Oral Oncology 87 (2018) 70–76

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Oral Oncology
journal homepage: www.elsevier.com/locate/oraloncology

The existence of early stage oral mucosal melanoma: A 10-year retrospective T

analysis of 170 patients in a single institute
⁎ ⁎
Yunteng Wua,1, Lizheng Wangb,1, Xuhui Maa,1, Wei Guoa, , Guoxin Rena,
a
Dept. of Oral & Maxillofacial – Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National
Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China
b
Department of Oral Pathology, Ninth People’s Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200011, China

A R T I C LE I N FO A B S T R A C T

Keywords: Background: Oral mucosal melanoma (OMM) is an aggressive tumor with an extremely low incidence, and the
Oral current TNM Staging System has classified all OMMs as high stage. However, controversy remains regarding the
Melanoma existence of early stage OMMs.
Invasion level Patients and methods: The clinical and pathological features, treatments and outcomes of 170 OMM patients
TNM Staging
treated in a single institution from January 2007 to July 2017 were retrospectively analyzed. Multivariate
analysis was performed to identify significant prognostic factors for overall survival (OS).
Results: Multivariate analysis identified positive cervical lymph nodes (p < 0.0001), nodular OMMs
(p < 0.0001), ulceration (p = 0.002), and level III or level IV invasion (p < 0.0001) as independent poor
prognostic factors for OS. Nodular OMM patients with a tumor size ≤1 cm had a better outcome than those with
a tumor size > 1 cm (p < 0.0001). Twenty-two patients with superficial invasion had a favorable survival
without the need of adjuvant therapy (postoperative chemotherapy or radiotherapy), and the current TNM
Staging System was not suitable for those patients. Patients with deep invasion were more likely to suffer from
recurrence and distant metastasis.
Conclusions: Tumor size ≤1 cm and OMM in situ, although extremely rare, do exist. It is advisable for AJCC to
consider tumor size ≤1 cm and OMM in situ as the early stage of OMM when updating the new Oral Melanoma
Staging System.

Introduction prevertebral space or mediastinum) [1]. No OMMs are staged as T1 or

Melanoma is a highly aggressive tumor arising from melanocytes
that are found predominantly in epidermis but seldom in oral mucosal
epithelium [1,2]. Oral mucosal melanoma (OMM) is extremely rare,
accounting for < 1% of all melanomas in the United State and about
7.5% in Asians [3,4]. A wide resection is considered the gold standard
for the treatment of OMM; and radiotherapy, chemotherapy and in-
terferon-α therapy are recommended only for high risk patients [5].
The prognosis of OMM is generally poor, with a 5-year overall survival
(OS) of only 12.3–35.3% over the past three decades [6–8]. Because of
their aggressive nature and extremely low incidence, all OMMs are
classified as high stage. Primary tumors are staged as either T3 (mu-
cosal disease), T4a (moderately advanced disease involving deep soft
tissue, cartilage, bone or skin), or T4b (very advanced disease involving
brain, dura, skull base, cranial nerves, masticator space, carotid artery,
T2, and the tumor size is quite large at the time of initial diagnosis in
most OMM patients. However, tumor size ≤1 cm and OMM in situ have
also been reported in a small number of patients [9,10]. Thus, the
staging of OMMs remains a controversial issue.
Our hospital is a leading center for the treatment of OMMs in China
that admits more than 40 new patients with primary OMMs per year.
Importantly, many individuals with suspected OMMs would also visit
our hospital in order to make an early diagnosis, making it possible for
the detection of early-stage OMMs. In this study, we retrospectively
analyzed the clinical features, pathology, treatments and outcomes of
170 T3 OMM patients treated in our hospital from January 2007 to July
2017. In doing so, we aimed to (1) define the clinical and pathological
features of T3 OMMs; (2) determine whether there exist early-stage
OMMs; and (3) identify significant prognostic factors for T3 OMMs.

⁎
Corresponding authors at: 639 Zhi Zao Ju Road, Shanghai, China.
E-mail addresses: guoweicn@yahoo.com (W. Guo), renguoxincn@hotmail.com (G. Ren).
1
Joint first author: These authors contribute equally to this study.

https://doi.org/10.1016/j.oraloncology.2018.10.022
Received 22 August 2018; Received in revised form 15 October 2018; Accepted 17 October 2018
Available online 24 October 2018
1368-8375/ © 2018 Elsevier Ltd. All rights reserved.
Y. Wu et al. Oral Oncology 87 (2018) 70–76

Patients and methods

A total of 170 T3 OMM patients (91 males and 79 females aged

23–79 years at diagnosis, including 114 patients of < 60 years and 56
patients of ≥60 years; mean age, 53 years) treated in the 9th Hospital
of Shanghai Jiaotong University from January 2007 to July 2017 were
retrospectively analyzed. The data collected included gender, age, pri-
mary site, tumor size, tumor type, cervical lymph node (CLN), therapy
mode, and survival time. Patients were excluded if they were above
80 years of age or had tumors arising from lip, amelanotic melanomas,
distant metastasis at diagnosis, or prior radiotherapy. Magnetic re-
sonance imaging (MRI) or computed tomography (CT) was used to
confirm T3 OMM and CLN status and to ensure that the tumor did not
involve deep soft tissue, alveolar bone or palate bone.

Pathology

The primary disease was diagnosed by biopsy, and tumors were Fig. 2. Most tumor cells are above the basement membrane and small cell
immunohistochemically stained for HMB-45, Melan-A and S-100 pro- clusters have invaded into the superficial lamina propria.
teins for diagnosis. All histological stainings were reviewed by pathol-
ogists in the hospital. The ulceration and invasion level that played an
important role in the prognosis of cutaneous melanoma were also
considered in this study [11–13]. The invasion level was determined by
referring to the Clark’s Staging criteria: level I (noninvasive, in situ,
Fig. 1), at which all tumor cells are above the basement membrane;
level II (micro invasive, partial in situ, Fig. 2), at which most tumor cells
are above the basement membrane and small cell clusters have invaded
into the superficial lamina propria; level III (partial invasive, Fig. 3), at
which most tumor cells are above the superficial lamina propria and
small cell clusters have invaded into the lamina propria; and level IV
(invasive, Fig 4), at which many tumor cells have invaded into the la-
mina propria or deep.
Upon the diagnosis of OMMs, radical resection was performed in all
patients for primary lesions with at least 1.0 cm of healthy tissues. Neck
dissection and postoperative chemotherapy or radiotherapy were per-
formed in some patients. Postoperative chemotherapy with DTIC (da-
carbazine injection; Nanjing Pharmaceutical Factory Co. Ltd., Jiangsu,
China) and CDDP (cisplatin injection; Qilu Pharmaceutical Co. Ltd.,
Fig. 3. Most tumor cells are above the superficial lamina propria and small cell
Shandong, China) was repeated every 3 weeks for 2 circles in cN0 pa- clusters have invaded into the lamina propria.
tients and for 4 circles in CLN positive patients, respectively. DTIC was
administered on days 2–5 at a dose of 250 mg/m2, and CDDP was ad-
ministered on day 1 at a dose of 75 mg/m2 (with hydration).

Statistical analysis

Survival was measured from the date of pathological diagnosis, and

Fig. 4. Most tumor cells have invaded into the lamina propria or deep.

patients still alive in July 2017 or lost to follow-up were censored.

Statistical analysis was performed using SAS 9.13. The survival rate was
calculated by the Kaplan-Meier method. The prognostic variables con-
sidered in this study included gender, age, primary site, tumor size,
Fig. 1. OMM in situ with all tumor cells above the basement membrane. tumor type, CLN, ulceration and invasion level. The statistical

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Y. Wu et al. Oral Oncology 87 (2018) 70–76

Table 1 2 patients (1.2%) and soft palate in 1 patient (0.6%), respectively, and
5-year OS of all patients by Prognostic Variables. the log-rank test showed that primary site also did not correlate with
Variable NO. of patients 5-Year OS P prognosis (p = 0.85).
%
Univariate Multivariate
Tumor type was an independent prognostic factor for OMM
Sex 0.48 –
Men 91 38 Clinically, pigmented OMM lesions can be macular or nodular [14].
Women 79 45
Macular melanoma has a smooth and flat surface with overlying mu-
Age 0.53 – cosa; while nodular melanoma is a polypoid, darkly pigmented tumor
< 60 y 114 48
that rarely has a radial growth phase around it. Of the 170 patients
≥60 y 56 40
retrospectively analyzed in this study, 111 patients (65%) had nodular
Primary site 0.85 –
melanomas with poorer prognosis than those with macular melanomas
Palate 69 49
Gum 90 37 (Log-rank = 33.19, p < 0.0001; Fig. 6). The multivariate analysis
Others 11 40 showed that tumor type was an independent prognostic factor for OS.
Tumor size 0.009 0.78
< 4 cm 93 48
Tumor size < 4 cm was not an independent prognostic factor for
≥4cm 77 18
OMM
Tumor type < 0.0001 < 0.0001
Macular 59 78
Nodular 111 22 The longest diameter of OMM was accurately measured. According
to our previous study, the cutoff was set to 4 cm [7]. As expected, pa-
CLN < 0.0001 < 0.0001
Positive 98 23
tients with tumors of < 4 cm in diameter had better outcomes than
Negative 72 67 those with tumors of ≥4 cm in diameter (Log-rank = 6.82, p = 0.009).
Ulceration < 0.0001 0.002
However, the multivariate analysis showed that tumor size was not an
Absent 122 49 independent prognostic factor for OS (p = 0.78).
Present 48 20

Invasive level < 0.0001 < 0.0001

Positive CLN was an independent poor prognostic factor for OMM
Level I or II 22 89
Level III or IV 148 35
A total of 98 patients (58%) had CLN metastases as confirmed by
neck dissection, including 78 patients (46%) at diagnosis and 20 pa-
significance of differences between survival curves was established by tients (12%) after initial radical resection and chemotherapy. Fig. 7
the log-rank test, and multivariate analysis was performed with the Cox showed that the 5-year OS was 23% in positive CLN patients and 67%
proportional hazard model. in cN0 patients, respectively (Log-rank = 24.15, p < 0.0001). Multi-
variate analysis identified positive CLN as an independent poor prog-
nostic factor for OS.
Results

Table 1 showed tumor characteristics of the 170 patients retro-
spectively analyzed in this study. The median follow-up for survivors
was 70 months (range: 6–135 months), and the five-year OS was about
42% (Fig. 5). The log-rank test showed that age did not correlate with
prognosis (p = 0.78). Lesions occurred on hard palate in 69 patients
(41%), gum in 90 patients (53%), buccal in 8 patients (4.7%), tongue in
Ulceration was an independent poor prognostic factor for OMM
Ulceration was found in 48 out of 170 patients (28%), and patients
with ulceration had a poorer outcome than those without ulceration
(Log-rank = 17.83, p < 0.0001; Fig.8). Multivariate analysis identified
ulceration as an independent poor prognostic factor for OS.

Fig. 5. The OS of all patients.

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Y. Wu et al.
Fig. 6. The OS by tumor type.
Invasion level of OMM
Of the 170 OMM patients, level I, level II, level III and level IV
invasion were identified in 6, 16, 25 and 123 patients, with a 5-year OS
of 100%, 86%, 41% and 33%, respectively. The multivariate analysis
showed that level I or level II patients had significantly better survival
than level III or level IV patients (Log-rank = 17.92, p < 0.0001;
Fig. 9). Table 2 showed that of the 22 patients with level I or level II
invasion, only two patients died; one patient had distant metastasis; and
four patients had positive CLN, all of which occurred more than a year
after initial radical resection and chemotherapy. As expected, level I or
level II invasion occurred mostly in patients with macular melanoma
(18/22) and a tumor size < 4 cm (21/22), as shown in Fig. 10. How-
ever, 4 nodular melanoma patients with a tumor size ≤1 cm were
identified to have level I or level II invasion.
Tumor size of nodular OMM
Although tumor size < 4 cm was not an independent prognostic
factor for OMM, nodular OMM patients with a tumor size ≤1 cm
Fig. 7. The OS by CLN status.
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Oral Oncology 87 (2018) 70–76
seemed to have a favorable outcome. Then, we further examined
whether tumor size ≤1 cm was an independent prognostic factor for
nodular OMM. The tumor characteristics of the 111 nodular OMM
patients were shown in Table 3. As expected, patients with a tumor size
≤1 cm (Fig. 11) had a significantly better outcome than those with a
tumor size > 1 cm (Log-rank = 7.89, p = 0.005). The multivariate
analysis showed that tumor size ≤1 cm was an independent prognostic
factor for OS. However, no macular melanoma with a tumor size ≤1 cm
was found.
Treatment for superficial invasion patients
Twenty-two patients were classified as level I or level II invasion, all
of whom received radical resection. These patients were also classified
as T3N0M0 according to the TNM classification, and then 19 patients
received postoperative therapy, including chemotherapy in 16 patients
and radiotherapy in 3 patients. Four nodular OMM patients received
prophylactic neck dissection, all of whom were CLN negative after neck
dissection. The 5-year OS was 100% in patients received adjuvant
therapy and 95% in patients did not receive adjuvant therapy,
Y. Wu et al. Oral Oncology 87 (2018) 70–76

Fig. 8. The OS by ulceration.

respectively (p = 0.62), indicating that adjuvant therapy was not ne- Table 2
cessary for these patients. Characteristics of early invasion patients.
Variable NO. of patients 5-Year OS % P
Treatment failure
CLN 0.26
Positive 4 75
Of the 170 patients, 9 (5%) were lost to follow up and 86 (51%)
Negative 18 94
died. Specifically, 45 died of distant metastasis, and 41 died of local
Tumor type 0.26
recurrence, including oral recurrence (n = 18) and neck recurrence
Macular 18 94
(n = 23). The most common site involved was lung (n = 18), bone Nodular 4 75
(n = 5), liver (n = 4) and brain (n = 4), and 11 patients had more than
Ulceration 0.56
two organs involved. Table 4 showed that patients with level III or level Absent 20 90
IV invasion were more likely to suffer from recurrence or distant me- Present 2 100
tastasis.
Treatment 0.53
Surgery only 3 100
Discussion Surgery with adjuvant therapy 19 87

OMM is one of the most malignant tumors in the head and neck
region. Although the American Joint Committee on Cancer (AJCC) has
classified all OMMs as high stage, controversy remains regarding the
existence of early stage OMMs. Of the 170 OMM patients retro-
spectively analyzed in this study, 11 nodular OMM patients were found
to have a tumor size ≤1 cm, all of whom had a favorable outcome. Our
previous study showed that nodular type was a poor prognostic factor
for OMM [7]. However, a favorable outcome can still be achieved if the
tumor is found in the early stage.

Fig. 9. The OS by invasion level.

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Y. Wu et al. Oral Oncology 87 (2018) 70–76

Table 4
The relationship between invasive level and treatment failure.
Invasive level Level I Level II Level III Level IV

NO. 5 17 25 123
CLN involved rate (NO.) 0 18% (4) 52% (13) 66% (81)
Treatment failure rate (NO.) 0 12% (2) 56% (14) 57% (70)
Die of Recurrence rate (NO.) 0 6% (1) 36% (9) 25% (31)
Distant metastasis rate (NO.) 0 6% (1) 20% (5) 32% (39)
5-year OS 100% 86% 41% 33%

In this study, tumor cells were found to be above the basement

membrane in five patients, which were classified as carcinoma in situ.
Carcinoma in situ has been shown to have favorable outcomes in many
malignant neoplasms, including breast cancer, Bowen’s disease, cer-
vical carcinoma, colon cancer and lung adenocarcinoma [17–21]. In the
Clark’s staging, level I invasion had the best outcome [22]. Although
mucosal melanoma in situ has also been reported in the literature, its
Fig. 10. The gross appearance of a macular OMM in situ.
outcome is unclear due to the rare incidence [23]. In this study, we
found that patients with level I or level II invasion had significantly
Table 3 better survival than patients with level III or level IV invasion.
5-year OS of nodular OMM by Prognostic Variables. Invasion level and ulceration are strongly associated with the out-
Variable NO. of patients P, chi-square come of cutaneous melanoma [24–26]. The eighth edition AJCC Mel-
anoma Staging System classifies nonulcerated melanomas less than
Univariate Multivariate
0.8 mm thick as T1a, and melanomas 0.8–1.0 mm thick regardless of
Tumor size 0.005, 7.89 0.005, 7.97 ulceration status or melanomas less than 0.8 mm thick with ulceration
≤1cm 11 as T1b [27]. We found that OMM patients with early invasion levels
> 1 cm 100 had a low incidence of recurrence and metastasis. In addition, adjuvant
CLN 0.006, 7.59 0.02, 5.45 therapy may be not necessary for OMM in situ, although it is re-
Positive 75 commended according to the staging of the TNM classification. Accu-
Negative 36 rate staging is important to guide optimal treatment strategy and
Ulceration 0.02, 5.73 0.04, 4.30 prognostic assessment, and it can also facilitate centralized cancer
Absent 71 registry reporting and the design, conduct and analysis of clinical trials
Present 40
[27].
Level of invasion 0.01, 6.17 – We argue that the current TNM staging system may not be applic-
I or II 4
able for OMM, and a more accurate staging system is need. The staging
III or IV 107
system of cutaneous melanoma may provide useful guidelines for the
staging of OMM. In this study, we found that invasion level and ul-
ceration were strongly associated with the survival of OMM patients,
and thus it is strongly advised that OMM in situ should be defined as T1
when updating the new Oral Melanoma Staging System. We also re-
commend that tumor size ≤1 cm should be considered in the new Oral
Melanoma Staging System. Unfortunately, the early invasion and
OMMs with a very small tumor size are rare both in our study and the
literature. Anyhow, there is a need for the early diagnosis of such an
aggressive tumor.

Conclusions

OMM is a highly aggressive tumor with an extremely low incidence,

and all of these tumors are classified as high stage in the current TNM
staging system. However, tumor size ≤1 cm and early invasive OMM in
situ, although rare, do exist. It is advisable for AJCC to consider tumor
size ≤1 cm and OMM in situ as the early stage of OMM when updating
the new Oral Melanoma Staging System.
Fig. 11. The gross appearance of a nodular OMM with a tumor size ≤1 cm.
Acknowledgements

Macular OMM is thought to be a favorable type of OMM. In this
study, we found no macular OMM with a tumor size ≤1 cm, indicating
that macular OMM could be associated with a long history of oral
melanin pigmentation. The histogenetic relationship between oral
pigmentation and OMM remains unclear. About 30–37% OMMs are
preceded by oral pigmentation persisting for several months or even
years [15,16], indicating the need for an early treatment or biopsy of
oral melanin pigmentation.
This work was supported by the Project of Science and Technology
Commission of Shanghai Municipality (Grant No. 10410711200 and
08140902100) and the Key Project of Science and Shanghai Health and
Family Planning Commission [No. 20154Y0057].
Disclosure
The authors have declared no conflicts of interest.

75
Y. Wu et al.
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