The prognosis of different distant metastases pattern in malignant tumors of the adrenal glands: A population-based retrospective study

Jia Miao; Haibin Wei; Jianxin Cui; Qi Zhang; Feng Liu; Zujie Mao; Dahong Zhang

doi:10.1371/journal.pone.0264431

. 2022 Mar 15;17(3):e0264431. doi: 10.1371/journal.pone.0264431

The prognosis of different distant metastases pattern in malignant tumors of the adrenal glands: A population-based retrospective study

Jia Miao ^1,^#, Haibin Wei ^2,^*, Jianxin Cui ^2,^#, Qi Zhang ², Feng Liu ², Zujie Mao ², Dahong Zhang ^2,^*

Editor: Filomena de Nigris³

PMCID: PMC8923449 PMID: 35290387

Abstract

Introduction

The present existing data on the association of metastatic sites and prognosis of patients with metastatic adrenal malignancy are limited. This study aims to investigate the impact of different distant metastases pattern on the survival of patients with adrenal malignancy.

Methods

A dataset from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) 18 Registries (2000–2017) was selected for a retrospective metastatic adrenal malignancy cohort study. There was information on distribution of metastatic lesions in bone, brain, liver, and lung in the SEER database. Kaplan-Meier analysis and nomogram analyses were applied to compare the survival distribution of cases. Univariate and multivariate cox regression models were used to analyze survival outcomes.

Results

From the SEER database, a total of 980 patients with primary metastatic adrenal malignancy from 2010 to 2017 were enrolled in this cohort study. Based on the initial metastatic sites, 42.3%, 38.4%, 30.5%, and 4.9% of patients were found bone, liver, lung, and brain metastasis, respectively. Patients who had a single site of distant metastases accounted for 52.6% (515/980) and had a better overall survival (OS) and cancer-specific survival (CSS) (both P < 0.001). In contrast with the tumor arising from the cortex, the tumor from the medulla showed better survival outcomes in both OS and CSS (P < 0.001).

Conclusion

Different histological types possess various metastatic features and prognostic values. Understanding these differences may contribute to designing targeted pre-treatment assessment of primary metastatic adrenal malignancy and creating a personalized curative intervention.

Introduction

Adrenal tumor is a rare malignancy that is infrequently encountered by oncologists, primary care physicians, and urologists. Although adrenal incidentalomas have been increasingly identified by more abdominal cross-sectional imaging studies, only 8% of adrenal incidentalomas are malignant [1, 2]. Although adrenal cortical carcinoma (ACC) is the most common histological type of adrenal malignancy, its annual incidence is 0.7–2 cases every year and its worldwide prevalence is 4 to 12 cases per 100,000 individuals every year [1, 3]. En bloc resection with negative margins (R0 resection) may be a better choice for patients with respectable adrenal tumor, but R0 resection is not possible in many patients, especially patients with tumor metastasis [4]. Further, 50% to 75% of adrenal masses may represent metastatic disease in patients with known cancer [5, 6]. Visceral metastases of adrenal malignancy might be associated with worse outcomes. Diagnosis and treatment do not equate with equivalent benefit for metastatic adrenal malignancy, and further understanding of outcome of adrenal malignancy, especially metastatic adrenal malignancy, might help make reasonable medical decision and save the unnecessary expend on the advanced tumor. Several studies have focused on evaluating the prognosis of metastases in primary metastatic adrenal malignancy [7–9]. However, to date little attention has been focused on the prognostic significance of the distant metastatic pattern of adrenal malignancy at the first diagnosis.

Currently, the relative research on primary metastatic adrenal malignancy is very limited, and little information available is derived from these case series and case reports [10, 11]. To our knowledge, there are no prior studies with a large sample size that investigated the potential prognostic value of site-specific metastases in adrenal malignancies. Since knowledge of prognosis of the different distant metastatic pattern has an important role in pre-treatment evaluation, our study aimed to describe the distant metastatic site, frequency of occurrence, and pattern of these metastases based on a large population by using an established national cancer registry, the Surveillance, Epidemiology, and End Results (SEER) database. The goal of this study was to provide a better understanding of the prognosis of the different distant metastatic pattern in adrenal malignancy patients and help in making a suitable clinical decision at the first diagnosis.

Materials and methods

Data source and patient selection

The data of this study were obtained from the National Cancer Institute’s SEER program dataset, a population-based cancer registry covering approximately 34.6% of the population in the United States. SEER*Stat software (SEER*Stat 8.3.6) was utilized to select eligible patients and define variables. The dataset from SEER Research Data, 18 Registries, Nov 2019 Sub (2000–2017) was selected for a retrospective primary metastatic adrenal malignancy cohort study. In this study, patients with primary metastatic adrenal malignancy were selected using inclusion and exclusion rules from 2010 to 2017. The inclusion criteria were as follows: (1) information on distant metastases in the enrolled patients should be confirmed, including bone, brain, liver, and lung; (2) the diagnosis was confirmed clinically or pathologically with confirmed age. Patients were excluded if the age and the survival months were unknown, or the oncological behaviors were not malignant.

Based on the ICD-O-3, we divided the histological type into the following three subgroups: ACC, Neuroblastoma (NE), and others. Residential areas were also divided into the following three subgroups: metropolis, nonmetropolis, and unknown.

Statistical analysis

The distribution of demographic factors and tumor characteristics were summarized with descriptive statistics. Categorical variables were compared using chi-square tests, and continuous variables were analyzed by the Mann Whitney test for non-normal distribution. Overall survival (OS) was calculated from the date of diagnosis to the date of death without limitation of any cause of death, or the date of the last follow-up. Cancer-specific survival (CSS) was defined as the interval from the date of diagnosis to death due to adrenal malignancy other than extra causes. Survival was analyzed by Kaplan-Meier methods, and the log-rank test was performed to evaluate the discrepancies between OS and CSS. The Cox proportional hazards regression model with the hazard ratio (HR) and the associated 95% confidence interval (CI) were utilized to evaluate the comparative risks of mortality. All statistical significance was 2-sided, P <0.05 was considered statistically significant. All the above methods were performed in Statistics software version SPSS 25.0 (IBM, NY, US).

Nomogram construction

A nomogram was built considered the factors of multivariate analysis and data availability. The maximum score for variable was 100 each. The performance of the nomogram was measured by concordance index (C-index) [12, 13]. Nomogram was performed in R version 4.0.0 software. (The R Foundation for Statistical Computing, Vienna, Austria. http://www.r-project.org).

Results

Patient demographics and clinical characteristics

A total of 2053 eligible patients with primary adrenal malignancy between 2010 and 2017 were identified from SEER database. Among these patients, the metastatic adrenal malignancy accounted for 47.74% (980/2053) at the time of diagnosis, including 493 men (50.3%) and 487 women (49.7%). The metastatic information on bone, brain, liver, and lung metastasis was collected in the SEER database.

The demographic characteristics of these patients are presented. (Table 1). The median age at diagnosis of the whole group was 21 years. Approximately 77.9% of patients’ ethnicity was white. The distribution of the number of patients annually (from 2010 to 2017) showed no significant difference. Primary adrenal malignancy on the left side was more common than that on the right side, especially in NE. In addition to the grade of unknown, the most common grade was poor differentiated (30.9%). Approximately more than half of the patients (71.8%) were from middle-income families. Most of the patients (90.1%) lived in metropolis. 48.3% of patients had tumor size ≤ 100mm, but 19.1% had unknown tumor size. According to the histological type, the clinicopathological information of patients is also shown (Table 1). Because the population of ACC and NE was large, the group of histology was divided into three types. The remarkable finding was that patients with NE were younger than those with the other types (P < 0.001).

Table 1. Demographical characteristics of patients.

Characteristics	Total(n = 980)	ACC(n = 334)	NE(n = 437)	Other(n = 209)
Age, years
Median	21	57	2	60
IQR	2–60	44–66	0–3	44–73
Race
White	763(77.9)	276(82.6)	328(75.1)	159(76.1)
Black	130(13.3)	30(9.0)	65(14.9)	35(16.7)
Other	83(8.5)	26(7.8)	43(9.8)	14(6.7)
Unknown	4(0.4)	2(0.6)	1(0.2)	1(0.5)
Gender
Male	493(50.3)	135 (40.4)	245(56.1)	113(54.1)
Female	487(49.7)	199 (59.6)	192(43.9)	96(45.9)
Years of diagnosis
2010	134(13.7)	42(12.6)	60(13.7)	32(15.3)
2011	112(11.4)	40(12.0)	45(10.3)	27(12.9)
2012	105(10.7)	43(12.9)	48(11.0)	14(6.7)
2013	127(13.0)	41(12.3)	62(14.2)	24(11.5)
2014	137(14.0)	40(12.0)	66(15.1)	31(14.8)
2015	126(12.9)	47(14.1)	56(12.8)	23(11.0)
2016	116(11.8)	39(11.7)	48(11.0)	29(13.9)
2017	123(12.6)	42(12.6)	52(11.9)	29(13.9)
Laterality
Left	485(49.5)	157(47.0)	237(54.2)	91(43.5)
Right	428(43.7)	159(47.6)	182(41.6)	87(41.6)
Bilateral, single primary	15(1.5)	2(0.6)	9(2.1)	4(1.9)
Unknown	52(5.3)	16(4.8)	9(2.1)	18(12.9)
Grade
Well	9(0.9)	6(1.8)	2(0.5)	1(0.5)
Moderately	13(1.3)	11(3.3)	0(0.0)	2(1.0)
Poorly	303(30.9)	29(8.7)	242(55.4)	32(15.3)
Undifferentiated	56(5.7)	14(4.2)	34(7.8)	8(3.8)
Unknown	599(61.1)	274(82.0)	159(36.4)	166(79.4)
Tumor size
≤100mm	473(48.3)	123(36.8)	251(57.4)	99(47.4)
>100mm, ≤200mm	291(29.7)	143(42.8)	96(22.0)	52(24.9)
>200mm	29(3.0)	26(7.8)	2(0.5)	1(0.5)
Unknown	187(19.1)	42(12.6)	88(20.1)	57(27.3)
Median income
<35,000	22(2.2)	7(2.1)	9(2.1)	6(2.9)
35,000–75,000	704(71.8)	229(68.6)	319(73.0)	156(74.6)
>75,000	254(25.9)	98(29.3)	109(24.9)	47(22.5)
Residential areas
Metropolis	883(90.1)	298(89.2)	402(92.0)	183(87.6)
Nonmetropolis	92(9.4)	36(10.8)	32(7.3)	24(11.5)
Unknown	5(0.5)	0(0.0)	3(0.7)	2(1.0)
Surgery
Yes	534(54.5)	123(36.8)	343(78.5)	68(32.5)
No	442(45.2)	209(62.6	93(21.3)	140(67.0)
Unknown	4(0.4)	2(0.6)	1(0.2)	1(0.5)
Metastasis site
Only Bone	236(45.9)	18(11.5)	185(71.7)	33(33.3)
Only Brain	7(1.4)	4(2.5)	1(0.4)	2(2.0)
Only Liver	153(29.8)	58(36.9)	68(26.4)	27(27.3)
Only Lung	118(23.0)	77(49.0)	4(1.6)	37(37.4)

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Abbreviations: ACC, adrenal cortical carcinoma; NE, neuroblastoma.

Distribution of metastasis pattern

The distributions of these patients in the sites of metastases of adrenal malignancy were presented in the Venn diagram (Fig 1). At the time of diagnosis, the most common site of metastases was bone (415 cases, 42.3%), followed by 376 (38.4%) patients with liver metastasis, 299 (30.5%) patients with lung metastasis, and 48 (4.9%) patients with brain metastasis. Patients who had a single site of distant metastases accounted for 52.6% (515/980), followed by two sites (233/980, 23.8%), three sites (47/980, 4.8%), and four sites (4/980, 0.4%). The clinical characteristics of these patients are presented (Table 2). The distribution of gender among the patients with bone metastasis and without bone metastasis was significantly different (P < 0.001). Depending on the histological type, the distribution was significantly associated with all four types of metastasis (all, P < 0.001). As for surgery, the distribution of patients was statistically significant except brain metastasis (P < 0.05).

Table 2. Clinical characteristics and metastasis sites.

Features	Bone metastasis (%)			Brain metastasis (%)			Liver metastasis (%)			Lung metastasis (%)
No	No	Yes	P	No	Yes	P	No	Yes	P	No	Yes	P
Age
Median	51	3	<0.	22	3	0.0	7	39	0.0	4	53	<0.
IQR	4~64	2~16	001	2~59	2~13	02	2~58	1~59	01	1~54	29~65	001
Race
White	452(59.2)	311(40.8)	>0.05^b	730(95.7)	33(4.3)	>0.05^b	466(61.1)	297(38.9)	>0.05^b	531(69.6)	232(30.4)	>0.05^b
Black	62(47.7)	68(52.3)		120(92.3)	10(7.7)		85(65.4)	45(34.6)		93(71.5)	37(28.5)
Other	49(59.0)	34(41.0)		78(94.0)	5(6.0)		51(61.4)	32(38.6)		54(65.1)	29(34.9)
Unknown	2(50.0)	2(66.7)		4(100.0)	0(0.0)		2(50.0)	2(50.0)		3(75.0)	1(25.0)
Gender
Male	257 (52.1)	236(47.9)	<0.001^a	465(94.3)	28(5.7)	>0.05^a	313(63.5)	180(36.5)	>0.05^a	360(73.0)	133(27.0)	<0.05^a
Female	308(63.2)	179(36.8)		467(95.9)	20(4.1)		291(59.8)	196(40.2)		321(65.9)	166(34.1)
Primary site
Cortex	153(80.5)	37(19.5)	<0.001^a	186(97.9)	4 (2.1)	<0.05^b	94(49.5)	96(50.5)	<0.05^a	95(50.0)	95(50.0)	<0.001^a
Medulla	16(47.1)	18(52.9)		29(85.3)	5(14.7)		20(58.8)	14(41.2)		23(67.6)	11(32.4)
Adrenal gland, NOS	396(52.4)	360(47.6)		717(94.8)	39(5.2)		490(64.8)	266(35.2)		563(74.5)	193(25.5)
Histologic type
ACC	276(82.6)	58(17.4)	<0.001^a	329(98.5)	5(1.5)	<0.001^a	165(49.4)	169(50.6)	<0.001^a	159(47.6)	175(52.4)	<0.001^a
NE	144(33.0)	293(67.0)		403(92.2)	34(7.8)		300(68.6)	137(31.4)		395(90.4)	42(9.6)
Other types	145(69.4)	64(30.6)		200(95.7)	9(4.3)		139(66.5)	70(33.5)		127(60.8)	82(39.2)
Laterality
Left	260(53.9)	225(46.4)	<0.05^b	454(93.6)	31(6.4)	>0.05^b	296(61.0)	189(39.0)	>0.05^a	336(69.3)	149(30.9)	>0.05^b
Right	255(59.6)	173(40.4)		414(96.7)	14(3.3)		270(63.1)	158(36.9)		301(70.3)	127(29.7)
Bilateral, single primary	11(73.3)	4(26.7)		14(93.3)	1(6.7)		6(40.0)	9(60.0)		12(80.0)	3(20.0)
Unknown	39(75.0)	13(25.0)		50(96.2)	2(3.8)		32 (61.5)	20(38.5)		32(61.5)	20(38.5)
Grade
Well	4(44.4)	5(55.6)	<0.001^b	1(11.1)	8(88.9)	<0.05^b	4(44.4)	5(55.6)	<0.05^b	4(44.4)	5(55.6)	<0.001^b
Moderately	3(23.1)	10(76.9)		1(7.7)	12(92.3)		2(15.4)	11(84.6)		5(38.5)	8(61.5)
Poorly	174(57.4)	129(42.6)		24(7.9)	279(92.1)		99(32.7)	204(67.3)		48(15.8)	255(84.2)
Undifferentiated	28(50.0)	28(50.0)		3(5.4)	53(94.6)		18(32.1)	38(67.9)		11(19.6)	45(80.4)
Unknown	206(34.4)	393(65.6)		19(3.2)	580(96.8)		253(42.2)	346(57.8)		231(38.6)	368(61.4)
Tumor size
≤100mm	237(50.1)	236(49.9)	<0.001^b	34(7.2)	439(92.8)	<0.05^b	170(35.9)	303(64.1)	>0.05^a	116(24.5)	357(75.5)	<0.001^a
>100mm, ≤≤200mm	99(34.0)	192(66.0)		7(2.4)	284(97.6)		116(39.9)	175(60.1)		122(41.9)	169(58.1)
>200mm	3(10.3)	26(89.7)		0(0.0)	29(100.0)		15(51.7)	14(48.3)		11(37.9)	18(62.1)
Median income
<35,000	15(68.2)	7(31.8)	>0.05^a	19(86.4)	3(13.6)	>0.05^b	15(68.2)	7(31.8)	>0.05^a	17(77.3)	5(22.7)	>0.05^a
35,000–75,000	394(56.0)	310(44.0)		668(94.9)	36(5.1)		439(62.4)	265(37.6)		489(69.5)	215(30.5)
>75,000	156(61.4)	98(38.6)		245(96.5)	9(3.5)		150(59.1)	104(40.9)		175(68.9)	79(31.1)
Residential areas
Metropolis	501(56.7)	382(43.3)	>0.05^b	840(95.1)	43(4.9)	>0.05^b	548(62.1)	335(37.9)	>0.05^b	617(69.9)	266(30.1)	>0.05^b
Nonmetropolis	60(65.2)	32(34.8)		87(94.6)	5(5.4)		53(57.6)	39(42.4)		60(65.2)	32(34.8)
Unknown	4(80.0)	1(20.0)		5(100.0)	0(0.0)		3(60.0)	2(40.0)		4(80.0)	1(20.0)
Surgery
Yes	295(55.2)	239(44.8)	<0.001^a	30(5.6)	504(94.4)	>0.05^a	151(28.3)	383(71.7)	<0.001^a	100(18.7)	434(81.3)	<0.001^a
No	119(26.9)	323(73.1)		18(4.1)	424(95.9)		224(50.7)	218(49.3)		199(45.0)	243(55.0)

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^a. The P value was obtained from Pearson chi-Square test.

^b. The P value was obtained from Fisher’s exact test.

Abbreviations: NOS, not otherwise specified; ACC, adrenal cortical carcinoma; NE, neuroblastoma.

The metastatic pattern of metastatic adrenal malignancy was exhibited in Table 3. Theoretically there were 15 metastatic forms, including 4 single metastases and 11 combinations of metastases. However, there were no relevant cases in this study in two types of metastatic forms, which were brain and liver metastases and brain and liver and lung metastases. We found bone metastasis was the most common metastasis in single metastatic patients (24.08%), followed by liver (15.71%), lung (12.04%) and brain (0.71%). As for two sites, the highest frequency was observed in patients with liver and lung metastases at 10.51% (103/980). Bone metastasis presented better survival rate in single metastasis. Patients with brain and lung metastases had the worse survival rate than other metastatic types in two sites metastases. In addition, median OS cannot be concluded in only bone metastasis and bone and brain metastases in Kaplan-Meier analysis.

Table 3. Frequencies of combination metastasis and 3, 5-y OS.

	Number (%)	3-y OS	5-y OS	Median OS (months)
One site
Only Bone	236 (24.08)	73.31%	67.80%	NA
Only Brain	7 (0.71)	0.00%	0.00%	2.0
Only Liver	154 (15.71)	48.05%	45.45%	15.0
Only Lung	118 (12.04)	25.42%	22.89%	9.0
Two sites
Bone and brain	25 (2.55)	80.00%	72.00%	NA
Bone and liver	73 (7.45)	54.79%	53.42%	41.0
Bone and lung	30 (3.06)	40.00%	36.67%	10.0
Brain and liver	0 (0.00)	0	0	/
Brain and lung	2 (0.20)	0	0	1.5
Liver and lung	103 (10.51)	22.33%	20.39%	3.0
Three sites
Bone and brain and liver	5 (0.51)	40.00%	40.00%	20.5
Bone and brain and lung	5 (0.51)	20.00%	20.00%	19.0
Bone and liver and lung	37 (3.78)	24.32%	21.62%	7.0
Brain and liver and lung	0 (0.00)	0	0	/
Four sites
Bone and brain and liver and lung	4 (0.41)	50.00%	50.00%	3.0

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NA: The median OS cannot be concluded because more than half of the patients still alive at the end of the follow up; /: The median OS cannot be calculated due to the absence of related cases.

Abbreviations: OS: overall survival.

Metastatic sites and survival outcomes

In this study, 550 deaths (56.10%) were observed. The mortality rate was high. We performed Kaplan-Meier analysis in patients with a single metastatic site (n = 515). It was routinely observed that patients with bone metastases had better outcomes in OS and CSS, compared with patients diagnosed with liver, lung, and brain metastases. Log-rank test was used to compare the number of all metastatic sites of adrenal malignancy in patients, and it was found that the patients with one metastatic site had significantly longer OS and CSS than those with more metastases (OS: HR = 1.618, 95% CI = 1.339–1.955; CSS: HR = 1.680, 95% CI = 1.373–2.054; both P < 0.001) (Fig 2). Patients with bone and liver metastases presented longer OS and CSS compared to those with lung and brain metastases in the group of only one metastatic site by using the log-rank test (P < 0.001) (Fig 3).

Fig 2 — Patients in one metastasis had significantly better survival both in OS and CSS; (a) OS; (b) CSS; OS, overall survival; CSS, cancer-specific survival; HR, hazard ratio; CI, confidence interval.

Fig 3 — Patients in bone metastasis had the best survival outcomes in OS and CSS. Brain metastasis had significantly shorter OS and CSS compared with other types of sites; (a) OS; (b) CSS; OS, overall survival; CSS, cancer-specific survival; HR, hazard ratio; CI, confidence interval.

Univariate survival analysis

Prognostic factors, including the site of metastases, gender, primary site, histological types, and residential areas, were analyzed in the univariate survival analysis (Table 4). Patients with brain metastasis exhibited the worst OS and CSS than those with the other three types of single metastasis (OS: HR = 7.447, 95% CI = 3.416–16.233; CSS: HR = 7.830, 95% CI = 3.143–19.506). We observed that females exhibited worse prognosis than males in OS and CSS (P < 0.05). Compared with the tumor arising from the cortex, the tumor arising from the medulla showed better survival outcomes (P < 0.001). Similarly, patients with NE seemed to have better OS and CSS than those with ACC. And patients with surgery had better OS and CSS than those without (P < 0.001). Also, there was a significant difference between patients who lived in metropolis and nonmetropolis. Patients who lived in metropolis presented a better survival.

Table 4. Univariate survival analysis predicting overall survival and cancer-specific survival in patients with four single metastases.

Risk Factors	Overall survival		Cancer-specific survival
Risk Factors	HR(95%CI)	P	HR(95%CI)	P
Metastasis site		<0.001		<0.001
Only Bone	Ref.		Ref.
Only Brain	7.447(3.416–16.233)	<0.001	7.830(3.143–19.506)	<0.001
Only Liver	2.527(1.853–3.447)	<0.001	2.499(1.788–3.492)	<0.001
Only Lung	4.128(3.037–5.610)	<0.001	3.069–5.923	<0.001
Gender		0.016		0.007
Male	Ref.		Ref.
Female	1.229(1.039–1.453)	0.016	1.280(1.071–1.531)	0.007
Primary site		<0.001		<0.001
Cortex	Ref.		Ref
Medulla	0.379(0.224–0.640)	<0.001	0.312(0.168–0.580)	<0.001
Histology		<0.001		<0.001
ACC	Ref.		Ref.
NE	0.169(0.136–0.210)	<0.001	0.162(0.129–0.204)	<0.001
Other types	0.865(0.710–1.054)	0.150	0.819(0.661–1.016)	0.069
Residential areas		<0.001		<0.001
Metropolis	Ref		Ref.
Nonmetropolis	1.667(1.288–2.158)	<0.001	1.729(1.313–2.276)	<0.001
Unknown	1.570(0.587–4.200)	0.369	1.429(0.459–4.450)	0.538
Surgery		<0.001		<0.001
Yes	Ref.		Ref.
No	3.307(2.779–3.936)	<0.001	3.263(2.713–3.923)	<0.001

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Abbreviations: HR, hazard ratio; CI, confidence interval; Ref, reference; ACC, adrenal cortical carcinoma; NE, neuroblastoma.

Multivariable survival analysis

The parameters, including metastatic site, gender, histology, primary site, residential areas and surgery, were selected in multivariate analysis. As for metastatic site, brain metastasis was still the worst prognostic metastasis both in OS and CSS. The same as the univariate analysis, primary site was an independent prognostic factor for adrenal metastatic cancer patients both in OS and CSS (P < 0.05). In the analysis of the primary site, the primary site in the cortex had a worse prognosis than that in the medulla in both OS and CSS (P < 0.05). With respect to the surgery, patients underwent the surgery showed the better prognosis for OS and CSS (all P < 0.001) (Table 5).

Table 5. Multivariate survival analysis predicting overall survival and cancer-specific survival in patients with four single metastases.

Characteristics	Overall survival		Cancer-specific survival
Characteristics	HR (95% CI)	P	HR (95% CI)	P
Metastasis site
Only bone	Ref.		Ref.
Only brain	11.133(2.074–59.757)	0.005	13.984(2.496–78.334)	0.003
Only liver	1.144(0.477–2.746)	0.763	1.458(0.571–3.724)	0.431
Only lung	1.228(0.543–2.776)	0.621	1.335(0.558–3.191)	0.516
Gender
Male	Ref.		Ref.
Female	0.904(0.526–1.554)	0.715	0.862(0.479–1.552)	0.621
Primary site
Cortex	Ref.		Ref.
Medulla	0.218(0.068–0.692)	0.010	0.181(0.048–0.678)	0.011
Histology
ACC	Ref.		Ref
NE	0.306(0.066–1.424)	0.131	0.287(0.061–1.355)	0.115
Others	1.196(0.493–2.898)	0.692	1.144(0.466–2.808	0.770
Residential areas
Metropolis	Ref		Ref
Nonmetropolis	1.840(0.889–3.808)	0.100	2.121(0.930–4.838)	0.074
Surgery
Yes	Ref.		Ref.
No	4.861(2.449–9.647)	<0.001	4.826(2.386–9.761)	<0.001

Open in a new tab

Abbreviations: HR, hazard ratio; CI, confidence interval; Ref, reference; ACC, adrenocortical carcinoma; NE, neuroblastoma.

Nomogram

A nomogram was established for OS based on the multivariate analysis results and data availability (Fig 4). We could predict the 1, 3, and 5 year survival probability in the base of the sum of the dot scale at the top and the points for every factor. The probabilities of 1, 3, and 5 year survival relied on the fractional proportion present at the bottom of the nomogram. The C-index was 0.76, which means the nomogram is a reliable model for predicting the OS of metastatic adrenal malignancy.

Discussion

Primary adrenal malignancy is rare, and metastatic adrenal malignancy is even rarer in clinical practice. Even in the SEER database, patients with primary metastatic adrenal malignancy are relatively less in number compared to patients with other malignancies. SEER breaks the barrier of minor cases series and isolated institutional studies and provides a platform for learning rare tumor deeply. With respect to the adrenal tumor, the only standard to indicate malignancy is the existence of metastasis [14]. In this study, we analyzed primary adrenal malignancy with distant sites of metastasis, including bone, brain, liver, and lung, as the recorded sites in the SEER database after 2010. At the time of diagnosis, the rate of metastasis to bone, liver, lung, and brain in adrenal malignancy patients was 42.3%, 38.4%, 30.5%, and 4.9%, respectively. There were plenty of articles about adrenal incidentaloma and adrenal metastasis secondary to other diseases [5, 6, 15], but relevant literature reports about primary metastatic adrenal malignancy were limited, which meant that few studies highlighted the relation between metastatic sites and survival. Our study was the first to explore the role of the metastatic site in adrenal malignancy patients’ survival using a large sample size. Besides, information on site-specific survival was also available to learn about the prognosis of metastatic adrenal malignancy in more detail.

Traditional studies about the incidence of ACC presented a bimodal age distribution in the first and fourth decades of life, which was in contrast with our study [16]. Interestingly, the result of the previous study based on the SEER registries and international registries was consistent with our study, and this discrepancy might be attributed to the differences in the time of diagnosis. To date, ACC has shown insignificant changes in survival outcomes [17–20]. In contrast, NE appears to show more preferable oncological outcomes with drastic improvements in treatment, and the 1-year CSS rate of NE has exceeded 90% [2]. The same phenomenon was also observed in our study. Metastatic NE had better oncological survival than metastatic ACC. Therefore, treatments of ACC still have a long way to go. Although there was a report about the diameter of the tumor being associated with the risk of malignancy [21], the SEER data included was not applicable for evaluating the risk, and over the half of the patients had incomplete data on tumor size.

In our analysis, the NE subtype had a significantly higher rate of bone metastasis (67%) while the ACC type was more likely to have lung (52.4%) and liver (50.6%) metastases. Males were more likely to have bone metastasis, and females were prone to develop liver and lung metastases. It makes sense since NE tends to affect males and ACC prefers the female sex, and that is why females exhibited worse prognosis than males in both OS and CSS. Irrespective of the population of adults or children with ACC, the ratio of females to males ranged from 1.5–2.5:1 [22, 23]. Females exhibited worse HR in univariate analysis because of the inferior prognosis and large population of ACC. It was interesting to observe that the lesion on the left side was prone to bone metastasis, and we also found that NE was related to laterality and the number of lesions on the left side was more than that on the right side. The same occurrence was reported in previous studies of ACC; the left side was more and easier to be affected [24–26]. Nevertheless, our study did not display this in ACC; may be the laterality was influenced by the patients. Besides, we noted that race, median household income, and residential areas were not associated with metastatic sites.

In survival analysis, we also obtained some findings. First, we found that patients with brain metastasis presented the worst OS and CSS in both univariate and multivariate survival analyses. The most common subtype of brain metastasis was NE. Some reports have described the potential relation between NE and brain [27, 28], but the explanation of this phenomenon remains obscure; more basic research is needed to explore the biological mechanisms. The primary site also showed significance in OS and CSS, even in multivariate analysis. Considering the primary site of subtype, we did not include this item in the nomogram because the primary sites of ACC were from the cortex.

To our knowledge, this is the first SEER-based study focusing solely on the hematogenous metastatic pattern of adrenal malignancy patients. Nevertheless, there are several limitations due to the retrospective nature of the study. At first, the database only provides information on synchronous metastasis to bone, brain, liver, and lung from 2010 and the follow-up time is not very long. Compared with metachronous metastasis, the patients of our study was relatively minor. Second, the lack of information regarding treatment regimens or surgery for the included patients might give rise to potential confounders.

Conclusion

In conclusion, heterogeneity exists in the oncological outcomes of patients with site-specific metastasis. Patients with bone metastasis appear to show the best oncologic survival and those with brain metastasis show the worst survival among those with single metastasis. The nomogram may help predict the 1-year, 3-year and 5-year overall survival in patients with primary metastatic adrenal malignancy. Relying on different histological types, there are numerous metastatic features and prognostic values. Knowledge of these differences in metastatic patterns and pathological types may contribute to designing targeted pre-treatment assessment of adrenal malignancy and making a personalized curative intervention. Further efforts are still need to investigate the relationship between more comprehensive factors and adrenal malignancy in the future.

Data Availability

The datasets analyzed during the current study are available in the SEER database, https://seer.cancer.gov/. The SEER database is a publicly available. Application methods can be found at https://seer.cancer.gov/data/access.html. A signed SEER Data-Use Agreement form is required to access the SEER data. Request forms may be accessed at https://seer.cancer.gov/seertrack/data/request. The SEER Program will process the request within 2 business days. We did not have any special access privileges. Any interested researchers can replicate our study by directly obtaining the data from the SEER database and following the protocol in our Methods section after gaining access.

Funding Statement

This study was supported by the Medical Scientific Research Foundation of Zhejiang Province (2018KY019 and 2021KY449).

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PLoS One. doi: 10.1371/journal.pone.0264431.r001

Decision Letter 0

Filomena de Nigris

19 Aug 2021

PONE-D-21-11886

The prognosis of different distant metastases pattern in malignant tumors of the adrenal glands: A population-based retrospective study

PLOS ONE

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Reviewer #1: Dear Editor, Zhang the interesting paper by ..et al the aims to investigate the impact of different 24 distant metastases pattern on the survival of patients with adrenal malignancy.

Major finds comes from the fact that many confounding factors are not evaluated such as tumor size, treatment regime, surgery, grade of tumor, so these events influence the follow up of patient and prognosis.

Another major point is that in lane 169 the authors indicated that site of metastases was an independent prognostic factor (P <0.05) from the table 4 seams that brain metastasis were statistically associated with prognosis

moreover in the presentation of data the authors should better indicate numerically if one condition improves the survival or prognosis . In tables are not indicated how many patients had one or more metastasis reported instead in Kaplan analysis

Minor points

The Ven diagramm needs a color legend

The quality of image is poor

Reviewer #2: The main points that the authors should clarify are the following:

1) what is the percentage of metastatic cancer at the time of diagnosis

2) how many patients have more than one metastasis

3) since it is not clear what the median survival range of subjects presenting metastases to bone versus brain is, the authors should better comment on the Kaplan-Meier analysis and indicate in the text which was the best survival with several metastatic sites

4) in the conclusions section, authors should more clearly describe whether knowledge of these differences in metastatic patterns could help better guide pre-treatment evaluation of cancer and determine interventions with curative intent.

Minor points

1) Authors should submit a figure legend for Figure 1 Figure 1

2) Authors should provide image with higher resolution, since image quality is poor

Reviewer #3: Dear Editor

In the present study, Zhang.et al performed several experiments aimed to prove the impact of different 24 distant metastases pattern on the survival of patients with adrenal malignancy.

The work is well elaborated, and the focus is very interesting. However, I find some parts of the article need to be improved and I have some revisions to add before acceptance. I recommend acceptance after revision.

Major finds

1) The authors should improve the clinical data added the percentage of metastatic cancer at diagnosis.

2) The authors should clarify which is the mean survival of metastases with bone compare to brain

3) The author should improve the comment about the “Kaplan analysis” and highlight which was the best survival with different metastatic sites in the text

4) In the "Conclusion" section the authors should better explain the impact of their work

Minor points

The authors should improve the quality of images

The “Ven diagram” needs a color legend

**********

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Reviewer #1: No

Reviewer #2: Yes: Concetta Schiano

Reviewer #3: No

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PLoS One. 2022 Mar 15;17(3):e0264431. doi: 10.1371/journal.pone.0264431.r002

Author response to Decision Letter 0

4 Sep 2021

Editorial Office,

PLOS ONE September 3rd, 2021

Dear Prof. Filomena de Nigris,

Thank you for your letter and advice regarding the review and revision of our manuscript entitled “The prognosis of different distant metastases pattern in malignant tumors of the adrenal glands: A population-based retrospective study”. The submission ID is PONE-D-21-11886. We have addressed all of the comments raised by the reviewers and have revised the paper accordingly. The amendments are highlighted in the revised manuscript. A point-to-point reply is included as follows. We are grateful to the high appreciations and constructive suggestions on our manuscript from you and three reviewers.

We would like to re-submit the revised manuscript for your consideration. We hope that the revision is acceptable, and we look forward to hearing from you soon.

Best Regards!

Yours sincerely,

Haibin Wei MD, and Da-hong Zhang, M.D.

1. Haibin Wei, Department of Urology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, No. 158, Shangtang Road, Xiacheng District, Hangzhou 310014, Zhejiang, China. Tel. +86 137 7786 0207. Fax: +86 571 85131448. Email address: whb-sysu@163.com.

2. Dahong Zhang, Department of Urology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, No. 158, Shangtang Road, Xiacheng District, Hangzhou 310014, Zhejiang, China. Tel. +86 571 8589 3312. Fax: +86 571 85131448. ORCID: 0000-0002-6934-7956. Email address: zhangdahong88@yeah.net.

We would like to express our sincere gratitude to the reviewers for their constructive and positive comments.

Reviewer #1:

Dear Editor, Zhang the interesting paper by ..et al the aims to investigate the impact of different 24 distant metastases pattern on the survival of patients with adrenal malignancy.

1. Major finds comes from the fact that many confounding factors are not evaluated such as tumor size, treatment regime, surgery, grade of tumor, so these events influence the follow up of patient and prognosis.

Response: The reviewer’s comment is well appreciated. Thank you for the reminder.

We do agree with you that some factors influence the follow up of patient and prognosis, such as tumor size, treatment regime, surgery, grade of tumor.

First, according to your comment, we added the variable “surgery” and defined the variable as the corresponding definition of the SEER database. As for table 2, we added “As for surgery, the distribution of patients was statistically significant except brain metastasis (P < 0.05).” to the corresponding section of the revised manuscript. As for univariate analysis, we added “And patients with surgery had better OS and CSS than those without (P < 0.001).”

Second, we have added new variables like tumor size and grade of tumor in table 1 and table 2 and made the corresponding changes in all relevant section of the manuscript. For table1, we added the corresponding description as “In addition to the grade of unknown, the most common grade was poor differentiated (30.9%).” and “48.3% of patients had tumor size �100mm, but 19.1% had unknown tumor size.” in the revised manuscript.

Third, although “SEER research data, 18 registries, Nov 2019 Sub (2000- 2017)” database has different variables and a larger sample size than other database, some of the data is incomplete, such as pathological grade. For the grade of tumor, the data for 82 % of the adrenal cortical carcinoma and 36.4% of the neuroblastoma were unknown, respectively. So we did not include it in univariate survival analysis to avoid the bias of incomplete data.

Fourth, this study focuses on evaluating prognosis of different distant metastases pattern in adrenal malignancy patients at the first diagnosis. We aimed to provide a better understanding of the prognosis before diverse treatments. Therefore, the other treatment strategies were not included in the study.

Thank you very much for your great comment.

2. Another major point is that in lane 169 the authors indicated that site of metastases was an independent prognostic factor (P <0.05) from the table 4 seams that brain metastasis were statistically associated with prognosis

Response: The reviewer’s comment is well appreciated. Thank you for your reminding. According to your comment, we have changed the sentence into “The parameters, including metastatic site, gender, histology, primary site, residential areas and surgery, were selected in multivariate analysis. As for metastatic site, brain metastasis was still the worst prognostic metastasis both in OS and CSS. The same as the univariate analysis, primary site was an independent prognostic factor for adrenal metastatic cancer patients both in OS and CSS (P < 0.05).” in the revised manuscript.

3. moreover in the presentation of data the authors should better indicate numerically if one condition improves the survival or prognosis.

Response: The reviewer’s comment is well appreciated. Thank you for your valuable advice.

First, we have added a new table titled “Frequencies of combination metastasis and 3, 5-y OS” in the revised manuscript. In this table, the 3, 5-y overall survival and median OS were shown numerically.

Second, in our study, with respect to the surgery, patients (suffering from a single metastasis) underwent the surgery showed the better prognosis for OS and CSS in univariate survival analysis and multivariable survival analysis. We do agree with you that specific digitization may be a good choice if some condition improves the survival or prognosis. This study focuses on prognosis of different distant metastases pattern, not on therapeutic intervention for metastatic adrenal malignancy patients. The optimization of intervention conditions will be an important part of subsequent research.

Thanks for your suggestion.

4. In tables are not indicated how many patients had one or more metastasis reported instead in Kaplan analysis.

Response: The reviewer’s comment is well appreciated. Thank you for your reminding. We have added a new table about the frequency of one or more metastasis.

First, the number of one site, two sites, three sites, and four sites are shown in Table 3, respectively.

Second, according to your comment, we have added “The metastatic pattern of metastatic adrenal malignancy was exhibited in Table 3. Theoretically there were 15 metastatic forms, including 4 single metastases and 11 combinations of metastases. However, there were no relevant cases in this study in two types of metastatic forms, which were brain and liver metastases and brain and liver and lung metastases. We found bone metastasis was the most common metastasis in single metastatic patients (24.08%), followed by liver (15.71%), lung (12.04%) and brain (0.71%). As for two sites, the highest frequency was observed in patients with liver and lung metastases at 10.51% (103/980). Lung metastasis presented better early survival rate in single metastasis. Patients with brain and lung metastases had the worse survival rate than other metastatic types in two sites metastases” in the revised manuscript.

Thank you for your suggestion.

5. Minor points

The Ven diagramm needs a color legend

The quality of image is poor

Response: The reviewer’s comment is well appreciated. We have modified the image according to journal’s requirements. We are grateful to the constructive suggestions on our manuscript from you.

Reviewer #2:

The main points that the authors should clarify are the following:

1. what is the percentage of metastatic cancer at the time of diagnosis.

Response: Thank you very much for your comment. According to your comment, we have added “A total of 2053 eligible patients with primary adrenal malignancy between 2010 and 2017 were identified from SEER database. Among these patients, the metastatic adrenal malignancy accounted for 47.74 %( 980/2053) at the time of diagnosis, including 493 men (50.3%) and 487 women (49.7%). The metastatic information on bone, brain, liver, and lung metastasis was collected in the SEER database." in the revised manuscript.

2. how many patients have more than one metastasis.

Response: The reviewer’s comment is appreciated. We added a new table about the frequency of four single metastases and 9 combinations of metastases. The number of one site, two sites, three sites, and four sites are shown in Table 3, respectively.

3. since it is not clear what the median survival range of subjects presenting metastases to bone versus brain is, the authors should better comment on the Kaplan-Meier analysis and indicate in the text which was the best survival with several metastatic sites

Response: Thank you for your reminding. We have added a new table about the median survival and the frequency of combination metastasis in this manuscript (Table 3). And we added “The metastatic pattern of metastatic adrenal malignancy was exhibited in Table 3. Theoretically there were 15 metastatic forms, including 4 single metastases and 11 combinations of metastases. However, there were no relevant cases in this study in two types of metastatic forms, which were brain and liver metastases and brain and liver and lung metastases. We found bone metastasis was the most common metastasis in single metastatic patients (24.08%), followed by liver (15.71%), lung (12.04%) and brain (0.71%). As for two sites, the highest frequency was observed in patients with liver and lung metastases at 10.51% (103/980). Lung metastasis presented better early survival rate in single metastasis Patients with brain and lung metastases had the worse survival rate than other metastatic types in two sites metastases. In addition, median OS cannot be concluded in only bone metastasis and bone and brain metastases in Kaplan-Meier analysis.” in the revised manuscript.

4. in the conclusions section, authors should more clearly describe whether knowledge of these differences in metastatic patterns could help better guide pre-treatment evaluation of cancer and determine interventions with curative intent.

Response:

The reviewer’s comment is well appreciated. Thank you for your constructive suggestion. We do agree with you that it is very necessary to clearly articulate the significance of metastatic patterns for pre-treatment evaluation and clinical interventions.

First, various prognostic values are associated with different metastatic sites, and knowledge of overall survival is very important for pre-treatment evaluation. According to your comment, we have added “The nomogram may help predict the 1-year, 3-year and 5-year overall survival in patients with primary metastatic adrenal malignancy.” of in the conclusions section of the revised manuscript.

Second, the phenomenon that metastatic neuroblastoma had better oncological survival than metastatic adrenal cortical carcinoma was observed in our study. Therefore, the prognosis of different pathological types is completely different for adrenal malignancy, which may remind us to choose different interventions with curative intent for different pathological types of tumors. According to your comment, we have changed this sentence to “Knowledge of these differences in metastatic patterns and pathological types may contribute to designing targeted pre-treatment assessment of adrenal malignancy and making a personalized curative intervention.” of in the conclusions section of the revised manuscript.

Third, diagnosis and treatment do not equate with equivalent benefit for metastatic adrenal malignancy, and further understanding of outcome of adrenal malignancy, especially metastatic adrenal malignancy, might help make reasonable medical decision and save the unnecessary expend on the advanced tumor. According to your comment, we have added this part in the introduction part due to the limited space in the conclusion part.

Fourth, we believe that pre-treatment evaluation and treatment decision-making is a gradual process, with the deepening of understanding of tumor biological behavior, development of new drugs and inspection methods, and the diversification of treatment methods. Therefore, we hope that subsequent research can help better guide pre-treatment evaluation of cancer and determine interventions with curative intent. According to your comment, we have added “Further efforts are still need to investigate the relationship between more comprehensive factors and adrenal malignancy in the future.” of in the conclusions section of the revised manuscript.

Thank you very much for your great comment.

5. Minor points

1) Authors should submit a figure legend for Figure 1 Figure 1

2) Authors should provide image with higher resolution, since image quality is poor

Response: The reviewer’s comment is well appreciated. We have added the figure legend in Figure1. Meanwhile, we have modified the image and upload the corresponding image. Thank you for your suggestion.

Reviewer #3:

Dear Editor

In the present study, Zhang.et al performed several experiments aimed to prove the impact of different 24 distant metastases pattern on the survival of patients with adrenal malignancy.

Major finds

1. The authors should improve the clinical data added the percentage of metastatic cancer at diagnosis.

Response: Thank you for your reminding. According to your comment, we have added “A total of 2053 eligible patients with primary adrenal malignancy between 2010 and 2017 were identified from SEER database. Among these patients, the metastatic adrenal malignancy accounted for 47.74 %( 980/2053) at the time of diagnosis, including 493 men (50.3%) and 487 women (49.7%). The metastatic information on bone, brain, liver, and lung metastasis was collected in the SEER database.” in the revised manuscript. Thank you for your suggestion.

2. The authors should clarify which is the mean survival of metastases with bone compare to brain

Response: The reviewer’s comment is appreciated. We have added a new table titled “Frequencies of combination metastasis and 3, 5-y OS” in the revised manuscript. In this table, the median survival time of all metastatic forms was presented. Brain metastasis showed worst survival outcomes in single metastasis. Thank you for your suggestion.

3. The author should improve the comment about the “Kaplan analysis” and highlight which was the best survival with different metastatic sites in the text

Response: The reviewer’s comment is well appreciated. We added the new table which clarified the survival rate and median survival. Meanwhile, we added “The metastatic pattern of metastatic adrenal malignancy was exhibited in Table 3. Theoretically there were 15 metastatic forms, including 4 single metastases and 11 combinations of metastases. However, there were no relevant cases in this study in two types of metastatic forms, which were brain and liver metastases and brain and liver and lung metastases. We found bone metastasis was the most common metastasis in single metastatic patients (24.08%), followed by liver (15.71%), lung (12.04%) and brain (0.71%). As for two sites, the highest frequency was observed in patients with liver and lung metastases at 10.51% (103/980). Lung metastasis presented better early survival rate in single metastasis. Patients with brain and lung metastases had the worse survival rate than other metastatic types in two sites metastases. In addition, median OS cannot be concluded in only bone metastasis and bone and brain metastases in Kaplan-Meier analysis.” in the revised manuscript.

Thank you so much for your comment.

4. In the "Conclusion" section the authors should better explain the impact of their work

Response: The reviewer’s comment is well appreciated. Thank you for your constructive suggestion. We do agree with you that it is very necessary to clearly articulate the significance of metastatic patterns for pre-treatment evaluation and clinical interventions.

Thank you very much for your great comment.

5. Minor points

The authors should improve the quality of images

The “Ven diagram” needs a color legend

Response: The reviewer’s comment is well appreciated. We have added the color legend in Figure1. Meanwhile, we have modified the image and upload the corresponding image. We are grateful to the constructive suggestions on our manuscript from you.

Attachment

Submitted filename: Response letter for PLOS ONE .doc

Click here for additional data file.^{(63KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0264431.r003

Decision Letter 1

Filomena de Nigris

5 Nov 2021

PONE-D-21-11886R1

The prognosis of different distant metastases pattern in malignant tumors of the adrenal glands: A population-based retrospective study

PLOS ONE

Dear Dr. Zhang

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Academic Editor

PLOS ONE

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #4: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #1: the authors answered all the questions so for me the work is acceptable.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

Reviewer #4: The authors have greatly improved their manuscript by the recent revisions. My suggestions are very minimal, and are made mostly to increase the rigor and reproducibility of the manuscript.

For all listed p-values (both in the text and in the tables), please provide the hypothesis test method that was used to obtain those values.

For age, it appears that data is reported as median +/- IQR, which is appropriate if the data is not normally distributed or skewed. However, it appears the hypothesis test method used on the age data is a student's t-test which has the assumption that that data is normally distrubted. This is a discrepancy. The authors should check whether the age data is normally distributed. If so, a t-test is appropriate and mean +/- SD should be reported. If the data is not normally distributed, then a Mann Whitney test should be used and median +/- IQR should be reported.

There appear to be some variables that have very small counts (less than 5). It is unclear why a chi-square test was used to analyze these instead of the more appropriate fisher exact test. Please rectify or indicate why the chisquare test is appropriate for all categorical variables, even when the sample size is small.

For Table 2, please indicate what hypothesis test was used to obtain each p-value.

For Table 3, what is the difference between NA & /? Why is median OS unable to be calculated for 2 or more situations?

For the Cox Proportional Hazards models, it would be nice to know why/how the variables were chosen to be included/excluded from the modeling. For instance, there are far more variables reported in Table 1 than used in the Cox modeling. It is unclear why this is so. Please justify.

**********

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Reviewer #1: No

Reviewer #2: Yes: Concetta Schiano

Reviewer #3: Yes: Laura Mosca

Reviewer #4: No

PLoS One. 2022 Mar 15;17(3):e0264431. doi: 10.1371/journal.pone.0264431.r004

Author response to Decision Letter 1

17 Dec 2021

We would like to express our sincere gratitude to the reviewers for their constructive and positive comments. Related images can be found in file labeled "Response letter for PLOS ONE''.

Reviewer #4:

The authors have greatly improved their manuscript by the recent revisions. My suggestions are very minimal, and are made mostly to increase the rigor and reproducibility of the manuscript.

1. For all listed p-values (both in the text and in the tables), please provide the hypothesis test method that was used to obtain those values.

Response: The reviewer’s comment is well appreciated. Thank you for the reminder.

First, we used chi- Square test in table2. Depending on the conditions of use, the p-values we obtained were derived from Pearson's chi-square test as well as Fisher exact test. Pearson’s chi-square test and Fisher’s exact test are tests of categorical variables. Pearson’s chi-square test assumes that the data: 1) are a simple random sample, 2) are of sufficient sample size and 3) are independent of each other. When cells are sparsely populated, considered any cell value is less than 5 with the traditional rules, Fisher’s exact test was employed [PMID: 28295394]. To be more precise, we have added corresponding annotation of different types of statistical methods in table2.

Second, COX regression model was used in table4 and table5. COX regression models can well address the diversity of survival time distributions in survival data, and can better perform censored data. We have used univariate COX regression analysis in table4 and multivariate COX regression analysis in table5.

Third, Kaplan-Meier method is often applied to estimate the probability of survival, and it was used in figure2 and figure3. We analyzed the data with log-rank test, which was considered an appropriate test for survival analysis [PMID: 28962743].

Thank you very much for your great comment.

2. For age, it appears that data is reported as median +/- IQR, which is appropriate if the data is not normally distributed or skewed. However, it appears the hypothesis test method used on the age data is a student's t-test which has the assumption that that data is normally distrubted. This is a discrepancy. The authors should check whether the age data is normally distributed. If so, a t-test is appropriate and mean +/- SD should be reported. If the data is not normally distributed, then a Mann Whitney test should be used and median +/- IQR should be reported.

Response: The reviewer’s comment is well appreciated. Thank you for your reminding.

First, we have checked that the age data is not normally distributed. So we used Mann Whitney test and reported median. You can find the median +/- IQR in Table1.

Second, we also checked the age data was not normally distributed in table 2 and added median +/- IQR for more completeness.

Third, we reviewed our manuscript under your instruction and found the mistake in Method section. For more rigorous, we revised the sentence into “Categorical variables were compared using chisquare tests, and continuous variables were analyzed by the Mann Whitney test for non-normal distribution” in the article.

Thank you for your suggestion.

3. There appear to be some variables that have very small counts (less than 5). It is unclear why a chi-square test was used to analyze these instead of the more appropriate fisher exact test. Please rectify or indicate why the chisquare test is appropriate for all categorical variables, even when the sample size is small.

Response: The reviewer’s comment is well valuable. Thank you for your suggestion.

First, as your comment, fisher exact test were more appropriate for use when one or more cells has a count of less than 5. We have conducted fisher exfact act for those variables actually. For table2, we selected appropriate P value for different variables according to the different conditions. To better illustrate the statistical method from which the P values are taken, we have added the corresponding P-values annotations as a and b in table 2. As for annotation a, the P value was selected from Pearson chi-Square.

Second, we believe that we have been misrepresented our statistical method in this paragraph. In SPSS 25, chi-Square included Pearson chi-Square, likelihood ratio and fisher exact test. We were going to describe chi-Square was used to analyze rather than Pearson chi-Square. To be more precise, we have changed the sentence into “Categorical variables were compared using chisquare tests, and continuous variables were analyzed by the Mann Whitney test for non-normal distribution.” in the article.

Third, take variable primary site for example, the P value was selected from Pearson chi-Square when comparing the patients with bone metastasis and without bone metastasis. As for brain metastasis, the P value was selected from fisher exact test, as shown in the figure below.

Thank you for your reminder.

4. For Table 2, please indicate what hypothesis test was used to obtain each p-value.

Response: The reviewer’s comment is well appreciated. Thank you for your reminding.

In table 2, we aimed to verify that there are differences in patients with metastasis and without metastasis for different variables. We used chi-Square test in table2. Depending on the conditions of use, the p-values we obtained were derived from Pearson's chi-square test as well as Fisher exact test. As shown in QUESTION1.

Take variable gender for example.

First, establishing test hypotheses and determining test levels.H0: the males and females have the same probability of suffering adrenal malignancy with bone metastasis and without bone metastasis,π1=π2.H1: the males and females have different probability of suffering adrenal malignancy with bone metastasis and without bone metastasis, π1≠π2 α=0.05.

Second, calculate the test statistic and obtain the p-value. In this hypothesis test, every cell is more than 5, Pearson Chi-square is reasonable accurate. And we can acquire the P value < 0.001, as shown the figure below.

Third, At the level of α =0.05, reject H0,accept H1, the distribution of gender among the patients with bone metastasis and without bone metastasis was significantly different.

Thank you for your suggestion.

5. For Table 3, what is the difference between NA & /? Why is median OS unable to be calculated for 2 or more situations?

Response: The reviewer’s comment is well appreciated.

First, / was used to indicate that the median OS cannot be calculated due to the absence of related cases. The number of cases of brain and liver metastases and brain and liver and lung metastases were zero. Therefore median OS cannot be calculated

Second, NA was used to present that the median OS unable to display even though the number of related cases were sufficient. The median OS is defined as “the length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that half of the patients in a group of patients diagnosed with the disease are still alive” in NCI's Dictionary, as shown in the figure below.

The median OS of those two group cannot be concluded because more than half of the patients still alive at the end of the follow up. Take the bone metastasis for example, we redrawn the survival curve, as shown in the figure below.

In this figure, we added the survival median line, and the curve of bone metastasis are consistent on the median line. So the median OS cannot be calculated in only bone metastasis and bone and brain metastases.

Third，to better present the difference between the NA & /, we have added corresponding annotations below the table. The annotation showed “the median OS cannot be concluded because more than half of the patients still alive at the end of the follow up” for NA and “the median OS cannot be calculated due to the absence of related cases” for /.

Thank you for your suggestion.

6. For the Cox Proportional Hazards models, it would be nice to know why/how the variables were chosen to be included/excluded from the modeling. For instance, there are far more variables reported in Table 1 than used in the Cox modeling. It is unclear why this is so. Please justify.

Response: Thank you very much for your comment.

This is a very interesting question. We did not present all variables reported in Table 1 but we have verified and included the variables with statistically significant. The variable such as years of diagnosis, laterality, median income were excluded because the p >0.05 and we commonly assumed that these variables are not significantly different. Other variables such as grade were excluded because the category unknown was unreasonably numerous. So we excluded variables that have no significance in the Cox modeling in order to be more concise and precise.

Thank you for your question.

We are grateful to the constructive suggestions on our manuscript from you.

Attachment

Submitted filename: Response letter for PLOS ONE.doc

Click here for additional data file.^{(263KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0264431.r005

Decision Letter 2

Filomena de Nigris

11 Feb 2022

The prognosis of different distant metastases pattern in malignant tumors of the adrenal glands: A population-based retrospective study

PONE-D-21-11886R2

Dear Dr. Zhang

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Filomena de Nigris, M.D., Ph.D.

Academic Editor

PLOS ONE

PLoS One. doi: 10.1371/journal.pone.0264431.r006

Acceptance letter

Filomena de Nigris

4 Mar 2022

PONE-D-21-11886R2

The prognosis of different distant metastases pattern in malignant tumors of the adrenal glands: A population-based retrospective study

Dear Dr. Zhang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Prof. Filomena de Nigris

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Attachment

Submitted filename: Response letter for PLOS ONE .doc

Click here for additional data file.^{(63KB, doc)}

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Data Availability Statement

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PERMALINK

The prognosis of different distant metastases pattern in malignant tumors of the adrenal glands: A population-based retrospective study

Jia Miao

Haibin Wei

Jianxin Cui

Qi Zhang

Feng Liu

Zujie Mao

Dahong Zhang

Roles

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Materials and methods

Data source and patient selection

Statistical analysis

Nomogram construction

Results

Patient demographics and clinical characteristics

Table 1. Demographical characteristics of patients.

Distribution of metastasis pattern

Fig 1. Venn diagram of the distribution of distant metastatic sites.

Table 2. Clinical characteristics and metastasis sites.

Table 3. Frequencies of combination metastasis and 3, 5-y OS.

Metastatic sites and survival outcomes

Fig 2. Kaplan-Meier curves of OS and CSS according to the number of metastatic sites.

Fig 3. Kaplan-Meier curves and log-rank test for OS and CSS according to the site of metastasis (only one site).

Univariate survival analysis

Table 4. Univariate survival analysis predicting overall survival and cancer-specific survival in patients with four single metastases.

Multivariable survival analysis

Table 5. Multivariate survival analysis predicting overall survival and cancer-specific survival in patients with four single metastases.

Nomogram

Fig 4. Nomogram for predicting the 1-year, 3-year and 5-year overall survival in patients with primary metastatic adrenal malignancy.

Discussion

Conclusion

Data Availability

Funding Statement

References

Decision Letter 0

Filomena de Nigris

Roles

Author response to Decision Letter 0

Decision Letter 1

Filomena de Nigris

Roles

Author response to Decision Letter 1

Decision Letter 2

Filomena de Nigris

Roles

Acceptance letter

Filomena de Nigris

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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