patients had higher mortality rates than divorced or wid-

owed patients 20 . Another large-scale survey found that married patients with oral and laryngeal cancer are less likely to have metastases 21
. A Swedish study found that divorce and bereavement are risk factors for esophageal and gastric cancer 22
. e relationship between marital status and prognosis may be inuenced by tumor stage, proportion of patients receiving treatment, and social support 23
-26 . A higher percentage of married laryngeal

cancer patients receive timely treatment, including surgery and adjuvant treatment, which may explain the

high survival rate. However, it emphasizes the interrelationship between marital status and survival rather than

causality. erefore, it is necessary to explore how marital status aects the potential mechanism of survival to

improve the outcome of patients with laryngeal cancer.

is study showed that marital status was associated with survival in patients with laryngeal cancer. We

hypothesize the following reasons for the benecial eect of married state on survival in patients with laryngeal

cancer. First, a happy marriage may result in a well-balanced emotional state, and a wholesome family environ

ment may ease work and social pressures. Second, married patients that have stable marriages usually are accom

panied by appropriate family nances. A commonly accepted explanation of why married people have lower

cancer mortality, was that it was related to better socioeconomic status. is was believed to buer the eects of

stressful events 27
,28 . Chronic stress may cause long-term secretion of cortisol 29
, which leads to reverse regulation

Figure2.

Kaplan-Meier survival curves for OS (A) and CSS (B) in dierent marital statuses. (OS: overall survival, CSS: cause-specic survival).

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of leukocytes by down-regulating the cortisol receptor of leukocytes. is downregulation, in turn, reduces

the ability of cells to respond to anti-inammatory signals and leads to the vigorous development of cytokine-

mediated inammatory processes 30
, which has been proven to be a poor prognostic factor for cancer 31
,32 . ird,

married patients have a wider social range than unmarried patients. ey have a broader information base regard-

ing medical equipment, experts, and treatment methods. is can help improve treatment outcomes 33
. Social networks inuence patient compliance, and good compliance ultimately aects a patients" health outcomes 34

In addition, our results raise another intriguing question as to why widowed patients exhibit worse clini

cal outcomes. ere is evidence to suggest that a widows" health is a problem before they are diagnosed with

cancer 35

. Studies have shown that the recent death of a husband results in a signicant decrease in the level of

Table 2. Univariate and multivariate survival analysis of OS in laryngeal cancer patients before PSM. Other 1 (Asian or Pacic Islander, American Indian/Alaska Native). Other 2 (Neoplasm, malignant; Carcinoma, NOS;

Carcinoma, undierentiated, NOS; Large cell carcinoma, NOS; Large cell neuroendocrine carcinoma; Spindle

cell carcinoma, NOS; Pseudosarcomatous carcinoma; Carcinoma, anaplastic, NOS; Non-small cell carcinoma;

Small cell carcinoma, NOS; Papillary squamous cell carcinoma; Verrucous carcinoma, NOS; Combined small

cell carcinoma; Papillary carcinoma, NOS; Basaloid squamous cell carcinoma; Lymphoepithelial carcinoma;

Basaloid carcinoma; Adenocarcinoma, NOS; Scirrhous adenocarcinoma; Adenoid cystic carcinoma; Neuroendocrine carcinoma, NOS; Mucoepidermoid carcinoma; Papillary carcinoma, follicular variant; Adenosquamous carcinoma; Adenocarcinoma with cartilaginous and osseous metaplasia; Adenocarcinoma with neuroendocrine dierentiation; Carcinoma in pleomorphic adenoma). OS, overall survival; PSM, propensity score matching; HR, hazard ratio; CI, condence interval.

Log-rank

2testPHR(95%CI)P

Sex2.5520.11

Male50.90%

Female48.90%

Age295.001 < 0.001P < 0.001

6556.30%Reference

6543.10%1.87(1.76-1.98)

Race64.141 < 0.001P < 0.001

White51.70%Reference

Black42.30%1.11(1.03-1.19)

Other 1

60.00%0.80(0.68-0.94)

Grade330.634 < 0.001P < 0.001

Grade I66.40%Reference

Grade II51.70%1.22(1.12-1.33)

Grade III/ Grade IV37.00%1.43(1.30-1.57)

Histologicaltype21.933 < 0.0010.007

Squamous cell carcinoma50.90%Reference

Other 2

40.10%1.21(1.05-1.40)

Surgery109.405 < 0.001P < 0.001

No46.30%Reference

Yes57.00%0.70(0.64-0.76)

AJCCstage1173.743 < 0.001P < 0.001

I71.10%Reference

II56.70%1.47(1.34-1.61)

III43.60%2.20(2.01-2.41)

IV30.10%3.38(3,11-3.68)

Radiotherapy20.714 < 0.0010.813

Yes53.80%Reference

No/unknown49.20%1.01(0.92-1.10)

Chemotherapy259.862 < 0.001P < 0.001

Yes39.70%Reference

No/unknown56.70%1.14(1.07-1.23)

Maritalstatus432.26 < 0.001P < 0.001

Married58.60%Reference

Widowed32.30%1.62(1.49-1.77)

Single44.30%1.34(1.24-1.44)

Divorced/Separated42.20%1.36(1.27-1.47)

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| (2021) 11:723 | www.nature.com/scientificreports/ natural killer (NK) cells in the widows" body 36
,37 . More importantly, NK cells are known to play an important role in the ght against cancer 38
. Compared with married patients, widowed patients had more psychologi

cal stress and less psychological support. is can cause disorders of the immune system and promote cancer

progression 39
. Such an alteration aects the release of glucocorticoids and catecholamines, further aecting the tumor microenvironment 40
,41 . An enhanced development of tumors results in a shortened survival time for widowed patients.

Although this study is both instructive and relevant to clinical practice, it has some limitations. First, the

marital status information provided in the SEER database is incomplete. It provides only marital status at the

time of diagnosis, and some patients" marital status may change during follow-up. In the same way, it does not

Table 3. Univariate and multivariate survival analysis of CSS in laryngeal cancer patients before PSM. Other 1 (Asian or Pacic Islander, American Indian/Alaska Native). Other 2 (Neoplasm, malignant; Carcinoma, NOS;

Carcinoma, undierentiated, NOS; Large cell carcinoma, NOS; Large cell neuroendocrine carcinoma; Spindle

cell carcinoma, NOS; Pseudosarcomatous carcinoma; Carcinoma, anaplastic, NOS; Non-small cell carcinoma;

Small cell carcinoma, NOS; Papillary squamous cell carcinoma; Verrucous carcinoma, NOS; Combined small

cell carcinoma; Papillary carcinoma, NOS; Basaloid squamous cell carcinoma; Lymphoepithelial carcinoma;

Basaloid carcinoma; Adenocarcinoma, NOS; Scirrhous adenocarcinoma; Adenoid cystic carcinoma; Neuroendocrine carcinoma, NOS; Mucoepidermoid carcinoma; Papillary carcinoma, follicular variant; Adenosquamous carcinoma; Adenocarcinoma with cartilaginous and osseous metaplasia; Adenocarcinoma with neuroendocrine dierentiation; Carcinoma in pleomorphic adenoma). CSS, cancer-specic survival; PSM, propensity score matching; HR, hazard ratio; CI, condence interval.

Log-rank

2testPHR(95%CI)P

Sex8.2670.0040.009

Male64.00%Reference

Female61.10%0.88(0.81-0.97)

Age41.735 < 0.001P < 0.001

6565.80%Reference

6560.30%1.55(1.44-1.67)

Race57.35 < 0.0010.037

White64.90%Reference

Black54.40%1.10(1.01-1.21)

Other 1

68.70%0.88(0.73-1.08)

Grade393.314 < 0.001P < 0.001

Grade I79.60%Reference

Grade II65.10%1.38(1.23-1.56)

Grade III/ Grade IV48.40%1.68(1.48-1.92)

Histologicaltype31.108 < 0.0010.002

Squamous cell carcinoma63.90%Reference

Other 2

49.70%0.76(0.64-0.90)

Surgery107.929 < 0.001P < 0.001

No59.40%Reference

Yes69.60%0.61(0.55-0.68)

AJCCstage1551.781 < 0.001P < 0.001

I85.70%Reference

II72.50%1.84(1.61-2.10)

III56.80%3.32(2.93-3.78)

IV38.70%5.94(5.27-6.70)

Radiotherapy10.4060.0010.729

Yes65.50%Reference

No/unknown62.60%0.98(0.87-1.09)

Chemotherapy409.833 < 0.0010.002

Yes49.60%Reference

quotesdbs_dbs27.pdfusesText_33

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