2015, Volume 31, Number 2, Page(s) 104-110
Immunohistochemical Characteristics of Cystic Odontogenic Lesions: A Comparative Study
Ayhan ÖZCAN, İbrahim YAVAN, Ömer GÜNHAN
Department of Pathology, Gülhane Military Medical Academy, School of Medicine, ANKARA, TURKEY
Keywords: Odontogenic tumors, Odontogenic cysts, Immunohistochemistry
Cystic ameloblastoma, keratocystic odontogenic tumor,
dentigerous cyst, and radicular cyst are the most commonly
encountered cystic odontogenic lesions. The aim of this study was
to investigate the expressions of survivin, E-cadherin, CD138, and
CD38 in these lesions and their potential diagnostic usage.
Material and Method: A total of 20 cases, consisting 5 radicular
cysts, 5 dentigerous cysts, 5 keratocystic odontogenic tumors and
5 cystic ameloblastomas were included in our series. For all cases,
sections from the selected blocks were stained against the antibodies
for survivin, E-cadherin, CD138, and CD38 on an automated device.
Results: All cystic ameloblastomas and keratocystic odontogenic
tumors showed diffuse and strong nuclear survivin expression.
No specific survivin immunoreactivity was observed in the
dentigerous and radicular cysts. E-cadherin expression was stronger
in all dentigerous cysts and radicular cysts when compared to
others. CD138 expression in stromal cells was prominent in cystic
ameloblastomas, but gradually decreased in the other three lesions.
All cases were negative for CD38.
Conclusion: In the present study, loss of E-cadherin expression in
epithelial cells, strong CD138 expression in stromal cells and strong
nuclear survivin expression both in epithelial and stromal cells in
cystic ameloblastomas and keratocystic odontogenic tumors were the
most remarkable findings. These findings are also reinforced by the
studies suggesting their role in the aggressiveness and pathogenesis
of these tumors.
Cystic ameloblastoma (CA), keratocystic odontogenic
tumor (KCOT), dentigerous cyst (DC), and radicular
cyst (RC) are the most commonly encountered cystic
odontogenic lesions. Among cystic odontogenic lesions,
ameloblastoma and keratocystic odontogenic tumors
(KCOTs) are regarded as benign, but they can be locally
invasive with extensive bone destruction.
Survivin, which is an inhibitor of apoptosis protein (IAP),
is a bifunctional protein that suppresses apoptosis by
inhibiting caspase activation while regulating cell division
and promoting cell proliferation, differentiation, and
angiogenesis at the same time1. Survivin is expressed in
many various human malignancies including hepatocellular
carcinoma, colorectal cancer, lung cancer, pancreatic and
kidney cancers, and osteosarcoma2-7. Survivin plays an
important role both in initiation and progression of these
tumors2-7. Over-expression of survivin is suggested
to be associated with aggressive behavior in KCOTs and
E-cadherin is the major Ca2+ dependent cell adhesion
molecule of epithelial cells and plays a role in morphogenesis
and the maintenance of the integrity of epithelial cells10,11. E-cadherin expression is inversely proportional to
the degree of differentiation in various cancers. Loss of
E-cadherin-mediated cell-cell adhesion is associated with
the progression of many carcinomas including breast,
bladder, gastric, squamous head and neck cancers12-15.
Loss of E-cadherin expression in the epithelium of invasive
squamous cell carcinomas and squamous intraepithelial
lesions of the uterine cervix and skin reduces the density
of Langerhans cells, and thus compromises the capacity of
dendritic cells to recognize tumor antigens16-18.
CD138 and CD38 have been widely used as plasma cells
markers in hematopoetic malignancies19,20. CD138,
also known as syndecan 1, is a transmembrane heparin
sulfate proteoglycan. CD138 (syndecan 1 is a highly
expressed antigen in epithelial cells. However, expressions
of other syndecans, syndecan 2 in mesothelial, endothelial,
neural and fibroblastic cells, syndecan 3 in neural cells, and
syndecan 4 in epithelial and fibroblastic cells, are known
not to be high in epithelial cells. CD138 (syndecan 1) is a
receptor for extracellular matrix proteins such as collagen,
fibronectin and thrombospondin, and participates in cell
proliferation, cell migration, and cell interactions19,20.
CD138 plays a role in the differentiation of B lymphocytes
to plasma cells and is observed in non-neoplastic plasma
cells, neoplastic plasma cells in multiple myeloma, and the
plasmacytic component in lymphoplasmacytic lymphoma20. It is also expressed in many solid tumors including
breast, colon, lung, prostate, and kidney cancers20-23. It modulates cancer cell proliferation and apoptosis, angiogenesis, tumor invasion, and metastasis21. Loss
of CD138 expression is associated with increased invasive
and metastatic potential in carcinomas22. It has been
suggested that CD138 is essential for the maintenance
of epithelial morphology and control of cytoskeletal
organization and its expression has prognostic value in
clinical outcome of ameloblastomas and odontogenic cysts24.
CD38 is a transmembrane molecule and found on the
surface of many immune cells including CD4+, CD8+, and
B lymphocytes, in addition to natural killer cells. CD38 also
functions in cell adhesion, signal transduction and calciumdependent
cell signaling pathways25,26.
The differential diagnosis in odontogenic cystic lesions and
the understanding of their pathogenesis are essential for their
accurate diagnosis and the determination of appropriate
treatment modalities. Although there are several studies
related to role of these proteins in odontogenic lesions
in English literatüre8,9,18,24,27-29, no comparative
and comprehensive study, in which the expression of these
proteins or adhesion molecules in odontogenic cystic
lesions have been evaluated, to our knowledge. Therefore,
we aim to evaluate the immunohistochemical expressions
of CD138 (syndecan-1), CD38, E-cadherin and survivin
in these cystic odontogenic lesions and investigate the
potential implications of their expressions among these
A total of 20 cases consisting 5 radicular cysts (RCs),
5 dentigerous cysts (DCs), 5 keratocystic odontogenic
tumors (KCOTs) and 5 cystic ameloblastomas (CAs)
were included in this study. For all cases, sections from
the selected blocks were stained against the antibodies for
survivin (Neomarkers, Labvision, Ab-2, clone 4F7, 1/100
dilution, avidin-biotin-peroxidase), E-cadherin (Dako,
Clone NCH-38, 1/100 dilution, avidin-biotin-peroxidase),
CD138 (Cell Marqoue, clone B-A38, 1/100 dilution, avidinbiotin-
peroxidase), and CD38 (Novocastra, clone NCLCD38-
290, 1/100 dilution, avidin-biotin-peroxidase) on an
automated device (Ventana, Benchmark XT). The staining
intensity was graded and recorded semi-quantitatively as 0
(no staining), 1+ (weak), 2+ (moderate) and 3+ (strong).
All staining scores were summarized in Table I
The features of survivin expression in the cystic odontogenic
lesions: All CAs (Figure 1A,B) and KCOTs (Figure 1C,D)
showed diffuse and strong nuclear survivin expression in
all epithelial and stromal cells with some weak cytoplasmic
staining, as well. Epithelial staining in these cases was
strongest in basal cell layer. In contrast, weak cytoplasmic
and nuclear staining in all epithelial layers with basal cell accentuation, and weak cytoplasmic and nuclear staining
in the stromal cells were seen in all DCs (Figure 1E,F) and
RCs (Figure 1G,H).
Click Here to Zoom
|Figure 1: The pattern of survivin expression in neoplastic and non-neoplastic odontogenic cystic lesions: A) H&E stained section of CA.
B) Strong nuclear and weak cytoplasmic survivin expression in all epithelial cell layers with suprabasal accentuation and all stromal cells
in CA. C) H&E stained section of KCOT. D) The staining pattern of survivin in KCOT is similar to CA. E) H&E stained section of DC.
F) Weak nuclear and cytoplasmic staining in all epithelial layers with basal cell accentuation, and weak cytoplasmic and nuclear staining
in the stromal cells in DC compared CA and KCOT. G) H&E stained section of RC. H) The staining pattern of survivin in RC is similar
to DC (H&E, and immunohistochemical stains; x100 for A-C, G, H panels; x200 for D and E panels).
The features of E-cadherin expression in the cystic odontogenic
lesions: E-cadherin expression was stronger in all DCs
(Figure 2A,B) and RCs (Figure 2C,D) when compared to
CAs (Figure 2E,F) and KCOTs (Figure 2G,H). E-cadherin
was strongly and equally expressed in all epithelial layers
of DCs and RCs. Its expression was strong and only
localized in basal and suprabasal cells of KCOTs excluding
parakeratotic cells. Weak (1+) E-cadherin expression with
suprabasal accentuation (2+) was seen in all lining layer
cells of CAs. E-cadherin in stromal cells was recorded as
negative in all cases (Table I).
Click Here to Zoom
|Figure 2: The pattern of E-cadherin expression in neoplastic and non-neoplastic odontogenic cystic lesions: A) H&E stained section of
DC. B) A strong E-cadherin expression in all epithelial cell layers in DC. C) H&E stained section of RC. D) E-cadherin expression in RC
is similar to DC. E) H&E stained section of CA. F) A weak E-cadherin expression in all epithelial cell layers with suprabasal accentuation
in CA. G) H&E stained section of KCOT. H) E-cadherin expression in KCOT is similar to CA. No E-cadherin expression in stromal cells
in the all cases (H&E and immunohistochemical stains; x100 for E-H panels; x200 for A-D panels).
The features of CD138 (syndecan-1) and CD38 expressions in
the cystic odontogenic lesions: Cytoplasmic CD138 expression
in stromal cells was the most striking finding in CAs (Figure
3A,B), but it gradually decreased in DCs (Figure 3C,D),
KCOTs (Figure 3E,F) and RCs (Figure 3G,H), respectively.
Membranous CD138 expression with basal cell accentuation
was seen in all epithelial layers of CAs, DCs and RCs, whereas
it was only detected in basal and suprabasal cells of KCOTs.
CD 38 was negative in all cases.
Click Here to Zoom
|Figure 3: The pattern of CD138 (syndecan 1) expression in neoplastic and non-neoplastic odontogenic cystic lesions: A) H&E stained
section of CA. B) Strong cytoplasmic CD138 expression in stromal cells in CA. C) H&E stained section of DC. D) Strong membranous
CD138 expression in epithelial cells in DC. The cytoplasmic CD138 expression in the stromal cells in DC is weaker compared CA.
E) H&E stained section of KCOT. F) Strong membranous CD138 expression in only basal and suprabasal cells, and weak cytoplasmic
CD138 staining in stromal cell in KCOT. G) H&E stained section of RC. H) Strong membranous CD138 expression in all epithelial cells
with basal cell accentuation, and weak cytoplasmic CD138 staining in stromal cell in RC (H&E and immunohistochemical stains; x100
for C-H panels; x200 for A and B panels).
Dentigerous cyst (DC) and radicular cyst (RC) are
nonneoplastic odontogenic lesions, whereas cystic
ameloblastoma (CA) and keratocystic odontogenic tumors
(KCOTs) are benign neoplastic odontogenic lesions and
they may become locally invasive lesions with extensive
Recently, some studies demonstrated that over-expression of
survivin is associated with the more aggressive and invasive
phenotype of oral squamous cell carcinoma30,31. In
the study of Kumamoto and Ooya8, over-expression of
survivin was demonstrated in ameloblastomas, and usually
detected in many peripheral columnar or cuboidal cells and
some central polyhedral cells. Andric et al. demonstrated
that nuclear survivin expression was usually evident in
basal layer cells of lining epithelial cells of KCOTs and
entire epithelial layer was uniformly stained in some cases9. They also documented that there was no or only weak
survivin staining in radicular or apical cysts. Our results
were concordant with the results of both studies. However,
there was no information regarding survivin expression in
stromal cells in them. Presented study also revealed that
strong cytoplasmic and nuclear survivin staining in stromal
cells was in CAs and KCOTs, but weak staining in DCs
and RCs. In the article of de Oliveira et al.27, survivin
staining patterns in DCs and KCOTs is also similar to our
observations. Furthermore, some authors hypothesized
that cytoplasmic survivin expression is responsible for
poor prognosis and for the resistance to therapy in oral
squamous cell carcinoma31. Although effects of nuclear
vs. cytoplasmic expression of survivin are still ambiguous,
some investigators have reported that predominantly
nuclear survivin over-expression is a negative prognostic
factor in oropharyngeal squamous cell carcinomas32. We
observed both nuclear and cytoplasmic survivin expression
in all cases in varying proportion.
Some authors suggested that loss of E-cadherin expression
in neoplastic odontogenic cysts such as CAs and KCOTs
reduces the density of Langerhans cells and thus compromises the capacity of dendritic cells to recognize
tumor antigens16-18. Our study revealed that E-cadherin
expression was stronger in non-neoplastic odontogenic
cysts (DCs and RCs) rather than neoplastic odontogenic
cysts (CAs and KCOTs). These findings support this theory
and are similar to the data of previous studies.
Some authors reported that loss of CD138 (syndecan 1)
expression in epithelial cells is associated with increased
invasive and metastatic potential in some cancers22,28.
Recently, Bologno-Malina et al. demonstrated that solid/
multicystic ameloblastomas had more aggressive biological
behavior than the unicystic ameloblastomas28. In our
series, all ameloblastomas were unicystic. In the study
of Nadalin et al.29, CD138 expression was detected in all epithelial layers of KCOTs, RCs and DCs. Our results
were similar to the findings of previous studies, but we also
observed CD138 expression in the stromal cells. CD138
is normally expressed in the epithelial cells and some
mesenchymal cells such as plasma cells and immature
B lymphocytes. However, it has been demonstrated that
CD138 is expressed by the stromal cells in the some
neoplastic and non-neoplastic odontogenic lesions
(ameloblastoma, KCOT and DC), and ovarian cancers, as
well as plasma cells24,33. It has also been stated that
the expression of CD138 is associated with poor prognosis24,33. CD138 (syndecan 1) shifting from epithelium to
stroma was reported in invasive non-odontogenic solid
tumors including breast, prostate, lung, and colon cancers21. Al-Otaibi et al. showed that CD138 expression was present in the stromal cells of ameloblastoma, KCOT and
DC24. A role of CD138 expression in the stromal cells and
extracellular matrix can be hypothesized as a critical factor
for tumorigenesis and local invasiveness of ameloblastomas24. We also observed CD138 expression in the stromal
cell in all cases, especially pronounced in CAs.
Although CD38 has a wider spectrum of B-cell staining
than does CD138, there is no expression in neoplastic or
non-neoplastic epithelial cells like CD138.
1- A weak E-cadherin expression in epithelial cells, strong
CD138 expression in stromal cells, and strong nuclear
survivin expressions both in epithelial and stromal cells
are characteristic features for CAs and KCOTs.
2- In contrast, a strong E-cadherin expression in epithelial
cells, weak CD138 expression in stromal cells, and weak
nuclear survivin expressions both in epithelial and
stromal cells are characteristic features for DCs and RCs.
3- Although stromal cells in all cases are expressed
CD138 and survivin in varying rates, E-cadherin is not
expressed by stromal cells in all cases.
4- CD38 is negative in all cases and is not a useful marker
in cystic odontogenic lesions.
An immunohistochemical panel consisting of survivin,
E-cadherin, and CD138 excluding CD38 antibody may be
useful in the diagnosis of cystic odontogenic lesions. These
findings are also reinforced by the studies suggesting their
role in the aggressiveness and pathogenesis of these tumors.
1) Altieri DC. Survivin, versatile modulation of cell division and
apoptosis in cancer. Oncogene. 2003;22:8581-9.
2) Chau GY, Lee AF, Tsay SH, Ke YR, Kao HL, Wong FH, Tsou AP,
Chau YP. Clinicopathological significance of survivin expression
in patients with hepatocellular carcinoma. Histopathology.
3) Chen WC, Liu Q, Fu JX, Kang SY. Expression of survivin and
its significance in colorectal cancer. World J Gastroenterol.
4) Falleni M, Pellegrini C, Marchetti A, Oprandi B, Buttitta F, Barassi
F, Santambrogio L, Coggi G, Bosari S. Survivin gene expression in
early-stage non-small cell lung cancer. J Pathol. 2003;200:620-6.
5) Osaka E, Suzuki T, Osaka S, Yoshida Y, Sugita H, Asami S,
Tabata K, Hemmi A, Sugitani M, Nemoto N, Ryu J. Survivin as
a prognostic factor for osteosarcoma patients. Acta Histochem
6) Sarela AI, Verbeke CS, Ramsdale J, Davies CL, Markham AF,
Guillou PJ. Expression of survivin, a novel inhibitor of apoptosis
and cell cycle regulatory protein, in pancreatic adenocarcinoma.
Br J Cancer. 2002;86:886–92.
7) Zamparese R, Pannone G, Santoro A, Lo Muzio L, Corsi F,
Pedicillo MC, Scillitani EL, Tortorella S, Staibano S, Piscuoglio S,
Lo Russo L, Bufo P. Survivin expression in renal cell carcinoma.
Cancer Invest. 2008;26:929-35.
8) Kumamoto H, Ooya K. Expression of survivin and X chromosomelinked
inhibitor of apoptosis protein in ameloblastomas. Virchows
9) Andric M, Dozic B, Popovic B, Stefanovic D, Basta-Jovanovic G,
Djogo N, Andjus P, Milasin J. Survivin expression in odontogenic
keratocysts and correlation with cytomegalovirus infection. Oral
10) Tang A, Amagai M, Granger LG, Stanley JR, Udey MC. Adhesion
of epidermal Langerhans cells to keratinocytes mediated by
E-cadherin. Nature. 1993;361:82-5.
11) Kohl K, Klein E, Koch S, Schnautz S, Bieber T. Migration and
differentiation of Langerhans cell precursors. Eur J Cell Biol.
12) Gabbert HE, Mueller W, Schneiders A, Meier S, Moll R, Birchmeier
W, Hommel G. Prognostic value of E-cadherin expression in 413
gastric carcinomas. Int J Cancer. 1996;69:184-9.
13) Lipponen P, Saarelainen E, Ji H, Aaltomaa S, Syrjänen K.
Expression of E-cadherin (E-CD) as related to other prognostic
factors and survival in breast cancer. J Pathol. 1994;174:101-9.
14) Bringuier PP, Umbas R, Schaafsma HE, Karthaus HF, Debruyne
FM, Schalken JA. Decreased E-cadherin immunoreactivity
correlates with poor survival in patients with bladder tumors.
Cancer Res. 1993;53:3241-5.
15) Mattijssen V, Peters HM, Schalkwijk L, Manni JJ, van ‘t Hof-
Grootenboer B, de Mulder PH, Ruiter DJ. E-cadherin expression
in head and neck squamous-cell carcinoma is associated with
clinical outcome. Int J Cancer. 1993;55:580-5.
16) Hubert P, Bousarghin L, Greimers R, Franzen-Detrooz E, Boniver
J, Delvenne P. Production of large numbers of Langerhans' cells
with intraepithelial migration ability in vitro. Exp Dermatol.
17) Galan A, Ko CJ. Langerhans cells in squamous cell carcinoma vs.
pseudoepitheliomatous hyperplasia of the skin. J Cutan Pathol.
18) Mello LA, Figueiredo AL, Ramos EA, Gurgel CA, Martins MD,
de Figueiredo CR, Cury PR, de Albuquerque Júnior RL, Ramalho
LM, Santos JN. CD1a-positive Langerhans cells and their
relationship with E-cadherin in ameloblastomas and keratocystic
odontogenic tumors. J Oral Pathol Med. 2013;42:454-61.
19) Chu PG, Arber DA, Weiss LM. Expression of T/NK-cell and
plasma cell antigens in nonhematopoietic epithelioid neoplasms.
An immunohistochemical study of 447cases. Am J Clin Pathol.
20) O'Connell FP, Pinkus JL, Pinkus GS. CD138 (syndecan-1), a plasma
cell marker immunohistochemical profile in hematopoietic and
nonhematopoietic neoplasms. Am J Clin Pathol. 2004;121:254-63.
21) Mennerich D, Vogel A, Klaman I, Dahl E, Lichtner RB, Rosenthal
A, Pohlenz HD, Thierauch KH, Sommer A. Shift of syndecan-1
expression from epithelial to stromal cells during progression of
solid tumours. Eur J Cancer. 2004;40:1373-82.
22) Gökden N, Greene GF, Bayer-Garner IB, Spencer HJ, Sanderson
RD, Gökden M. Expression of CD138 (Syndecan-1) in renal
cell carcinoma is reduced with increasing nuclear grade. Appl
Immunohistochem Mol Morphol. 2006;14:173-7.
23) Ozcan A, Celik E, Karslioğlu Y, Basal S. CD138 expression in
renal tumors and its usage in the differential diagnosis. Turkish
Journal of Pathology. 2011;27:110-5.
24) Al-Otaibi O, Khounganian R, Anil S, Rajendran R. Syndecan-1
(CD 138) surface expression marks cell type and differentiation in
ameloblastoma, keratocystic odontogenic tumor, and dentigerous
cyst. J Oral Pathol Med. 2013;42:186-93.
25) Matutes E. New additions to antibody panels in the
characterisation of chronic lymphoproliferative disorders. J Clin
26) Orciani M, Trubiani O, Guarnieri S, Ferrero E, Di Primio R. CD38
is constitutively expressed in the nucleus of human hematopoietic
cells. J Cell Biochem. 2008;105:905-12.
27) de Oliveira MG, Lauxen Ida S, Chaves AC, Rados PV, Sant'Ana
Filho M. Odontogenic epithelium: Immunolabeling of Ki-67,
EGFR and survivin in pericoronal follicles, dentigerous cysts and
keratocystic odontogenic tumors. Head Neck Pathol. 2011;5:1-7.
28) Bologna-Molina R, Mosqueda-Taylor A, Lopez-Corella E,
Almeida OP, Carrasco-Daza D, Garcia-Vazquez F, Farfan-
Morales JE, Irigoyen-Camacho ME, Damián-Matsumura P.
Syndecan-1 (CD138) and Ki-67 expression in different subtypes
of ameloblastomas. Oral Oncol. 2008;44:805-11.
29) Nadalin MR, Fregnani ER, Silva-Sousa YT, Perez DE. Syndecan-1
(CD138) and Ki-67 expression in odontogenic cystic lesions. Braz
Dent J. 2011;22:223-9.
30) Lo Muzio L, Farina A, Rubini C, Pezzetti F, Stabellini G, Laino G,
Santarelli A, Pannone G, Bufo P, de Lillo A, Carinci F. Survivin as
prognostic factor in squamous cell carcinoma of the oral cavity.
Cancer Lett. 2005;225(1):27-33.
31) Engels K, Knauer SK, Metzler D, Simf C, Struschka O, Bier
C, Mann W, Kovács AF, Stauber RH. Dynamic intracellular
survivin in oral squamous cell carcinoma: Underlying molecular
mechanism and potential as an early prognostic marker. J Pathol.
32) Preuss SF, Weinell A, Molitor M, Semrau R, Stenner M, Drebber
U, Wedemeyer I, Hoffmann TK, Guntinas-Lichius O, Klussmann
JP. Survivin and epidermal growth factor receptor expression in
surgically treated oropharyngeal squamous cell carcinoma. Head
33) Davies EJ, Blackhall FH, Shanks JH, David G, McGown AT,
Swindell R, Slade RJ, Martin-Hirsch P, Gallagher JT, Jayson
GC. Distribution and clinical significance of heparan sulfate
proteoglycans in ovarian cancer. Clin Cancer Res. 2004;10:5178-86.