Annals of Diagnostic Pathology xxx (2015) xxxxxx

Contents lists available at ScienceDirect

Annals of Diagnostic Pathology

Original Contribution

Oral syphilis: report of three cases and characterization of the

inammatory cells
Luciana Rocha Strieder, DDS a, Jorge Esquiche Len, PhD b,
Yasmin Rodarte Carvalho, PhD c, Estela Kaminagakura, PhD d,
a
Science and Technology Institute, University of So Paulo State, So Jos dos Campos, So Paulo, Brazil
b
Discipline of Oral Pathology, School of Dentistry of Ribeiro Preto, University of So Paulo, Ribeiro Preto, So Paulo, Brazil
c
Department of Biopathology and Oral Diagnosis, Science and Technology Institute, University of So Paulo State, So Jos dos Campos, So Paulo, Brazil
d
Discipline of Stomatology, Science and Technology Institute, University of So Paulo State, So Jos dos Campos, So Paulo, Brazil

a r t i c l e i n f o a b s t r a c t

Available online xxxx Syphilis is a sexually transmitted infectious disease caused by Treponema pallidum. This study reports 3 cases of
Keywords: syphilis and highlights the importance of identifying oral lesions for its nal diagnosis. Case 1: a 48-year-old
Infection disease male patient presented with a bleeding ulcer in the lower lip. Overall clinical examination revealed patchy alopecia
Treponema pallidum and skin target lesions. Case 2: a 61-year-old male patient presented with white spots on the lateral tongue and
Sexually transmitted diseases
nodules on the dorsum of the tongue. Overall clinical examination showed erythematous target lesions on the
abdomen, forearm, palms of the hand, and soles of the feet. Case 3: a 17-year-old male patient presented with
an ulcerated lesion on the tongue and lymph node involvement. The following serologic tests were requested:
Venereal Disease Research Laboratory, uorescent treponemal antibodyabsorption, antiHIV-1 and antiHIV-2,
and antihepatitis C virus. An incisional biopsy revealed epithelial hyperplasia associated with intense and diffuse
mononuclear inammatory cell inltration consisting mainly of plasma cells, in a perivascular and perineural
distribution. The nal diagnosis in the 3 patients was syphilis. Treatment consisted of 1 weekly dose of penicillin
(2.4 million units, intramuscular) for 2 or 3 weeks. Immunohistochemical reactions for XIIIa, CD3, CD20, CD68,
CD163, S100, CD1a, CD11c, CD83, CD138, and CD208 were performed. Clinicians should be familiarized with
oral syphilis lesions in order to be able to diagnose this emerging infectious disease of variable clinical presentation.
2015 Elsevier Inc. All rights reserved.

1. Introduction
Syphilis is an infectious disease caused by Treponema pallidum.
Transmission of the disease occurs through sexual contact, vertical
transmission, or, less frequently, blood transfusions or reused sharp ob-
jects [1,2]. Syphilis is an emerging disease, and an increase in the num-
ber of cases has been observed in recent years [3].
Syphilis can be divided into different stages: primary, secondary, la-
tent, and tertiary [4]. The rst sign of syphilis is a hard chancre, and the
lips are the most affected extragenital site [1]. Oral lesions are observed
in at least 30% of patients with secondary syphilis and appear as white
plaques, papules, or nodules [3]. Involvement of the palms and soles is
characteristic of this stage [2]. After the second stage, the disease enters
long periods of latency that can last from 10 to 30 years [2,5]. In the third
stage, there is involvement of the skin, mucosa, cardiovascular and cen-
tral nervous systems [2,6], liver, spleen, and other organs [5]. Gingival
lesions are characteristic of this stage and may perforate the palate
and destroy the nasal septum [2].
Corresponding author at: Av. Eng. Francisco Jos Longo, No. 777, Bairro, Jardim So
Dimas, 12245 000, So Jos dos Campos, SP, Brazil. Tel.: +55 12 39479401.
E-mail addresses: lucianastrieder@hotmail.com (L.R. Strieder), jleon@forp.usp.br
(J.E. Len), yasmin@fosjc.unesp.br (Y.R. Carvalho), estela@fosjc.unesp.br
(E. Kaminagakura).
The objectives of the present study were to report 3 cases of syphilis
with variable clinical characteristics and to highlight the importance of
identifying oral lesions for the denitive diagnosis and for establishing
adequate therapeutic protocols.
2. Case report
2.1. Case 1
A 48-year-old male patient sought the stomatology outpatient clinic of
Universidade Estadual Paulista Jlio de Mesquita Filho, So Jos dos
Campos, So Paulo, with a 5-month history of a wound in the lower lip,
which spontaneously bleeds at night (Fig. 1A). During anamnesis, the pa-
tient reported that he had seen a physician who prescribed Neomicina
ointment (30 g, betamethasone valerate + neomycin sulfate, Bunker
Indstria Farmacutica LTDA, So Paulo, Brazil), which did not result in
improvement. The patient was submitted to a chest x-ray because of his
chronic dry cough, but no pulmonary alterations were detected. The pa-
tient was a smoker and chronic drinker for 34 years and had worked as
a stonemason under sun exposure without protection for decades. He
also reported signicant weight loss in the last months. Overall clinical ex-
amination revealed alopecia (Fig. 1B), erythematous lesions on the skin
(Fig. 1C), and an ulcer with a hemorrhagic crust on the left side of the

http://dx.doi.org/10.1016/j.anndiagpath.2015.01.003
1092-9134/ 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Strieder LR, et al, Oral syphilis: report of three cases and characterization of the inammatory cells, Ann Diagn Pathol
(2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.01.003
2 L.R. Strieder et al. / Annals of Diagnostic Pathology xxx (2015) xxxxxx

Fig. 1. Case 1. (A) Initial clinical appearance showing an ulcer in the lower lip. (B) Hair loss. (C) Skin target lesion. (D) Mucosal fragment exhibiting parakeratinized stratied epithelium
with acanthosis and intense inammation in the connective tissue (hematoxylin and eosin [H&E], magnication 100). (E) Perivascular distribution of inammatory cells, particularly
plasma cells (hematoxylin and eosin, magnication 400).

lower lip (Fig. 1A). No lesions on the palms and soles or interdigital con- epithelial hyperplasia, exocytosis, and intraepithelial microabscesses, in
dylomata were observed. addition to intense perivascular and perineural plasma cell inltration
The clinical diagnostic hypotheses were immune-mediated diseases (Fig. 2G-I). The results of the serologic tests (VDRL, FTA-Abs, anti-HIV,
such as erythema multiforme and infectious diseases such as syphilis and and anti-HCV) showed in Table 1 indicated secondary syphilis. The pa-
tuberculosis. An incisional biopsy of the oral lesion was performed, tient was referred to an infectologist and was treated with 1 weekly
which revealed a mucosal fragment covered with parakeratinized strati- dose of penicillin (2.4 million units, IM) for 2 weeks.
ed pavement epithelium exhibiting areas of acanthosis, intracellular
edema, and exocytosis associated with a focal area of supercial ulceration
2.3. Case 3
(Fig. 1D). There was an intense subepithelial inammatory cell inltrate
consisting mainly of plasma cells, which exhibited a perivascular and peri-
A 17-year-old male patient presented with a 2-month history of an ulcer
neural distribution pattern in the underlying connective tissue (Fig. 1E).
on the lateral border of the tongue. During anamnesis, the patient reported
The following serologic tests were requested and the results are
the use of oral mouth rinse and Omcilon A Orabase ointment (triamcinolone
shown in Table 1: Venereal Disease Research Laboratory (VDRL), uores-
acetonide, Bristol-Myers Squibb Farmacutica S.A., Santo Amaro, So Paulo,
cent treponemal antibodyabsorption (FTA-Abs), antiHIV-1 and anti
Brazil), without satisfactory results. Extraoral clinical examination revealed a
HIV-2, and antihepatitis C virus (HCV). The clinical and histopathologic
4-cm nodule in the upper neck region that was mobile, tender to palpation,
ndings and serologic tests conrmed the diagnosis of secondary syphilis.
and asymptomatic (Fig. 3A). Intraoral examination showed a 3-cm asymp-
The patient was referred to an infectologist and was treated with 1
tomatic ulcer on the right lateral border of the tongue (Fig. 3B).
weekly dose of penicillin (2.4 million units, intramuscular [IM]) for 3
The differential clinical diagnoses included neoplastic and infectious
weeks (Fig. 1F).
diseases. An incisional biopsy of the tongue lesion was performed, and
microscopic analysis revealed pseudoepitheliomatous hyperplasia, exo-
2.2. Case 2
cytosis, and intraepithelial microabscesses (Fig. 3C). Moreover, there
was a prominent subepithelial inammatory inltrate, as well as evident
A 61-year-old male patient was referred to our service because of a
perivascular and perineural plasma cell inltration (Fig. 3D). The nal di-
2-month history of white spots on the tongue. Overall clinical examina-
agnosis of syphilis was made based on the serologic tests (VDRL, FTA-
tion revealed red target lesions on the abdomen, soles of the feet, and
Abs, anti-HIV, and anti-HCV) whose results are summarized in Table 1.
palms of the hands (Fig. 2A-C). On intraoral examination, nodular-
The patient was referred to an infectologist and treated with 1 weekly
papular lesions measuring approximately 1 cm were observed on the
dose of penicillin (2.4 million units, IM) for 2 weeks.
dorsum of the tongue (Fig. 2D) and erythematous lesions on the palate
(Fig. 2E). Furthermore, a well-delimited white spot containing a small
area of ulceration and showing no painful symptoms was noted on 3. Immunohistochemical analysis
the ventral surface of the tongue (Fig. 2F). During anamnesis, the patient
reported self-medication with uconazole (150 mg/wk) for 3 weeks All tissue specimens were xed in 10% neutral-buffered formalin for
due to a lesion in the genital region, but without improvement. 24 hours at room temperature, embedded in parafn at 55C, and cut
In view of the differential diagnosis of secondary syphilis, a biopsy of into consecutive parallel 3-m-thick sections. For immunohistochemistry,
the tongue lesion was performed. Microscopic analysis showed intense the slides were hydrated and treated with hydrogen peroxide.
For retrieval of the XIIIa, CD3, CD20, CD68, CD163, S100, CD1a,
CD11c, CD83, CD138, and CD208 epitopes, the tissue specimens were
Table 1
pretreated with 10 mM sodium citrate buffer, pH 6.0, in a pressure cook-
Serologic results of the 3 cases reported
er. The CD123, CD303, and CD207 epitopes were unmasked by pressure
Case VDRL FTA-Abs HIV HVC cooker pretreatment in 10 mM Tris/1 mM EDTA buffer, pH 9.0. The sec-
1 1:1024 + + tions were then successively incubated with the primary antibodies
2 1:520 + (Table 2). Next, the sections were incubated with the secondary anti-
3 NAa + NAa NAa bodies conjugated with streptavidin-biotin-peroxidase (K0690; Univer-
a
Patient refused to inform. sal Dako LSAB + Kit, Peroxidase, Carpinteria, California). The reactions

Please cite this article as: Strieder LR, et al, Oral syphilis: report of three cases and characterization of the inammatory cells, Ann Diagn Pathol
(2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.01.003
 L.R. Strieder et al. / Annals of Diagnostic Pathology xxx (2015) xxxxxx 3

Fig. 2. Case 2. Red target lesions. (A) Sole of the foot. (B) Abdomen. (C) Palm of the hand. (D) Nodular lesions on the dorsum of the tongue. (E) Erythematous lesions on the hard palate.
(F) Ulcer on the ventral surface of the tongue. (G) Photomicrograph showing epithelial hyperplasia (hematoxylin and eosin [H&E], magnication 100). (H) Inammatory cells, especially
plasma cells, beneath the epithelium (H&E, magnication 200). (I) Perivascular and perineural plasma cell inltration (H&E, magnication 200).

were developed with diaminobenzidine, and the sections were counter-
stained with Carazzi hematoxylin.
A larger number of CD3+ cells than CD20+ cells were observed in the
lesions. CD138 staining revealed numerous plasma cells, highlighting their
perivascular and perineural distribution pattern. The percentage of
CD68+ and CD163+ cells was similar and the staining pattern was diffuse,
suggesting an M2-macrophage phenotype. However, no organized granu-
lomas were observed. Dendritic cell (DC) markers revealed numerous
XIIIa+ and S100+ cells, and CD11c+ cells, followed by CD1a+ and
CD207+ cells. CD123+ and CD303+ cells were scarce; however, these lat-
ter presented in lesser number. Similarly, mature DCs highlighted by CD83
and CD208 markers were scanty (Fig. 4AL). Except S100 and CD1a and
CD207, all other DC markers showed preferential connective tissue location.
4. Discussion
Syphilis is currently considered an emerging disease [4], which is
mainly acquired through sexual contact with an infected lesion [3],

Fig. 3. Case 3. (A) Lymph node enlargement in the neck. (B) Ulcer on the right lateral border of the tongue. (C) Photomicrograph showing pseudoepitheliomatous hyperplasia and inam-
matory cells in connective tissue (hematoxylin and eosin [H&E], magnication 100). (D) Inltration of inammatory cells in a neurovascular bundle (H&E, magnication 400).

Please cite this article as: Strieder LR, et al, Oral syphilis: report of three cases and characterization of the inammatory cells, Ann Diagn Pathol
(2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.01.003
4 L.R. Strieder et al. / Annals of Diagnostic Pathology xxx (2015) xxxxxx

Table 2
List of primary antibodies

Antibodies Dilutions Clone Supplier

CD1a 1:400 010 DakoCytomation, Glostrup, Denmark

CD3 1:500 Polyclonal DakoCytomation
CD11c 1:500 5D1 Leica Biosystems Newcastle, Ltd,
Newcastle-upon-Tyne, England, UK
CD20 1:2000 L26 DakoCytomation
CD68 1:3000 KP1 DakoCytomation
CD83 1:100 1H4b Leica Biosystems Newcastle, Ltd
CD123 1:200 BR4MS Leica Biosystems Newcastle, Ltd
CD207 1:200 12D6 Monosan, Uden, the Netherlands
CD208 1:500 1010E1.01 Dendritics, Lyon, France
CD303 1:500 124B3.13 Dendritics
S100 1:300 Polyclonal Leica Biosystems Newcastle, Ltd
XIIIa 1:100 E980.1 Leica Biosystems Newcastle, Ltd

Fig. 4. Immunohistochemical results. (A) Numerous CD3-positive cells, especially in the
subepithelial region (diaminobenzidine [DAB], magnication 200). (B) Few CD20-positive
cells (DAB, magnication 200). (C) Diffuse CD68 immunoexpression (DAB, magnication
200). (D) Diffuse pattern of CD163-positive cells (DAB, magnication 200). (E) S100+
expression in numerous inammatory cells with dendritic morphology (DAB, magnica-
tion 200). (F) Few CD1a-positive cells in the epithelium (DAB, magnication 200).
(G) Numerous XIIIa-positive cells in a subepithelial location (DAB, magnication 200).
(H) Scarce CD208-positive cells (DAB, magnication 400). (I) CD138 immunoexpression
highlighting plasma cells and the hyperplastic squamous epithelium. (DAB, magnication
200). (J) In the connective tissue, scarce CD303-positive cells were observed (DAB, mag-
nication 200). (K) CD123-positive cells were more numerous than the CD303-positive
cells (DAB, magnication 200). (L) At a deeper level, CD138 highlighted numerous plasma
cells surrounding skeletal muscle bers (DAB, magnication 200).
saliva, or blood [5,7]. The sex industry, promiscuous behavior, a reduction in
the use of condoms, and the practice of oral sex have caused the increase in
cases [2,5,7], especially among young patients, a group in which sexually
transmitted diseases are more common [8]. However, 2 of the cases report-
ed here were married adult men who reported extramarital sexual relations
with different women and who refused to inform their partners about the
disease. This fact favors the dissemination of the disease and delays the di-
agnosis and treatment for infected individuals. Men are 14 times more af-
fected than women [7]. Of these, 83.9% are men who have had
homosexual relations [9], such as case 3 who was a homosexual adolescent
boy. In the case of this group and of heterosexuals, the interaction between
HIV infection and syphilis is of great clinical and epidemiologic interest [5].
In the present study, the HIV test results were negative. However, case 1
was infected with HCV, in contrast to the ndings of Price et al [10].
Clinically, primary syphilis is characterized by the presence of a hard
chancre, which is an asymptomatic ulcerated lesion with indurated
margins [1,8]. The lesions are generally solitary [3,11] and rarely occur
in the mouth [4], but if present, the lips are the most affected site [3].
An association with painless regional lymphadenopathy has been re-
ported [1,8]. Primary chancres heal spontaneously within 4 to 5 weeks
without leaving scars [1,2,8]. Extragenital chancres appear in 5% to
14% of cases; two-thirds of these cases occur in the mouth or perioral re-
gion after unprotected oral sex [12], as reported by patient 3.
An expressive and rapid increase in the number of disease-causing
microorganisms and, consequently, in the clinical manifestations is ob-
served in secondary syphilis [2]. In the skin, the lesions can be symmet-
rical and appear as rose-colored patches in 75% of patients [1]. The
syphilitic roseola is the rst clinical sign of secondary syphilis [12],
and involvement of the palms of the hands and soles of the feet is char-
acteristic [2]. Some patients present with diffuse or marked alopecia in
the temporoparietal and occipital region, known as patchy alopecia
[2,11]. In the present study, patients 1 and 2 had multiple skin lesions,
although case 1 exhibited no erythematous spots in the palms or
soles, only case 2. The loss of hair and eyebrows [12] was observed in pa-
tient 1, a nding seen in only 5% to 6% of affected patients [5].
Oral lesions of secondary syphilis are typically multiple and symptomat-
ic [2,8,13]. Lesions in the upper lip are more common in men, whereas
those in the lower lip are more common in women [3]. Patient 1 had a sin-
gle lesion in the lower lip. Secondary syphilis lesions can appear as multiple
mucosal spots surrounded by erythema on the soft palate, tongue, and oral
mucosa [1]. Nodular lesions on the tongue are uncommon [3]. However,
case 2 presented with multiple papular-nodular lesions on the tongue, an
ulcerated lesion on the ventral surface of the tongue, and erythematous
areas on the palate. All cases reported here exhibited variable clinical char-
acteristics, a fact that makes the nal diagnosis of syphilis difcult.
There is a broad spectrum of differential diagnoses of syphilis due to
the variable clinical manifestation of the disease [4]. When affecting the
lip, syphilis lesions can simulate squamous cell carcinoma [3]. Erythema
multiforme affects the mucosa and skin, and its most marked character-
istics are target-shaped erythematous rings on the palms and soles and
ulceration with crusting on the lip [14]. For these reasons, the clinical di-
agnosis in case 1 was erythema multiforme, although the patient did not
report the use of drugs, episodes of herpes simples, or food allergy.

Please cite this article as: Strieder LR, et al, Oral syphilis: report of three cases and characterization of the inammatory cells, Ann Diagn Pathol
(2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.01.003
 L.R. Strieder et al. / Annals of Diagnostic Pathology xxx (2015) xxxxxx
The diagnosis of syphilis is generally based on clinical, microscopic,
and serologic ndings. The last is essential because the clinical and micro-
scopic ndings are variable and relatively nonspecic [5]. Considering
only microscopic features, the intense subepithelial plasma cell inltra-
tion frequently observed in syphilis should be differentiated from idio-
pathic plasmacytosis, IgG4-related sclerosing disease, contact stomatitis,
candidiasis, inammatory pseudotumor, and plasmacytoma [15]. Primary
and secondary syphilis is characterized by plasma cell inltration which
extends deeply beyond the lamina propria and around capillaries and
nerve bundles [5]. In the lamina propria, plasma cells, together with lym-
phocytes and macrophages, arrange themselves in a band-like pattern
(lichenoid inltration) [5]. Tertiary oral syphilis is characterized by
pseudoepitheliomatous hyperplasia and granulomatous inammation
with a central zone of acellular necrosis, accompanied by histiocytes
and multinucleated giant cells. Obliterating endarteritis is observed in
all stages of the disease [5]. In the present study, histochemical staining
with Warthin-Starry stain was performed and no structures compatible
with spirochetes were detected. The presence of bacterial colonies in
oral mucosal biopsies [12] impairs the interpretation of the results of
Warthin-Starry staining, thus limiting its use. In addition, the sensitivity
of this method is 41% when biopsies are evaluated. Immunohistochemis-
try shows a higher sensitivity (71%) than Warthin-Starry staining (41%)
for the assessment of secondary syphilis lesions.
In the present study, we evaluated the immunohistochemical prole
of the inammatory cell inltrate using a broad panel of antibodies. The
results showed a larger number of T cells than B cells, whereas numerous
plasma cells were observed in a subepithelial location and in the deeper
connective tissue compartments. No evident granuloma formation was
noted; however, the observation of diffuse CD68/CD163 staining in the bi-
opsy samples suggests an M2-macrophage phenotype. The classically ac-
tivated M1-macrophages (HLA-DR+/CD68+) are highly aggressive
against bacteria and produce large amounts of pro-inammatory cyto-
kines. The alternatively activated anti-inammatory M2-macrophages
(CD68+/CD163+) exert different functions, such as the regulation of im-
munity, maintenance of tolerance, and tissue repair [16]. Moreover,
plasmacytoid DCs were scarce in the connective tissue, and the larger
number of CD123+ cells compared with CD303+ cells indicates a mature
phenotype of plasmacytoid DCs. Finally, the detection of a larger number
of S100+, XIIIa+ and CD11c+ cells, followed by CD1a+ and CD207+
cells (all of them immature DC markers), compared with CD83+ and
CD208+ cells (which are mature DC markers), in the biopsy samples sug-
gests functional abnormalities of DCs in patients with syphilis, a fact that
might be of importance for the understanding of immune dysregulation
in this disease [17].
There are 2 nonspecic (nontreponemal) serologic tests for the diag-
nosis of syphilis: VDRL [11,12] and rapid plasma reagin [1,11,12]. If the
results of these tests are positive, more specic (antitreponemal) tests
are used for conrmation [1]: FTA-Abs [12], microhemagglutination
assay for T pallidum antibodies, and T pallidum particle agglutination
assay [12]. In the present study, all cases were tested positive in the
VDRL and FTA-Abs assays. The 2 tests were requested at the same
time because of their accessible cost and rapid execution and because
of the strong clinical suspicion of syphilis, especially in case 2.
Syphilis is a disease with devastating effects if untreated [11]. Although
effective and low-cost treatment is available, syphilis continues to be a public
health problem [2]. Penicillin [18] is effective at any stage, with the regres-
sion of primary and second lesions after a single application [1]. In the pres-
ent study, the efcacy of this drug was demonstrated by the administration
of a weekly dose of 2.4 million units (IM) and the observation of complete
remission of the lesions after the rst dose. However, the patients should
be followed up by serologic testing at 6 and 12 months posttreatment [11].
Please cite this article as: Strieder LR, et al, Oral syphilis: report of three cases and characterization of the inammatory cells, Ann Diagn Pathol
(2015), http://dx.doi.org/10.1016/j.anndiagpath.2015.01.003
5
Syphilis has important implications for clinicians because manifesta-
tions can occur in the mouth and perioral region and primary and sec-
ondary lesions are highly contagious. Furthermore, the variable
clinical presentation of syphilis can delay the diagnosis and treatment,
favoring dissemination of the disease. For these reasons, dentists should
get familiarized with the clinical manifestations of syphilis. In view of
the increase in the number of syphilis cases, awareness and prevention
campaigns should be implemented.
Authors' contributions
Luciana Rocha Strieder and Estela Kaminagakura were involved in
clinical attendance and drafting the manuscript. Jorge Esquiche Len
performed the microscopic and immunohistochemical analyses. Yasmin
Rodarte Carvalho performed the microscopic analyses. The nal version
was revised and approved by all the authors.
Acknowledgments
The authors would like to thank Mrs Nilma Aparecida Mota-Mota for
help with the laboratory tests. L.R.S. was the recipient of a master's fel-
lowship from Fundao de Amparo Pesquisa do Estado do Amazonas
(FAPEAM; Edital 003/2013, Decision 028/2014).
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