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. 2018 May 2;7(6):2307–2318. doi: 10.1002/cam4.1475

Clinicopathological characteristics and survival outcomes in Paget disease: a SEER population‐based study

Yang Zhao 1,2,†, He‐Fen Sun 1,2,†, Meng‐Ting Chen 1,2, Shui‐Ping Gao 1,2, Liang‐Dong Li 1,2, Hong‐lin Jiang 3, Wei Jin 1,2,✉
PMCID: PMC6010794  PMID: 29722170

Abstract

The objective of this study was to investigate the clinicopathological characteristics and survival outcomes of Paget disease (PD), Paget disease concomitant infiltrating duct carcinoma (PD‐IDC), and Paget disease concomitant intraductal carcinoma (PD‐DCIS). We identified 501,631 female patients from 2000 to 2013 in the Surveillance, Epidemiology, and End Results (SEER) database. These identified patients included patients with PD (n = 469), patients with PD‐IDC (n = 1832), and patients with PD‐DCIS (n = 1130) and infiltrating ductal carcinoma (IDC) (n = 498,076). Then, we compared the clinical characteristics of these patients with those who were diagnosed with IDC during the same period. The outcomes of these subtypes of breast carcinoma were different. Based on the overall survival, the patients with PD‐IDC had the worst prognosis (5‐year survival rate = 84.1%). The PD‐DCIS had the best prognosis (5‐year survival rate = 97.5%). Besides, among patients with Paget disease, the one who was married had a better prognosis than who were not. And, according to our research, the marital status was associated with the hormone receptor status in patients with PD‐IDC. Among three subtypes of Paget disease, patients with PD‐IDC had the worst prognosis. Besides, patients who were unmarried had worse outcomes. And the marital status of patients with PD‐IDC is associated with hormone status. The observation underscores the importance of individualized treatment.

Keywords: Infiltrating ductal carcinoma; Paget disease; surveillance, epidemiology, and end results

Introduction

Breast cancer is the most common cancer in women across the world. According to the WHO experts in the world each year, there are revealed from 800,000 up to 1 million new cases of breast cancer 1. Paget disease is a rare form of breast cancer that occurs in the mouth of the excretory ducts of the nipple. This rare abnormality occurs in 0.5–5% of all cases of breast cancer 2. PD is characterized by an ulcerated, ulcerated, crusted, or scaling lesion on the nipple that can extend to the areola 3. Paget's disease of the nipple is characterized by histopathological infiltration of neoplastic cells with glandular features in the epidermal layer of the nipple–areolar complex. The pathologic mechanism of PD is still unclear. However, there are two kinds of explanation of the pathologic origin of the Paget disease epidermotropic and transformation theory 4, 5. The former one considered that the cells came from the underlying ductal tumor and then move along the lactiferous ducts to the nipple. And the other theory suggested that the cells were in situ in the major lactiferous sinuses.

Characterized by malignant crusting or ulceration of the nipple, Paget disease can present in one of three ways. The first one is in conjunction with an underlying invasive cancer. The second one is in conjunction with underlying ductal carcinoma in situ (DCIS). The last one is alone without any underlying invasive breast carcinoma or DCIS 6. The Paget disease can be treated by central lumpectomy with breast conservation. However, the prognosis of the PD is not well. IDC is the most common breast carcinoma subtype during the world. Recent study has suggested that patients with Paget disease conjunction with invasive cancer had worse prognosis 7. Nevertheless, study about all these three kinds of PD is not being researched. And study on relationship between PD and the IDC is rare. Previous study described that Paget disease alone without an underlying cancer is rare, and it presents utmost 8% of patients with Paget disease 8.

Married persons enjoy overall better health and increase life expectancy compared the unmarried (divorced, separated, and never married) 9, 10. Previous studies have indicated a survival advantage for married persons living with cancer 11, 12, 13. And a research found that married men and women with cancer to have a 15% reduced risk of death 14. We compared with unmarried men and women in different subtypes of Paget disease. Besides the different outcomes in unmarried patients, we found the correlation between the marital status and the hormone status and the human epidermal growth factor receptor II, which can guide the individualized treatment in clinic.

Materials and Methods

Ethics statement

We obtained permission to access the SEER research data. The data downloaded from the SEER do not require informed patient consent. Besides, our research was approved by the Ethical Committee and Institutional Review of Fudan University Shanghai Cancer Center (FDUSCC). The methods were performed in accordance with the approved guidelines.

Data source

We examined the data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, which contains the population‐based central cancer registries of 18 geographically defined regions. For this study, we use the November 2014–18 submission.

Patient selection

We use the histopathology codes from the International Classification of Disease for Oncology third edition (ICD‐O‐3) to select female patients. In the ICD‐O‐3, the codes are defined as follows: code 8500 (ductal carcinoma), code 8540 (mammary Paget disease), code 8541 (Paget disease with infiltrating ductal carcinoma), and code 8543 (Paget disease with intraductal carcinoma). According to the ICD‐O‐3, we defined and choose the patients who had the PD (ICD‐O‐3 code 8540/3), PD‐IDC (ICD‐O‐3 code 85413), PD‐DCIS (ICD‐O‐3 code 8543/3), and IDC (ICD‐O‐3 code 8500/3). In this study, women who were diagnosed as all three kinds of PD and ICD between 2000 and 2013 were included (n = 501,631). And these identified patients included patients with PD (n = 469), patients with PD‐IDC (n = 1832), and patients with PD‐DCIS (n = 1130) and infiltrating ductal carcinoma (IDC) (n = 498,076).

Statistical analysis

Overall survival (OS) was measured from the date on which the first‐time definite diagnosis was made until the date of death, the date last known to be alive, or September 2013. Disease‐specific survival (DSS) was measured from the date of diagnosis to the date of death which is associated with breast carcinoma. The National Cancer Institute's SEER*Stat software package (version 6.1.4; built on April 13, 2005) was used to calculate incidence rates. Baseline patient demographic characteristics and tumor information were compared using the Pearson's chi‐square test for categorical variables. Survival curves were plotted according to the Kaplan–Meier method and compared using the log‐rank test in a univariate analysis. Cox regression analysis was performed to compute hazard ratios and 95% confidence intervals (95% CIs) and to evaluate the effects of confounding factors. All the tests were two sided, and P values less than 0.05 were considered statistically significant. All the statistical analyses were performed using SPSS statistical software, version 22.0 (IBM Corp, Armonk, NY).

Results

Clinicopathological characteristics of PD

Overall 447,401 patients who were diagnosed with breast carcinoma were evaluated. We evaluated 447,401 patients with breast cancer. Among these patients, 443,970 were with infiltrating ductal breast carcinoma, 469 were with mammary Paget disease, 1832 were with Paget disease with infiltrating ductal carcinoma, and 1130 were with Paget disease with intraductal carcinoma. The demographics and clinicopathological characteristics of PD, PD‐IDC, and PD‐DCIS were compared with IDC. And the results are summarized in Table 1. Using the Pearson's chi‐square test, for PD and IDC, the significant variables were age (P < 0.001), marital status (P < 0.001), laterality (P < 0.001), tumor size (P < 0.001), lymph node status (P < 0.001), Grade (P < 0.001), AJCC stage (P < 0.001), ER (estrogen receptor) status (P < 0.001), PR (progesterone receptor) status (P < 0.001), HER2 (human epidermal growth factor receptor 2) status (P < 0.001), and whether had radiation treatment (P < 0.001). For PD‐IDC and IDC, the significant characteristics were race (P = 0.011), marital status (P < 0.001), tumor size (P < 0.001), lymph node status (P < 0.001), Grade (P < 0.001), AJCC stage (P < 0.001), ER status (P < 0.001), PR status (P < 0.001), HER2 status (P < 0.001), and whether had radiation treatment (P < 0.001). For PD‐DCIS and IDC, the considerable characteristics were age (P < 0.001), marital status (P < 0.001), tumor size (P < 0.001), Grade (P < 0.001), AJCC stage (P < 0.001), ER status (P < 0.001), PR status (P < 0.001), HER2 status (P < 0.001), and whether had radiation treatment (P < 0.001).

Table 1.

Characteristics of patients with Paget disease and infiltrating duct carcinoma

Clinical characteristics PDN IDCN P‐value PD‐IDCN IDCN P‐value PD‐DCISN IDCN P‐value
Age at diagnosis (years) 18–49 114 158,076 <0.001 665 158,076 0.536 292 159,076 <0.001
50–79 355 285,894 1167 285,894 838 285,894
Race White 393 360,769 0.111 1446 360,769 0.011 948 360,769 0.069
Black 45 41,277 206 41,277 87 41,277
Other 31 41,924 180 41,924 95 41,924
Marital status Married 216 243,680 <0.001 903 243,680 <0.001 561 243,680 <0.001
Not married 204 181,155 856 181,155 529 181,155
Unknown 49 19,134 73 19,134 40 19,134
Laterality Left 237 224,866 <0.001 959 224,866 0.446 614 224,866 0.066
Right 226 218,611 872 218,611 516 218,611
Paired site 6 409 1 409 0 409
Unknown 0 84 0 84 0 84
Tumor size (cm) <2 54 25,463 <0.001 41 25,463 <0.001 20 25,463 <0.001
2.1–5 249 280,120 1098 280,120 672 280,120
>5 9 7136 28 7136 6 7136
Unknown 157 131,251 665 131,251 432 131,251
Lymph node status Negative 158 257,428 <0.001 807 287,428 <0.001 645 257,428 0.539
Positive 311 186,542 1025 186542 485 186,542
Grade I 11 84,295 <0.001 113 84,295 <0.001 17 84,295 <0.001
II 23 176,027 526 176,027 108 176,027
III 41 160,309 1003 160,309 396 160,309
IV 3 5015 44 5015 237 5015
Unknown 391 18,324 146 18,324 372 18,324
AJCC stage 0 83 5 <0.001 4 5 <0.001 160 5 <0.001
I 11 70,594 153 70,594 19 70,594
II 2 42,900 106 42,900 11 42,900
III 4 13,995 95 13,995 3 13,995
IV 3 6346 21 6346 1 6346
Unknown 366 310,130 1453 310,130 936 310,130
ER status Negative 74 92,846 <0.001 769 92,846 <0.001 408 92,846 <0.001
Positive 67 318,298 849 318,298 237 318,298
Borderline 0 701 11 701 1 701
Unknown 328 32,125 203 32,125 484 32,125
PR status Negative 95 136,827 <0.001 983 136,827 <0.001 467 136,827 <0.001
Positive 37 268,719 613 268,719 138 268,719
Borderline 0 2063 11 2063 2 2063
Unknown 337 36,361 225 36,361 523 36,361
HER2 status Negative 7 106,696 <0.001 123 106,696 <0.001 7 106,696 <0.001
Positive 17 21,261 210 21,261 33 21,261
Borderline 0 3124 8 3124 3 3124
Unknown 445 312,889 1491 312,889 1087 312,889
Radiation No 384 215,199 <0.001 1348 215,199 <0.001 918 215,199 <0.001
Yes 67 213,217 435 213,217 191 213,217
Unknown 18 15,554 49 15,554 21 15,554
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AJCC, American Joint Committee on Cancer; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IDC, infiltrating duct carcinoma; PD‐IDC, Paget disease concomitant infiltrating duct carcinoma; PD‐DCIS, Paget disease concomitant intraductal carcinoma, unmarried group included divorced, separated, single (never married), and widowed.

Table 2 presents the distribution of characteristics of women with breast cancer stratified by marital status. For patients with PD, the clinicopathologic characteristics were age at diagnosis (P = 0.002), race (P = 0.027), laterality (P = 0.004), tumor size (P < 0.001), lymph node status (P = 0.001) and radiation situation (P < 0.001). The hormone status did not have statistical significance. However, according to the analyses, patients who were diagnosed with PD‐IDC had different statistical factors. The hormone status had statistical significance—ER status (P = 0.01), PR status (P = 0.006), and HER2 status (P = 0.025). Meanwhile, for patients with PD‐DCIS, the associations were different again. Among the three hormones, only HER2 had statistical significance (P = 0.01). Other characteristics were age (P < 0.001), race (P = 0.012), and AJCC stage (P < 0.001). Be differ from the other two subtypes, the marital status of patients with PD‐DCIS had no significant correction with the radiation status.

Table 2.

The association between clinical characteristics of Paget disease and marital status

Categories Married (n) Unmarried (n) Unknown (n) P‐value
PD
Age at diagnosis (years) 18–49 69 36 9 0.002
50–79 147 168 40
Race White 187 170 36 0.027
Black 16 24 5
Other 13 10 8
Laterality Left 109 113 15 0.004
Right 107 86 33
Paired site 0 5 1
Unknown 0 0 0
Tumor size (cm) <2 16 25 13 <0.001
2.1–5 134 101 14
>5 0 5 4
Unknown 66 73 18
Lymph node status Negative 84 69 5 0.001
Positive 132 135 44
Grade I 6 5 0 0.523
II 10 13 0
III 22 14 5
IV 2 1 0
Unknown 176 171 44
AJCC stage 0 49 28 6 0.177
I 7 3 1
II 0 1 1
III 2 2 0
IV 2 1 0
Unknown 156 169 41
ER status Negative 33 34 7 0.249
Positive 38 26 3
Borderline 145 144 39
Unknown 216 204 49
PR status Negative 48 39 8 0.641
Positive 18 17 2
Borderline 0 0 0
Unknown 150 148 39
HER2 status Negative 4 3 0 0.695
Positive 10 6 1
Borderline 0 0 0
Unknown 202 195 48
Radiation No 174 173 37 <0.001
Yes 36 27 4
Unknown 6 4 8
PD‐IDC
Age at diagnosis (years) 18–49 407 240 18 <0.001
50–79 496 616 55
Race White 740 653 53 <0.001
Black 58 137 11
Other 105 66 9
Laterality Left 481 443 35 0.715
Right 422 412 38
Paired site 0 1 0
Unknown 0 0 0
Tumor size (cm) <2 14 23 4 0.189
2.1–5 553 506 39
>5 14 14 0
Unknown 322 313 30
Lymph node status Negative 407 366 34 0.562
Positive 496 490 39
Grade I 43 67 3 0.169
II 266 236 24
III 498 469 36
IV 25 18 1
Unknown 71 66 9
AJCC stage 0 1 3 0 0.411
I 86 60 7
II 45 58 3
III 49 41 5
IV 13 8 0
Unknown 709 686 58
ER status Negative 397 347 25 0.01
Positive 424 391 34
Borderline 3 8 0
Unknown 79 110 14
PR status Negative 492 456 35 0.006
Positive 314 279 20
Borderline 5 4 2
Unknown 92 117 16
HER2 status Negative 56 63 4 0.025
Positive 114 88 8
Borderline 5 1 2
Unknown 728 704 59
Radiation No 634 660 45 <0.001
Yes 244 174 17
Unknown 16 22 11
Age at diagnosis (years) 18–49 407 240 18 <0.001
50–79 496 616 55
Race White 740 653 53 <0.001
Black 58 137 11
Other 105 66 9
Laterality Left 481 443 35 0.715
Right 422 412 38
Paired site 0 1 0
Unknown 0 0 0
Tumor size (cm) <2 14 23 4 0.189
2.1–5 553 506 39
>5 14 14 0
Unknown 322 313 30
Lymph node status Negative 407 366 34 0.562
Positive 496 490 39
Grade I 43 67 3 0.169
II 266 236 24
III 498 469 36
IV 25 18 1
Unknown 71 66 9
AJCC stage 0 1 3 0 0.411
I 86 60 7
II 45 58 3
III 49 41 5
IV 13 8 0
Unknown 709 686 58
ER status Negative 397 347 25 0.01
Positive 424 391 34
Borderline 3 8 0
Unknown 79 110 14
PR status Negative 492 456 35 0.006
Positive 314 279 20
Borderline 5 4 2
Unknown 92 117 16
HER2 status Negative 56 63 4 0.025
Positive 114 88 8
Borderline 5 1 2
Unknown 728 704 59
Radiation No 634 660 45 <0.001
Yes 244 174 17
Unknown 16 22 11
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AJCC, American Joint Committee on Cancer; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IDC, infiltrating duct carcinoma; PD‐IDC, Paget disease concomitant infiltrating duct carcinoma; PD‐DCIS, Paget disease concomitant intraductal carcinoma, unmarried group included divorced, separated, single (never married), and widowed.

Comparison of survival between three subtypes of Paget disease and IDC

Utilizing the Kaplan–Meier method, we analyzed all these four subtypes (PD, PD‐IDC, PD‐DCIS, and IDC) of mammary carcinoma. On the basis of the OS, the different outcomes of four subtypes of breast carcinoma are shown distinctly in Figure 1. Patients with PD‐DCIS had the best prognosis with a 5‐year OS 83.6%. The one worse than the PD‐DCIS was IDC. The 5‐year OS of patients with IDC was 81.1%. Then, the next one was PD. The 5‐year OS of patients with PD was 72.9%. The one with worst outcomes was PD‐IDC, whose 5‐year OS was 71.4%. Then, we analyzed the cases utilizing the DSS, and the comparison of different kinds of mammary cancer is shown in Figure 2. The patients with PD‐DCIS had the best prognosis with a 5‐year survival rate of 98.2%. The worse one was patients with PD. Its 5‐year survival rate was 92.4%. The survival rate of patients with IDC was 91%. And patients who were diagnosed with PD‐IDC had the worst outcomes. Its 5‐year survival rate was 84.1%. Apparently, the results of the analyses based on the OS and DSS had a little difference. Based on the OS, the results showed that the prognosis of PD was worse than IDC. However, based on the DSS, the outcome of the IDC was worse than PD. Meanwhile, the prognostic indicators can be found during the univariate analysis.

Figure 1.

Figure 1

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According to the ICD‐O‐3, the codes are defined: code 8500 (ductal carcinoma), code 8540 (mammary Paget disease), code 8541 (Paget disease with infiltrating ductal carcinoma), and code 8543 (Paget disease with intraductal carcinoma). Overall survival (OS) was measured from the date on which the first‐time definite diagnosis was made until the date of death, the date last known to be alive, or September 2013.

Figure 2.

Figure 2

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According to the ICD‐O‐3, the codes are defined: code 8500 (ductal carcinoma), code 8540 (mammary Paget disease), code 8541 (Paget disease with infiltrating ductal carcinoma), and code 8543 (Paget disease with intraductal carcinoma). Disease‐specific survival (DSS) was measured from the date of diagnosis to the date of death which is associated with breast carcinoma.

The survival analyses in subtypes of Paget disease

According to the Kaplan–Meier method and compared utilizing the log‐rank test, we analyzed the Paget disease and its indicator which were associated with the prognosis. The results of the analyses are shown in Table 3. For PD, indicators which had significance were age at diagnosis (P < 0.001), marital status (P < 0.001), tumor size (P < 0.001), lymph node status (P < 0.001), and AJCC stage (P < 0.001). For PD‐IDC, the significant indicators were age at diagnosis, marital status, tumor size, lymph node status, Grade, AJCC stage, and ER status. Meanwhile, the significant indicators of PD‐DCIS were age at diagnosis (P < 0.001), marital status (P < 0.001), tumor size (P < 0.001), lymph node status (P < 0.001), AJCC stage (P < 0.001), HER2 status (P < 0.001), and radiation or not (P = 0.007).

Table 3.

Survival analyses–univariate analyses of Paget disease

PD PD‐IDC PD‐DCIS
Variables Category P‐value Variables Category P‐value Variables Category P‐value
Age at diagnosis (years) 18–49 <0.001 Age at diagnosis (years) 18–49 <0.001 Age at diagnosis (years) 18–49 <0.001
50–79 50–79 50–79
Race White 0.052 Race White 0.296 Race White 0.253
Black Black Black
Other Other Other
Marital status Married <0.001 Marital status Married <0.001 Marital status Married <0.001
Not married Not married Not married
Unknown Unknown Unknown
Laterality Left 0.112 Laterality Left 0.561 Laterality Left 0.162
Right Right Right
Paired site Paired site Paired site
Unknown Unknown Unknown
Tumor size (cm) <2 <0.001 Tumor size (cm) <2 <0.001 Tumor size (cm) <2 <0.001
2.1–5 2.1–5 2.1–5
>5 >5 >5
Unknown Unknown Unknown
Lymph node status Negative <0.001 Lymph node status Negative <0.001 Lymph node status Negative <0.001
Positive Positive Positive
Grade I 0.069 Grade I 0.016 Grade I 0.313
II II II
III III III
IV IV IV
Unknown Unknown Unknown
AJCC stage 0 <0.001 AJCC stage 0 <0.001 AJCC stage 0 <0.001
I I I
II II II
III III III
IV IV IV
Unknown Unknown Unknown
ER status Negative 0.954 ER status Negative 0.004 ER status Negative 0.363
Positive Positive Positive
Borderline Borderline Borderline
Unknown Unknown Unknown
PR status Negative 0.758 PR status Negative 0.055 PR status Negative 0.565
Positive Positive Positive
Borderline Borderline Borderline
Unknown Unknown Unknown
HER2 status Negative 0.161 HER2 status Negative 0.348 HER2 status Negative <0.001
Positive Positive Positive
Borderline Borderline Borderline
Unknown Unknown Unknown
Radiation No 0.085 Radiation No 0.077 Radiation No 0.007
Yes Yes Yes
Unknown Unknown Unknown
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AJCC, American Joint Committee on Cancer; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IDC, infiltrating duct carcinoma; PD‐IDC, Paget disease concomitant infiltrating duct carcinoma; PD‐DCIS, Paget disease concomitant intraductal carcinoma, unmarried group included divorced, separated, single (never married), and widowed.

Using Cox regression analysis was performed to compute hazard ratios and 95% confidence intervals. Choosing the variates which were significant in the univariate analyses, the multivariate analysis was performed. And the results are shown in Table 4. For PD, significant indicators of prognosis were age at diagnosis (P = 0.005, HR = 0.449, 95% CI, 0.257–0.787), race (P = 0.014), marital status (P < 0.001), tumor size (P = 0.033), lymph node status (P < 0.001, positive, HR = 0.417, 95% CI, 0.264–0.658), and Grade (P = 0.042). The P‐value of AJCC stage was larger than 0.05 (P = 0.203). For PD‐IDC, variates which had prognostic significance were age at diagnosis (P < 0.001, HR = 0.347, 95% CI, 0.283–0.425), marital status (P < 0.001), tumor size (P < 0.001), lymph node status (P < 0.001, positive, HR = 0.437, 95% CI, 0.366–0.522), Grade (P = 0.049), AJCC stage (P < 0.001), and ER status (P = 0.034, positive, HR = 0.453, 95% CI, 0.195–1.052). The statistic significant indicators of the patients with PD‐DCIS were age at diagnosis (P < 0.001, HR = 0.309, 95% CI, 0.203–0.469), marital status (P < 0.001, not married, HR = 0.504, 95% CI, 0.269–0.945), tumor size (P < 0.001), lymph node status (P < 0.001, positive, HR = 0.546, 95% CI, 0.424–0.704), HER2 status (P = 0.004, positive, HR = 9.502, 95% CI, 2.758–32.734), and radiation or not P = 0.001, yes, HR = 2.183, 95% CI, 0.688–6.922).

Table 4.

Survival analyses–multivariate analyses of Paget disease

Variables Category Hazard ratio 95% Confidence interval P‐value
PD
Age at diagnosis (years) 18–49 1 Referent 0.005
50–79 0.449 0.257–0.787
Race White 1 Referent 0.014
Black 3.772 1.366–10.413
Other 5.495 1756–17.2
Marital status Married 1 Referent <0.001
Not married 0.379 0.214–0.672
Unknown 0.887 0.528–1.491
Tumor size (cm) <2 1 Referent 0.033
2.1–5 1.417 0.806–2.494
>5 0.651 0.429–0.988
Unknown 1.506 0.509–4.454
Lymph node status Negative 1 Referent <0.001
Positive 0.417 0.264–0.658
Grade I 1 Referent 0.042
II 1.065 0.3–2.86
III 2.537 1.239–5.139
IV 0.714 0.313–1.628
Unknown 1.404 0.189–10.436
AJCC stage 0 1 Referent 0.203
I 0.795 0.353–1.793
II 0 0
III 0 0
IV 1.613 0.204–12.763
Unknown 5.224 1.449–18.837
PD‐IDC
Age at diagnosis (years) 18–49 1 Referent <0.001
50–79 0.347 0.283–0.425
Race White 1 Referent 0.77
Black 0.556 0.813–1.47
Other 0.472 0.795–1.643
Marital status Married 1 Referent <0.001
Not married 0.625 0.427–0.914
Unknown 1.053 0.728–1.523
Tumor size (cm) <2 1 Referent <0.001
2.1–5 2.537 1.662–3.873
>5 0.915 0.769–1.088
Unknown 1.255 0.685–2.302
Lymph node status Negative 1 Referent <0.001
Positive 0.437 0.366–0.522
Grade I 1 Referent 0.049
II 0.696 0.439–1.103
III 0.946 0.683–1.311
IV 1.155 0.855–1.561
Unknown 0.855 0.705–2.256
AJCC stage 0 1 Referent <0.001
I 0 0
II 0.548 0.256–1.172
III 0.67 0.329–1.364
IV 1.055 0.632–1.764
Unknown 4.754 2.48–9.112
ER status Negative 1 Referent 0.034
Positive 0.453 0.195–1.052
Borderline 0.438 0.19–1.007
Unknown 1.329 0.373–4.732
PR status Negative 1 Referent 0.212
Positive 2.12 0.931–4.827
Borderline 1.818 0.799–4.138
Unknown 2.477 0.66–9.29
PD‐DCIS
Age at diagnosis (years) 18–49 1 Referent <0.001
50–79 0.309 0.203–0.469
Race White 1 Referent 0.63
Black 1.058 0.619–1.808
Other 1.288 0.67–2.475
Marital status Married 1 Referent <0.001
Not married 0.504 0.269–0.945
Unknown 1.237 0.675–2.266
Tumor size (cm) <2 1 Referent <0.001
2.1–5 4.82 2.351–9.88
>5 1.035 0.772–1.388
Unknown 1.617 0.218–11.983
Lymph node status Negative 1 Referent <0.001
Positive 0.546 0.424–0.704
Grade I 1 Referent 0.332
II 0.35 0.085–1.447
III 0.74 0.457–1.198
IV 0.891 0.663–1.198
Unknown 0.786 0.569–1.088
ER status Negative 1 Referent 0.3
Positive 1.424 0.759–2.672
Borderline 0.922 0.486–1.749
Unknown 0.968 0.23–14.54
PR status Negative 1 Referent 0.898
Positive 0.857 0.467–1.574
Borderline 1.047 0.513–2.134
Unknown 0 0
HER2 status Negative 1 Referent 0.004
Positive 9.502 2.758–32.734
Borderline 0.614 0.084–4.466
Unknown 0 0
Radiation No 1 Referent 0.001
Yes 2.183 0.688–6.922
Unknown 1.096 0.33–3.638
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AJCC, American Joint Committee on Cancer; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IDC, infiltrating duct carcinoma; PD‐IDC, Paget disease concomitant infiltrating duct carcinoma; PD‐DCIS, Paget disease concomitant intraductal carcinoma, unmarried group included divorced, separated, single (never married), and widowed.

The association between Paget disease and patient's marital status

According to the Kaplan–Meier method and compared using the log‐rank test, we analyzed the Paget disease and the marital status. And Figure 3 presents the correlation. For patients with PD (Fig. 3A), the married patients had the best prognosis with a 5‐year OS of 85.6%. The unmarried patients (included single patients who never married, widowed, divorced, and separated patients) had worse outcomes with a 5‐year OS of 65.2%. Patients whose marital status was unknown had the worst diagnosis with a 5‐year OS of 48.7%. And the difference between them had statistical significance (P < 0.001). For patients who were diagnosed with PD‐IDC (Fig. 3B), the married patients had the best prognosis with a 5‐year OS of 78.7%. The next was patients who were unmarried with a 5‐year OS of 64.1%. For this subtype, the patients whose marital status was unknown had the almost similar 5‐year OS of 64.9%. And the difference was statistically significant as well (P < 0.001). For patients with PD‐DCIS (Fig. 3C), the 5‐year OS was 90.8% (married), 76.3% (unmarried), and 76.2% (unknown).

Figure 3.

Figure 3

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According to the Kaplan–Meier method and compared using the log‐rank test, we analyzed the Paget disease and the marital status. (A) The association between marital status and clinical prognosis in patients with PD. (B) The association between marital status and clinical prognosis in patients with PD‐IDC. (C) The association between marital status and clinical prognosis in patients with PD‐DCIS.

Discussion

Previous study had reported that patients who were diagnosed of Paget disease with underlying invasive cancer had poor tumor characteristics 15. A previous research showed that the Paget disease with underlying invasive cancer had tumors with Grade 3 histology 8. In 1881, Thin observed that the nipple lesion contained malignant cells which were correlated to the underlying cancer 16. And this observation suggested the process of intraductal extension of cancer through the major lactiferous sinuses. We call it “pagetoid spread” nowadays. Histologically, Paget cells are large cells with pale, clear cytoplasm. It has enlarged nucleoli located within the epidermis and along the basal layer. The most widely accepted hypothesis to explain the origin of Paget cells is the epidermotropic theory. And this theory considered that Paget cells are derived from an underlying mammary adenocarcinoma 17. Evidence supporting the epidermotropic theory is based on studies showing that Paget disease is associated with an underlying breast carcinoma in most patients 18, 19, 20. Binding of heregulin to its receptor on Paget cells can induce chemotaxis of these breast cancer cells, and the cells eventually migrate into the overlying nipple epidermis 21. It is noteworthy that Paget cells and the underlying associated ductal carcinoma share the same immunohistochemical profile 22 and the same patterns of gene expression.

In allusion to different subtype of Paget disease, we found that the significantly associated indicators were different. Unmarried patients of PD, including those who were widowed, divorced, and never married, were at significantly great risk of existing lymph node metastasis. Meanwhile, for patients of PD‐IDC, we found that the hormone status was related to the human epidermal growth factor receptor II. However, for the patients with PD‐DCIS, only human epidermal growth factor receptor II had statistical significance. The association between marital status and these indicators was significant for every malignancy evaluated. Previous studies have linked marriage to improvements in cardiovascular, endocrine, and immune function, and marriage may be a determinant of the magnitude and presence of this effect 23, 24. Cortisol levels seem to be lower in patients with cancer who have adequate support networks, and diurnal cortisol patterns have been linked with natural killer cell count and survival in patients with cancer25, 26, potentially providing a physiologic basis for the psychologically based data described previously 27. Further investigations on this subject are warranted.

However, the study also had some limitations. The SEER database did not give us enough information about the lymphovascular invasion which can be regarded as the prediction of lymph node metastasis. Besides, the follow‐up of many patients was limited. And the information of systemic therapy of the patients was lack according to the SEER system. Based on the SEER database, the HER2 status was tested from 2010; however, the cases were from 2000 to 2013. Apparently, analyses of the HER2 were limited. And it made us unable to explore the clinical significance of HER2 status. Therefore, our study was limited by lack of some information. Besides, there is potential for misclassification of marital status. We did not take into account changes of marital status which may have occurred during the follow‐up period. And this phenomenon may have influenced our results. Thus, our findings may underestimate the protective effect that marriage has on breast cancer outcome. We defined that the single category contained divorcees, widows, and never married women. However, previous studies had found that there may be some difference among groups of unmarried women. Although the difference existed, the unmarried women fare worse than the married counterparts.

In conclusion, our study showed patients with PD‐IDC have the worst prognosis. Among all these three kinds of Paget disease, unmarried patients had worse outcomes. And the marital status of patients with PD‐IDC is associated with hormone status and HER2 status. The observation underscores the importance of individualized treatment.

Conflict of Interests

The authors declare no conflict of interests.

Acknowledgments

This work was supported by the grant from National Natural Science Foundation of China (81773093, 81472669) and a Municipal Human Resources Development Program for Outstanding Leaders in Medical Disciplines in Shanghai (2017BR028).

Cancer Medicine 2018; 7(6):2307–2318

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