Journal of Cancer Therapy, 2013, 4, 1283-1289
http://dx.doi.org/10.4236/jct.2013.48151 Published Online October 2013 (http://www.scirp.org/journal/jct)
1283
Nuclear Odontogenic Ameloblast-Associated Protein
(ODAM) Correlates with Melanoma Sentinel
Lymph Node Metastasis
Sagar S. Gandhi1,2, Daniel P. Kestler2,3, Charles T. Bruker4, James M. McLaughlin1,2, Robert E. Heidel2,
Sabina Siddiqui5, James S. Foster2,3, Keith D. Gray1,2, John Bell1,2, Alan Solomon 2,3, James Lewis1,2
1Department of Surgery, University of Tennessee Medical Center-Knoxville, Knoxville, USA; 2Graduate School of Medicine, Uni-
versity of Tennessee Medical Center-Knoxville, Knoxville, USA; 3Department of Medicine, University of Tennessee Medical Cen-
ter-Knoxville , Knoxville, USA; 4Department of Pathology, Boca Raton Regional Hospital, Boca Raton, USA; 5Department of Sur-
gery, University of Michigan School of Medicine, Ann Arbor, USA.
Received August 8th, 2013; revised September 2nd, 2013; accepted September 9th, 2013
Copyright © 2013 Sagar S. Gandhi et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
We have examined primary tumor sections from melanoma patients by immunohistochmistry (IHC) for the presence of
the odontogenic ameloblast-associated protein (ODAM). Within these patient tissues we have observed a correlation of
nuclear ODAM staining in the primary tumors with sentinel lymph node (SLN) metastasis. Surgically, SLN invasion in
melanoma is considered an important indicator of more aggressive, invasive melanoma and to date there are limited
biomarkers which strongly correlate with metastatic disease. The observation that ODAM staining in melanoma associ-
ates with SLN invasion may have important prognostic implications which could assist in the management of mela-
noma. Notably, ODAM expression may correlate with pathway-signaling we have previously reported to be affected by
ectopic ODAM expression in cultured melanoma and breast cancer cell lines.
Keywords: Melanoma; Sentinel Lymph Node Metastases; ODAM; Immunohistochemistry
1. Introduction
Melanoma metastasis is predicted by factors that reflect
biologic behavior such as primary tumor Breslow thick-
ness, mitotic rate, and ulceration [1,2]. Sentinel lymph
node (SLN) status in melanoma remains the single most
important predictor of overall survival [3-5]. In addition,
records from the AJCC Melanoma Staging Database
demonstrate that as Breslow thickness increases, a sig-
nificant decline in both 5- and 10-year survival rates is
observed, and recent data demonstrate a significant cor-
relation between survival and the primary tumor mitotic
rate. Notably, survival rates of patients with an ulcerated
melanoma and similar Breslow thickness are signifi-
cantly worse compared to non-ulcerated matched pri-
mary tumors [2]. Many potential biomarkers for mela-
noma have been reported, but their clinical significance
largely remains undetermined [6]. Molecular factors in-
fluencing primary melanoma growth and metastasis re-
flect dysregulation of normal cellular signaling pathways,
and these factors continue to be intensively investigated,
both with respect to potential therapeutic advances and
for utility as prognostic indicators [7].
ODAM is a protein initially identified as the amyloid-
forming component in a rare dental neoplasm, calcifying
epithelial odontogenic tumor or Pindborg tumor. The
protein has been detected in a broad range of epithelial
tissues and in multiple human cancers including those of
the breast, esophagus, gastric tissues, and bronchial epi-
thelium [8,9]. The potential role of this protein as a
marker of disease status and survival in breast cancer
has been reported as increased nuclear ODAM staining
of primary breast tumors across disease staging [10]. A
portion of patients (up to ~13% in late stage) who were
ODAM-positive exhibited improved survival compared
to stage-matched ODAM-negative breast cancer patients
while the remaining bulk (~87%) of late stage ODAM-
positive tumor patients did not exhibit a survival benefit,
suggesting at least two patients’ outcome groups associ-
ated with ODAM-expressing breast tumors [10]. Based
on previous observations that lymph node-positive breast

Nuclear Odontogenic Ameloblast-Associated Protein (ODAM) Correlates
with Melanoma Sentinel Lymph Node Metastasis
1284
cancer patients are often positive for nuclear ODAM
staining, together with the propensity of melanomas to
metastasize into regional lymph nodes, we examined
ODAM expression in primary tumors and lymph node
biopsies of patients with SLN-positive (Stage III) and
SLN-negative (Stage I-II) melanoma. This allowed us to
test whether nuclear ODAM staining in primary mela-
noma could predict sentinel node positivity. We report
our findings as follows.
2. Materials and Methods
2.1. Melanoma Patient Tumor Tissue
Patients diagnosed with melanoma were identified retro-
spectively through our institutional tumor registry from
years 2000-2006. Only cases with available primary tu-
mor and SLN tissue were evaluated. Histological features
of the primary tumors were recorded for both the SLN-
negative and positive samples, along with overall sur-
vival (OS) and recurrence data obtained from our patient
database. Archived formalin-fixed paraffin embedded tu-
mor tissues were cut and immunostained with murine
monoclonal anti-ODAM antibody 8B4, as previously
reported [10] and detailed below.
2.2. IHC Analysis
Two micrometer thick formalin-fixed paraffin embedded
melanoma sections were mounted on charged slides
(Fisherbrand Superfrost/Plus, Thermo-Fisher), dried over-
night at room temperature, and deparaffinized to water.
Sections were immersed in antigen-retrieval solution
(Biogenex Citra Plus, BioGenex, San Ramon, CA, USA)
and subjected to standard blocking procedures. Anti-
ODAM antibody was applied at 1:7500 in diluent (Dako,
#S-3022), incubated overnight (5˚C), and visualized us-
ing the ImmPRESS polymerized enzyme-linked reporter
system followed by the ImmPACT diaminobenzidine de-
tection kit (Vector Laboratories, Burlingame, CA, USA).
External positive controls were utilized for slide inter-
pretation with each batch of patient tumor-slides while,
benign structures present in each study section served as
internal controls.
Tumor tissue obtained from each block was stained by
hematoxylin-eosin and reviewed in conjunction with im-
munostained slides. The presence or absence of ODAM
immunostaining was determined in the neoplastic cells of
each case and staining was assessed and reported, for the
nucleus only, as negative or positive. Nuclear positivity
was defined by the presence of distinct smooth homoge-
nous staining of at least 50% of tumor cell nuclei, and
negativity was defined as a near complete lack of nuclear
immunostaining in essentially all tumor cells of interest
(less than 1% of nuclei) as in previous studies [10]. This
was based on the observed distribution of nuclear
ODAM staining where positive tumors exhibited staining
in essentially all (greater than 90%) cell nuclei while
staining was present in less than 1% of cell nuclei in tu-
mors designated as ODAM-negative. Thus, tumors with
a percent reactivity between 1% and 90% were rare, and
50% reactivity was chosen as a cutoff to provide a study
design that minimized ambiguity. In practice, no tumors
exhibited reactivity near the 50%-positive cutoff. Stain-
ing for ODAM was graded in blinded fashion by a single
peer reviewed pathologist (CTB).
2.3. Statistics
Descriptive statistics were conducted for the Breslow
thickness, age, gender, and months to follow-up. An in-
dependent samples t-test was used to compare Breslow
values on SLN-positive and SLN-negative groups. In the
event of a violation of a statistical assumption, a non-
parametric Mann-Whitney U test was employed. Unad-
justed odds ratios (OR) with 95% confidence intervals
(CI) were calculated to compare ODAM staining and
SLN status to various discrete variables including recur-
rence, cancer status, and cancer death. Logistic regres-
sion analysis was employed to yield multivariate adjusted
odds ratios when predicting for SLN positivity. Statisti-
cal significance was assumed at a p < 0.05 level and all
analyses were conducted using SPSS Version 19 soft-
ware (SPSS, Chicago, IL).
3. Results
3.1. Patient Sample Populations
Our institutional tumor registry contained 270 cases of
primary melanoma treated from 2000-2006. Complete
data and adequate tissue samples were available for 44 of
these patients (21 SLN-positive patients and 23 SLN-
negative patients). Inadequate tissue samples, incomplete
medical records, non-sentinel lymph node biopsies and
patients who underwent lymphadenectomies were ex-
cluded. All patients had invasive melanoma. Table 1
depicts patient demographics and primary tumor charac-
teristics for each cohort. Demographics were not signifi-
cantly different but was close to significance in regards
to Breslow thickness (p = 0.09). Ulceration was not sig-
nificantly different between cohorts, 13 versus 10 in the
SLN-positive and SLN-negative cohorts, respectively (p
= 0.61).
3.2. ODAM Immunostaining
Immunostaining for ODAM showed that both the nu-
cleus and cytoplasm of benign melanocytes stain strongly
ositive for ODAM, while in melanoma, staining of the p

Nuclear Odontogenic Ameloblast-Associated Protein (ODAM) Correlates
with Melanoma Sentinel Lymph Node Metastasis
1285
Table 1. Melanoma patient characteristicsa.
SLN-NEGATIVE SLN-POSITIVE ODAM-NEGATIVE ODAM-POSITIVE
AGE (Median) 68 (44 - 85) 54 (34 - 75) 68 (34 - 85) 56 (39 - 80)
GENDER (M:F) 10:13 12:9 8:15 14:7
LOCATION
Extremities 14 8 13 9
Trunk 4 9 7 6
Head 5 4 3 6
MEDIAN BRESLOW (Range) 2 mm (0.35 - 7) 3.38 mm (0.32 - 16) 2.48 mm (0.35 - 10) 2.75 mm (0.32 - 16)
ULCERATION PRESENT 10 13 13 10
aCohort Demographics are separated by sentinel lymph node-negative (Stage I/II), sentinel lymph node-positive (Stage III), ODAM-negative, and ODAM-
positive melanoma.
cytoplasm is consistently diminished and nuclear staining
is variable. In ODAM-negative melanoma there is no
nuclear staining of the primary tumor (Figure 1), while
ODAM-positive melanoma exhibits readily demonstrable
staining in the cell nucleus (Figure 2). Primary tumors in
the SLN-positive cohort were significantly more likely to
exhibit nuclear localization of ODAM as recorded in
Table 2. Sixteen of 21 specimens (76%) in the SLN-
positive patients stained for ODAM compared to 5 of 23
(22%) in the SLN-negative patients (Odds Ratio (OR) =
11.52, 95% CI 2.81, 47.23). SLN staining for ODAM
corresponded with the primary tissue staining pattern in
all specimens. No SLN stained positive for ODAM
unless the primary tumor was ODAM-positive as well.
Our study had 13 thin melanomas (≤1 mm), 5 of which
(38%) were ultimately Stage III. Notably, of these five,
four stained positive for ODAM. Also, 4 of 13 thin
melanomas were ulcerated; 1 of these was SLN-negative,
3 were SLN-positive, and ODAM status correlated with
SLN status in all samples from ulcerative tumors.
3.3. Recurrence and Survival Analyses
Median follow-up for the SLN-positive and negative
cohorts was 37 months (range of 7 - 68) and 47 months
(range of 4 - 64), respectively. Four patients were lost to
follow-up, all of which were in the SLN-negative group
(half were ODAM-positive). Logistic regression analysis,
given in Table 3, found that when controlled for Breslow
thickness and ulceration, participants that stained ODAM-
positive were 35 times more likely to be SLN-positive
(OR = 35, 95% CI 4.05 - 302.26). Breslow thickness was
close to showing a significant association (OR 1.48, 95%
CI 0.96 - 2.27, p = 0.077).
As shown in Table 4, disease recurrence developed in
10 of 18 (55.5%) node positive patients and 2 of 22
(9.1%) node negative patients (OR = 12.5, 95% CI 2.23,
70.19). Three patients in the SLN-positive group were
found to have metastatic disease during staging after ini-
tial wide local excision and SLN biopsy and were thus
considered never disease free. Subset analysis of ODAM-
positive patients irrespective of nodal status demon-
strated that 10 of 20 (50%) ODAM-positive patients had
recurrence versus 2 of 20 (10%) in the ODAM-negative
group (OR = 9, 95% CI 1.64, 49.45). Overall survival
(OS) was 10 of 21 (48%) in the SLN-positive group and
18 of 23 (79%) in the SLN-negative group (3.96, 95% CI
1.07, 14.67). OS in the ODAM-positive group was 11 of
21 (52%) versus 17 of 23 (74%) for ODAM-negative
primary tumors (OR = 0.39, 95% CI 0.11, 1.38) as dis-
played in Table 5.
4. Discussion
Our study revealed that SLN-positive primary tumors
(Stage III) were significantly more likely to exhibit nu-
clear ODAM upon IHC staining, and thus suggests that
nuclear ODAM localization is associated with more in-
vasive tumors. Furthermore, 4 of 5 SLN-positive thin
melanomas (<1 mm) were found to be nuclear ODAM-
positive. Since an estimated 5% - 8% of thin melanomas
metastasize to lymph nodes, SLN biopsies are not rou-
tinely performed in these cases [5]. We propose that
preoperative staining of melanoma, and particularly thin
melanoma, for ODAM may guide operative management
and patient treatment.
ODAM is expressed in a broad range of normal epi-
thelial tissues and malignancies [8,9]. During dental de-
velopment the protein is secreted from ameloblasts and
associated with the junctional epithelium at the incisor
enamel interface [11,12]. Late in dental development
ODAM localizes to the ameloblast nucleus and mediates
direct activation of MMP-20/enamelysin gene expression
[13]. Thus, while its roles have not been fully delineated,

Nuclear Odontogenic Ameloblast-Associated Protein (ODAM) Correlates
with Melanoma Sentinel Lymph Node Metastasis
1286
Figure 1. ODAM-negative primary melanoma (stage I). Left:
hematoxylin-eosin stain. Right: anti-ODAM immunostain.
Arrows indicate tumor cell nuclei. Note brown staining of
phagocytic cells with lack of nuclear staining in tumor cells.
Original magnifications 200×.
Figure 2. ODAM-positive primary melanoma (stage III).
Left: hematoxylin-eosin stain (original magnification 100×).
Right: anti-ODAM immunostain (original magnification
200×). The arrows indicate two of numerous ODAM-posi-
tive tumor cell nuclei.
ODAM exhibits potential cell signaling functions both in
the nucleus and through interactions with extracellular
matrix components, suggesting classification of ODAM
as a matricellular protein [12-14]. Proteins of this subset
include the tenascin, osteopontin, thrombospondin, SPARC
(osteonectin), SPARCL1 (Hevin), and CCN proteins.
This class of proteins has been suggested to contribute to
melanoma progression by supporting cellular release from
keratinocyte control [15].
The high degree of cellular organization of normal dif-
ferentiated tissues is often lost in cancer. The detection of
ODAM nuclear localization in melanoma is consistent
with the observation of other proteins, such as activating
transcription factor 2 (ATF2), showing increased local-
ization to the nucleus in metastatic melanoma [16]. Nu-
clear re-localization of forkhead box 03 (FOXO3a), β-
catenin, and a number of other proteins is proving to be a
determining factor in tumor cell growth and invasiveness
associated with a broad range of malignancies including
melanoma [17-19].
As of yet, no singular molecular biomarkers have pro-
ven clinical utility for predicting the progression of mela-
noma to metastasis [20-22]. Previous studies have dis-
cussed biomarkers such as S100B and lactate dehydro-
genase as prognostic indicators for melanomas [6,20-24].
These biomarkers are elevated in advanced disease, and
their presence indicates poor prognosis and diminished
survival. However, they are not routinely used in clinical
practice for early stage disease. Similarly, markers for
lymphatic vessel density have been utilized as predictors
of SLN metastasis, but this requires analysis of multiple
antigens by IHC and a high degree of variability has been
reported [25]. Recent reports have also described two
potential biomarkers for melanoma identified by mono-
clonal antibodies KBAb2 and PNL2 and observed in
over 85% of cases but the associated antigens have not,
to date, been identified [26].
A previous retrospective study of breast cancer tumor
sections at our institution demonstrated a statistically sig-
nificant correlation between the presence of nuclear ODAM
and tumor stage [10]. Our current study also demon-
strates that ODAM expression correlates with melanoma
recurrence, survival, and that Breslow thickness approach-
ed significance when associated with ODAM staining.
These observations underlie recent research in our
laboratory which demonstrated profound growth inhibi-
tion in vitro and in vivo with human breast cancer cells
engineered to express ODAM. This corresponds with
suppression of the PI3K/AKT/mTOR signaling pathway
[27,28]. Notably, melanoma exhibits frequent dysregula-
tion of the PI3K/AKT/mTOR and RAS/RAF/MAPK sig-
naling pathways [7,29,30] and we have observed growth
suppression in vitro and AKT inhibition upon ectopic
ODAM expression in human melanoma cell lines [28].
This suggests potential impacts on tumor cell behavior,
disease progression, and therapeutic outcomes when
ODAM is expressed in these malignancies. Yet, in the
presence of functional, or dysregulated signaling path-
way components, these effects may differ. Our studies
thus serve to highlight the complex interactions between
signaling pathways in melanoma, given that single drug
inhibitors can yield contrary effects on tumor behavior
dependent upon the cellular context [31-34].
Recognizing the complexity of ODAM function with
respect to cellular localization, and the participation of
multiple signaling pathways in driving melanoma growth,
clarification of the role of ODAM expression in mela-
noma biology is necessary both in mechanistic terms, and
as support for any possible clinical utility of staining for
ODAM. The study described herein was of moderate size
and retrospective in nature. Thus, the correlation of ODAM
expression with SLN positivity and overall survival will be
better delineated by analyses comprised of greater sample
size and longer follow-up intervals, which will allow for
increased statistical power in the results. Further, a clear as-
sessment of the association of ODAM with melanoma
spread will also depend on studies which place ODAM ex-
pression in the context of evolving subtype classifications
for melanoma [35] and the associated molecular hallmarks
of these subtypes (e.g.; BRAF V600E, c-KIT, NRAS, cy-
clin D).

Nuclear Odontogenic Ameloblast-Associated Protein (ODAM) Correlates
with Melanoma Sentinel Lymph Node Metastasis
1287
Table 2. Distribution of ODAM staining of primary tumor tissuea.
ODAM-POSITIVE (n = 21) ODAM-NEGATIVE (n = 23) ODDS RATIO/CI
SLN-POSITIVE 16 5
SLN-NEGATIVE 5 18
11.52/95% CI (2.81, 47.23)
aODAM staining of primary tumor tissue for lymph node-positive melanoma (Stage III) and lymph node-negative melanoma (Stage I/II).
Table 3. Logistic regression analysis results for ODAM staining, Breslow thickness values, and ulceration of primary mela-
nomas.
ODDS RATIO 95% CI p-value
ODAM 35 (4.05, 302.3) 0.001
BRESLOW 1.48 (0.96, 2.27) 0.07
ULCERATION 2.08 (0.31, 14.16) 0.46
Table 4. Recurrence rates of melanoma patients subdivided by sentinel ly mph node and ODAM status.
RECURRENCE NO RECURREN CE NEVER DISEASE FREE ODDS, RATIO/CI
SLN-POSITIVE 10 8 3
SLN-NEGATIVE 2 20 1
12.5/95% CI (2.23, 70.19)
ODAM-POSITIVE 10 10 1
ODAM-NEGATIVE 2 18 3
9.0/95% CI (1.64, 49.45)
Table 5. Overall survival of melanoma patients subdivided by sentine l lymph node and ODAM status.
ALIVE MEDIAN FOLLOW-UP (months)ODDS RATIO/CI
SLN-POSITIVE 10 37
SLN-NEGATIVE 18 47
3.96/95% CI (1.07, 14.67)
ODAM-POSITIVE 11 38
ODAM-NEGATIVE 17 46
0.39/95% CI (0.11, 1.38)
5. Conclusion
In summary, our results indicate that nuclear localization
of ODAM in primary melanoma specimens corresponds
with an increased likelihood of SLN metastasis and as
such may have important prognostic implications. Further,
this correlation may foster an understanding of the com-
plex genetics, host-interaction and signaling pathways
involved with both nodal and distant metastases in mela-
noma. Future studies will require analysis of additional
specimens from melanoma or other malignancies exhib-
iting ODAM expression, with an aim of further correlat-
ing ODAM expression with disease characteristics, and
its possible relationship to known regulatory biomarkers.
6. Acknowledgements
This Research was supported in part through grants from
the Susan G. Komen Foundation (DPK) and the Univer-
sity of Tennessee Medical Center Physicians Medical
Education Research Foundation (JL). The authors also
wish to acknowledge Sallie Macy for her efforts towards
the immunohistochemistry studies.
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