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A proposal for a TNM staging system for extramammary Paget disease:

Retrospective analysis of 301 patients with invasive primary tumors

Article in Journal of Dermatological Science · June 2016

DOI: 10.1016/j.jdermsci.2016.06.004

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A proposal for a TNM staging system for extramammary Paget disease:

Retrospective analysis of 301 patients with invasive primary tumors
Kuniaki Oharaa,b , Yasuhiro Fujisawac,* , Koji Yoshinoa , Yoshio Kiyoharad,
Takafumi Kadonoe, Yozo Murataf , Hisashi Uharag, Naohito Hattah , Hiroshi Uchii ,
Shigeto Matsushitaj , Tatsuya Takenouchik , Toshihiko Hayashil , Kenichi Yoshimuram ,
Manabu Fujimotoc
a
Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, Japan
b
Toranomon Hospital, Japan
c
University of Tsukuba, Japan
d
Shizuoka Cancer Center, Japan
e
University of Tokyo, Japan
f
Hyogo Cancer Center, Japan
g
University of Shinshu, Japan
h
Toyama Prefectural Central Hospital, Japan
i
University of Kyushu, Japan
j
University of Kagoshima, Japan
k
Niigata Cancer Center Hospital, Japan
l
University of Hokkaido, Japan
m
University of Kanazawa, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Background: Although extramammary Paget disease (EMPD) usually appears as carcinoma in situ, it
Received 5 April 2016 sometimes becomes invasive (iEMPD) and fatal. However, a TNM staging system for iEMPD has yet to be
Received in revised form 12 May 2016 established.
Accepted 2 June 2016
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
Keywords: to be associated with survival such as distant metastasis, lymph node (LN) metastasis, and primary tumor
Extramammary paget disease
status were evaluated using the log-rank test.
Invasive
Prognosis
Results: We enrolled 301 iEMPD patients, of whom 114 had remote metastases (49 had both distant and
Distant metastasis LN metastasis; 2, distant metastasis only; and 63, LN metastasis only) and the remaining 187 patients had
Lymph node metastasis no remote metastasis. Distant metastasis (M1) showed worse survival (P < 0.00001). In the analysis of the
Lymphovascular invasion 250 patients without distant metastasis, LN metastasis also showed worse survival (P < 0.00001). Among
Tumor thickness the patients with LN metastasis, 2 or more LN metastases (N2) showed worse survival than did single LN
TNM staging system 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.
ã 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights
reserved.

Abbreviations: EMPD, extramammary Paget disease; iEMPD, invasive EMPD; LN,
lymph node.
* Corresponding author at: 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
E-mail address: fujisan@md.tsukuba.ac.jp (Y. Fujisawa).
1. 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

http://dx.doi.org/10.1016/j.jdermsci.2016.06.004
0923-1811/ ã 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: K. Ohara, et al., A proposal for a TNM staging system for extramammary Paget disease: Retrospective analysis
of 301 patients with invasive primary tumors, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.06.004
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2 K. Ohara et al. / Journal of Dermatological Science xxx (2016) xxx–xxx
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 [5–7]. 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.
2. Materials and methods
2.1. 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); histopatho-
logical findings of the surgical specimen (tumor thickness, invasion
level, presence of lymphovascular invasion); survival data. Lymph
node status was assessed using the criteria of the Union for
International Cancer Control for cutaneous squamous carcinoma,
and LNs suspected of harboring metastasis were defined as
lymphadenopathy. The data for 301 of the 350 patients were used
for further analysis because we eliminated 38 who had intra-
epithelial carcinoma and 11 who lacked detailed primary tumor
information (Fig. 1). This study was approved by the institutional
review board and conformed to the ethical guidelines of the 1975
Declaration of Helsinki.
Fig. 1. Patients enrolled in this study.
Please cite this article in press as: K. Ohara, et al., A proposal for a TNM staging system for extramammary Paget disease: Retrospective analysis
of 301 patients with invasive primary tumors, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.06.004
2.2. Histologic examination
The resected primary tumors were examined with routine
hematoxylin and eosin (H-E) staining. We classified these 301
patients by depth of invasion and lymphovascular invasion. The
thickness of the primary tumor was determined by measuring the
depth of the deepest invasion from the granular layer. If there was
no granular layer such as mucosa, the thickness was measured
from the border of the horny and the spinous layers. The level of
invasion was graded according to the Clark level of invasion that is
commonly used for melanoma: invasion of the papillary dermis,
level II; invasion throughout the papillary dermis down to and
touching the reticular dermis, level III; invasion of the reticular or
deep dermis, level IV; invasion of the fat layer below the reticular
dermis, level V. Lymphovascular invasion was determined by using
H-E stained specimens.
2.3. Lymph node metastasis
Basically, LN metastasis was determined by using H-E stained
specimens. However, patients with apparent metastasis according
to clinical or imaging studies (computed tomography or ultraso-
nography) were also classified as having LN metastasis.
2.4. Distant metastasis
Distant metastasis was determined by using imaging studies
(chest X-ray, computed tomography, or ultrasonography). LN
metastasis beyond the regional lymphatic basin was also classified
as distant metastasis.
2.5. Follow-up
The patients were monitored by physical examination every
3–6 months, and their survival data including survival length and
cause of death were recorded.
2.6. Statistical analysis
Disease-specific survival was estimated using Kaplan-Meier
curves, and the log-rank test was used to compare the differences
in their disease-specific survival. Probability values less than 0.05
were regarded as significant. All statistical analyses were
performed using Stat Flex version 6.0 (Artech, Osaka, Japan).
2.7. Determination of factors for staging
We evaluated the factors that might be associated with
prognosis, such as distant metastasis, LN metastasis, and primary
tumor status, step by step using the log-rank test (Fig. 1).
3. 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
22 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 inva-
sion, a factor reported to be associated with poor survival, was seen
in 75 patients (25%). Remote metastasis was present in 114
patients; 49 had both distant and LN metastases, 2 had distant
metastasis only, and 63 had LN metastasis only. Among the 112
patients diagnosed as having LN metastasis, 86 of the metastases
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Table 1 had a 5-year survival rate of only 7%, whereas 84% for those
Demographic of 301 enrolled patients in this study.
without metastasis (P < 0.00001, log-rank test). We defined
Age patients with distant metastasis as M1.
Average 72.1
Median 73.0
3.2. LN metastasis
Range 50–94

Sex We classified 250 patients without distant metastasis on the

Male/Female 231/70 basis of the site of the metastasis (unilateral or bilateral regional LN
basins) and the number of affected LNs. As shown in Fig. 3a, the
Primary site
classification by site failed to show significant differences between
Genitalia only 270 (89%)
Genitalia + perianal 20 (7%) bilateral metastasis and unilateral or no metastasis. On the other
Perianal only 5 (1.5%) hand, classification by number of affected LNs showed significant
Axillary only 2 (0.5%) differences (Fig. 3b). Interestingly, no significant difference was
Others 4 (1%)
found between patients with 1 LN metastasis and no LN metastasis
Tumor thickness (mm)
(P = 0.14). From this result, we suggest that the number of
Average 3.7 metastases will predict survival better than the site of LN
Median 1.5 metastasis. We defined patients with 1 LN metastasis as N1, and
those with 2 or more LN metastases, as N2.
Classification by thickness
21 mm 112 (37%)
1<, 22 mm 53 (18%) 3.3. Primary tumor
2<, 24 mm 46 (15%)
4mm< 80 (27%) One hundred eighty-seven patients did not have remote (LN or
Unknown 10 (3%) distant) metastasis. We classified these patients by the thickness of
Classification by invasion level
the tumor, level of invasion, and lymphovascular invasion (Fig. 4a,
II 130 (43%) b, c). Among these, those with tumor thickness greater than 4 mm
III 32 (11%) showed worse survival than did those with tumor thickness equal
IV 82 (27%) to or less than 4 mm (P = 0.032), and those with lymphovascular
V 46 (15%)
invasion (P = 0.022) showed worse survival than did those without.
Unknown 11 (4%)

Lymphovascular invasion
Present 74 (25%)

Remote metastasis
Distant metastasis 51 (17%)
Distant metastasis only 2
With LN metastasis 49
LN metastasis only 63 (21%)

were confirmed pathologically and the remaining 26 were

determined by radiological or clinical examination, or by both.

3.1. Distant metastasis

First, we categorized patients according to distant metastasis.

As shown in Fig. 2, patients with distant metastasis (51 patients)

Fig. 3. Kaplan-Meier survival curves of patients without distant metastasis

classified by the status of lymph node metastasis.
a. Patients were classified by the site of metastasis: unilateral or bilateral lymph
node metastasis.
b. Patients were classified by the number of metastases: 1 lymph node metastasis or
Fig. 2. Kaplan-Meier survival curves of all 301 patients classified by the status of 2 or more lymph node metastases.
distant metastasis. (***: P<0.001).

Please cite this article in press as: K. Ohara, et al., A proposal for a TNM staging system for extramammary Paget disease: Retrospective analysis
of 301 patients with invasive primary tumors, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.06.004
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4 K. Ohara et al. / Journal of Dermatological Science xxx (2016) xxx–xxx

Fig. 4. Kaplan-Meier survival curves of patients without distant or lymph node metastasis classified by the status of the primary tumor.
a. Patients were classified by the status of primary tumor thickness.
b. Patients were classified by the status of primary tumor invasion level.
c. Patients were classified by the status of lymphovascular invasion.
(TT, tumor thickness; v/ly, lymphovascular invasion)
(*: P<0.05, **: P<0.01).

On the other hand, no significant difference was found between
those with Clark’s level V and others (P = 0.11), nor between those
with level IV+V and those with level II+III (P = 0.09). Thus, we
defined patients with a primary tumor greater than 4 mm in
thickness or with lymphovascular invasion as T2, and patients who
did not meet these criteria were defined as T1.
Several previous studies by other investigators indicated that
the perianal location was a sign of poor prognosis [11,12]; however,
in this cohort, no difference was found between the perianal
location and other locations (data not shown).
3.4. Stage classification by TNM status
On the basis of the TNM classification, we attempted to create a
“simple” staging system because of the relatively small number of
patients in the study compared with other common types of

Table 2
TNM and stage classification system for EMPD.

TNM

0 1 2
T Tumor in situ Tumor thickness24 mm AND no lymphovascular invasion Tumor thickness > 4 mm OR lymphovascular
invasion
N No LN metastasis 1 LN metastasis 2 or more LN metastasis
M No distant or LN metastasis beyond regional LN Distant organ metastasis or LN metastasis beyond regional LN (–)
basin basin

Staging
T N M
I 1 0 0
II 2
IIIa Any 1
IIIb 2
IV Any 1

Please cite this article in press as: K. Ohara, et al., A proposal for a TNM staging system for extramammary Paget disease: Retrospective analysis
of 301 patients with invasive primary tumors, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.06.004
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cancer. Basically, we classified patients into 4 stages: patients with
distant metastasis as stage IV, with LN metastasis as stage III, with
an advanced primary tumor as stage II, and with an early primary
tumor as stage I. We divided stage III into IIIa and IIIb according to
the number of LNs affected: 1 LN metastasis as IIIa and 2 or more
LN metastases as IIIb (Table 2, Fig. 5). As shown in the figure, all
groups other than stage II and IIIa separated well with statistical
significance. These 2 groups showed similar survival curves, and
both had statistically distinct survival curves as compared with
stages I and IIIb. These results indicated that stage II and IIIa have a
similar risk of tumor-related death.
3.5. Recurrence
The patterns of recurrence among the patients with localized
disease (stage I+II) and regional disease (IIIa+b) are shown in
Table 3. Almost half of the patients with regional disease
developed recurrence, whereas only 9% of patients with localized
disease did. The mortality rate among the patients who developed
recurrence was similar in both groups (35% and 45%, respectively).
The proportion of distant metastases in all recurrences was 38% (6
of 16) among the patients with localized disease, but 69% (20 of 29)
among those with regional disease (P = 0.04, chi-square test).
4. 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 a certain cancer, there
were only 495 EMPD patients including 82 patients with LN or
distant metastasis during the period between 1973 and 2009 on
the database of Surveillance, Epidemiology, and End Results (SEER)
program data [1]. On the other hand, it has been reported that the
incidence of EMPD is higher among Asians than among whites: 0.9
patients in 100,000 person-years in Whitess [1], but up to 10
patients in 100,000 in Asians [15]. We organized an EMPD study
group in Japan and could accumulate data on 301 EMPD patients
with invasive tumors. Other than the report on 56 iEMPD patients
by Dai et al. [10], most of the previous studies [5,6,8,9,11,13,16,17]
reported on as many as 70% of patients with intraepithelial tumors,
which theoretically have no chance of developing metastasis. To
Fig. 5. Kaplan-Meier survival curves of all 301 patients classified by the proposed
TNM staging system.
(*: P<0.05, **: P<0.01, ***: P<0.001).
Please cite this article in press as: K. Ohara, et al., A proposal for a TNM staging system for extramammary Paget disease: Retrospective analysis
of 301 patients with invasive primary tumors, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.06.004
5
the best of our knowledge, our study contained the largest number
of iEMPD patients reported until now.
In 1993, we [5] proposed a preliminary TNM staging system for
EMPD, which was introduced in the General Rules for Clinical and
Pathological Studies on Malignant Neoplasm of the Skin from the
Japanese Skin Cancer Society [18]. Briefly, primary tumor status is
classified by the depth of invasion and lymphovascular invasion;
LN status is classified by the site of metastasis (unilateral or
bilateral inguinal nodes); distant metastasis is defined as
metastasis in an LN beyond the regional lymphatic basin or in a
distant organ. However, that classification was based on 109 EMPD
patients, of whom only 33 had iEMPD, and it has never been
substantiated by a large set of data.
For nodal metastasis, a report by Hatta et al. [6], a coinvestigator
of the present study, showed that classification by site seemed to
reflect survival. On the other hand, several reports indicated that
the number of affected lymph nodes correlated better with
survival than did the affected site [9,11]. However, these reports
included patients with distant metastasis in the survival analysis,
which made it difficult to interpret the results. Thus, in our
analysis, we analyzed 250 patients without distant metastasis to
see which classification method would reflect survival better. As
shown in Fig. 3a and b, the number of LN metastases could
distinguish survival curves better than could affected sites, leading
us to conclude that the number of affected LNs reflects prognosis
better than does the site of metastasis.
For the primary tumor, in many previous studies the following
factors were shown to be associated with survival: tumor
thickness [11,19], invasion level of the tumor [5,6,9,10], and
lymphovascular invasion [5,9,10,19]. As shown in Fig. 4a and c, our
analysis confirmed that tumor thickness and lymphovascular
invasion were associated with worse survival, whereas level of
invasion was not. We do not have a clear explanation for this
result; however, there was a trend toward worse survival from
level II+III to level IV+V (Fig. 4b, P = 0.09), indicating the possibility
that our study population was not large enough to reach statistical
significance.
Considering the factors evaluated above, we propose the TNM
staging system for EMPD as shown in Table 2. Using our system,
patients could be classified into 5 groups, most showing a distinct
survival curve (Fig. 5). It is noteworthy that patients with stage IIIa
(1 LN metastasis) showed an equivalent survival curve to patients
with stage II (localized disease), indicating that early lymphatic
spread might be controlled by the current surgery-based
treatment. On the other hand, once the tumor spread to 2 or
more LNs, the prognosis was very poor: the 5-year survival rate
dropped to 40%.
This staging system can provide better prognostic information
than those of the currently available systems. For example, the
WHO staging system for skin cancer classifies the primary tumor
by the greatest dimension of the tumor, but several studies have
shown that tumor size did not correlate with prognosis [6,10].
Moreover, the WHO staging system does not consider the number
of LNs affected, meaning it categorizes 1 LN metastasis and
multiple LN metastasis into the same stage.
Several limitations of our study must be acknowledged. First, all
of the data were collected retrospectively. Second, there were only
6 tumor-related deaths (3.2%) among the 187 patients with
localized disease, making it difficult to determine the primary
tumor factors that might be associated with prognosis. Third, the
patient population in this study was solely based on Japanese
patients and needs to be validated using data sets from other
countries. We propose this classification system as a draft that
should be reevaluated and modified. Nevertheless, this classifica-
tion is simple and provides prognostic information that would be
important when considering further treatment, including
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6 K. Ohara et al. / Journal of Dermatological Science xxx (2016) xxx–xxx

Table 3
Pattern of recurrence and outcome.

Pattern of recurrence Localized disease (I + II) n = 187 Regional disease (IIIa + b) n = 63

Local LN Distant n (%) death n (%) death

* 4 (2%) 0/4 4 (6%) 0/4
* 4 (2%) 0/4 4 (6%) 0/4
* 2 (1%) 1/2 10 (16%) 6/10
* * 2 (1%) 1/2 1 (2%) 0/1
* * 0 0 2 (3%) 2/2
* * 3 (2%) 3/3 7 (11%) 5/7
* * * 1 (1%) 1/1 1 (2%) 0/1
Total 16 (9%) 6/16 29 (46%) 13/29

investigative adjuvant treatment. We hope that this classification
will help the planning of clinical trials in the future.
5. 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 our staging
system to enhance its reliability.
Funding source
None.
Conflict of interest
None.
Acknowledgements
We are grateful to Brian K. Purdue and Flaminia Miyamasu for
their English revision.
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Please cite this article in press as: K. Ohara, et al., A proposal for a TNM staging system for extramammary Paget disease: Retrospective analysis
of 301 patients with invasive primary tumors, J Dermatol Sci (2016), http://dx.doi.org/10.1016/j.jdermsci.2016.06.004
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