A proposal for a TNM staging system for extramammary Paget disease: Retrospective analysis of 301 patients with invasive primary tumors

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Highlights

  • TNM staging system for iEMPD has not yet been established.

  • To establish TNM staging system, we retrospectively collected 301 patients with invasive extramammary Paget’s disease.

  • 51 had distant metastasis and 112 had LN metastasis at diagnosis.

  • Distant metastasis, 2 or more lymph node metastases, lymphovascular invasion and tumor thickness over 4 mm correlated with worse survival.

  • We propose a TNM staging system for EMPD using simple factors for classification (distant metastasis, LN metastasis and local tumor status).

  • Each stage had a statistically distinct survival curve.

Abstract

Background

Although extramammary Paget disease (EMPD) usually appears as carcinoma in situ, it sometimes becomes invasive (iEMPD) and fatal. However, a TNM staging system for iEMPD has yet to be established.

Objective

The aim of this study was to establish a TNM staging system for iEMPD.

Methods

We retrospectively collected iEMPD patients treated at 12 institutes in Japan. Factors reported to be associated with survival such as distant metastasis, lymph node (LN) metastasis, and primary tumor status were evaluated using the log-rank test.

Results

We enrolled 301 iEMPD patients, of whom 114 had remote metastases (49 had both distant and LN metastasis; 2, distant metastasis only; and 63, LN metastasis only) and the remaining 187 patients had no remote metastasis. Distant metastasis (M1) showed worse survival (P < 0.00001). In the analysis of the 250 patients without distant metastasis, LN metastasis also showed worse survival (P < 0.00001). Among the patients with LN metastasis, 2 or more LN metastases (N2) showed worse survival than did single LN metastasis (N1, P = 0.02). Lastly, in the analysis of the 187 patients without metastasis, tumor thickness of over 4 mm or lymphovascular invasion showed worse survival (T2, P < 0.05 and P < 0.001, respectively). Patients with neither of these features were defined as T1. From these results, we propose this TNM staging system: stage I, T1N0M0; stage II, T2N0M0; stage IIIa, anyTN1M0; stage IIIb, anyTN2M0; stage IV, anyTanyNM1. Other than stages II and IIIa, each stage had a statistically distinct survival curve.

Conclusion

We propose a TNM staging system for EMPD using simple factors for classification that could provide important prognostic information in managing EMPD. However, accumulation of more patient data and further revision of the system are required.

Introduction

The incidence of extramammary Paget disease (EMPD) is reported to be rare, ranging from 0.1 to 2.4 patients per 1,000,000 person-years [1], [2]. It typically appears as carcinoma in situ and has a favorable prognosis because of the slow development of the disease [3], [4]. However, once it progresses to an invasive tumor, invasive EMPD (iEMPD), it metastasizes mainly through the lymphatic channels and becomes fatal [5], [6], [7]. The proportion of EMPD patients with iEMPD is reported to be low: the invasive form has been reported in only 20% of all EMPD cases [1], [8]. Although the exact numbers are unknown, occurrence of lymph node (LN) and distant metastasis in iEMPD have been reported to be 34% to 61% [6], [7], [9], [10]. In cancer treatment, a TNM staging system is crucial not only for estimating the survival of each patient but also for determining the population at high risk and for discovering new treatment methods. However, owing to the rarity of the disease, accumulation of data on a sufficient number of patients to create a disease-specific TNM staging system for EMPD has thus far not been achieved. In our study, we collected and analyzed data on 301 iEMPD patient from 12 institutes in Japan and propose a new EMPD-specific TNM staging system based on the prognostic analyses.

Section snippets

Patients

We retrospectively collected 350 iEMPD patients treated from 1998 to 2012 at 12 institutes in Japan. We excluded patients with intraepithelial tumors because intraepithelial tumors theoretically have no chance of metastasis or of becoming fatal. The following patient data were collected: demographic features (age and gender at presentation); clinical presentation (presence of nodule, size of the whole lesion, and presence of lymphadenopathy); histopathological findings of the surgical specimen

Results

The summary of this cohort is shown in Table 1. The average age was 72.2 years and the male/female ratio was 3.37, male dominant. The average tumor thickness was 3.7 mm with a median thickness of 1.5 mm. One hundred sixty-five patients (55%) had tumors ≦2 mm in thickness according to Breslow’s classification for melanoma. One hundred sixty-four patients (54%) had level II or III tumors according to Clark’s classification. Lymphovascular invasion, a factor reported to be associated with poor

Discussion

Currently, the staging systems for penile, vaginal, and skin appendage cancers are adopted when reporting iEMPD with stage classifications because no staging classification system for EMPD has been established [10], [13], [14]. However, using another staging system is inappropriate because each such staging system has been established on the basis of data specific to a particular kind of cancer. Although a large number of patient data is required to establish a staging classification system for

Conclusions

We collected and analyzed 301 patients with iEMPD. The factors associated with survival were tumor thickness, lymphovascular invasion, number of LN metastases, and distant metastasis. On the basis of our results, we propose a TNM staging system for iEMPD. In addition, most of the distant metastases occurred after or synchronously with LN metastasis, which raises the possibility that lymphatic spread is the primary event of tumor dissemination. We should continue to accumulate data and revise

Funding source

None.

Conflict of interest

None.

Acknowledgements

We are grateful to Brian K. Purdue and Flaminia Miyamasu for their English revision.

References (19)

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