Head and Neck Pathol (2009) 3:195–206

DOI 10.1007/s12105-009-0127-0

ORIGINAL PAPER

Syphilis: The Renaissance of an Old Disease with Oral

Implications
Giuseppe Ficarra Æ Roman Carlos

Received: 29 May 2009 / Accepted: 2 July 2009 / Published online: 22 July 2009
Ó Humana 2009

Abstract Syphilis is caused by Treponema pallidum an Introduction

anaerobic filamentous spirochete. In recent years, striking
outbreaks have occurred in USA, Canada, Russia, China Syphilis is an infectious disease caused by a spirochete
and some areas of Central and Eastern Europe. Main epi- called Treponema pallidum which has a tropism for several
demiology changes reflect sex industry, sexual promiscu- organs and tissues in the body causing complex clinical
ity, decreasing use of barrier protection (i.e. condoms) due manifestations [1–3]. The precise origin of syphilis is
to false sense of security that nowadays sexually trans- unknown although two main theories prevail. One is that
mitted diseases are curable and lack of pertinent knowl- the disease was endemic to America and brought to Europe
edge. Considering that the initial presentation of syphilis after Columbus discovery in 1492. The other one suggests
may be the oral cavity, it is of great relevance to include that syphilis was endemic to central Africa and reached
this disease in the differential diagnosis of unusual oral Europe before the voyage of Columbus [4]. Recently, a
ulcerations and white patches. Primary syphilis is a highly DNA-related strain of T. pallidum, which causes a disease
infectious disease in which inappropriate treatment may be with mix features of syphilis and yaws, has been fund in an
apparently curative while the patient remains highly isolated tribe living in Guyana. It has been suggested that
infectious. It is then of pivotal importance that clinicians this organism may represent the progenitor from which
maintain a high clinical index of suspicion. At the present T. pallidum has evolved thousands of years ago [5].
time, clinical-pathologic correlation together with serologic Transmission of syphilis occurs mostly through sexual
studies remain essential in establishing the diagnosis of intercourse and sites of inoculations are usually genital but
syphilis. can also be extragenital [1–3]. Despite the introduction, in
the mid-twentieth century, of penicillin it has been
Keywords Syphilis
Oral cavity
Treponema pallidum impossible to eradicate this disease and it remains a rele-
vant problem among the ailments of mankind and its
incidence is rapidly increasing in several parts of the world
[6–9].
The aim of this paper is to review the epidemiologic and
G. Ficarra clinical aspects of syphilis, the oral manifestations and its
Reference Center for the Study of Oral Diseases, Azienda interplay with HIV infection.
Ospedaliero-Universitaria, Florence, Italy

G. Ficarra (&)
Department of Odonto-Stomatology, University of Florence, Epidemiology
Viale Morgagni 85, Florence, Italy
e-mail: gificarr@tin.it In the USA, in the first half of the twentieth century,
syphilis was a frequent infection (66.4 cases per 100.000
R. Carlos
Pathology Division, Centro Clı́nico de Cabeza y Cuello, persons in 1947) and a leading cause of heart and neuro-
Guatemala City, Guatemala logical diseases [3, 6, 9]. In 1940s the introduction of
196 Head and Neck Pathol (2009) 3:195–206

penicillin therapy and prevention efforts made the disease other virulent treponemes cannot be cultivated in vitro
rare. Since the 1950s in the USA periodic epidemics have [2, 3].
been observed with peaks around the 1990 followed by a The primary mode of syphilis transmission is sexual
progressive decline of prevalence by the year 1993 until the contact. After T. pallidum penetrates through the genital
year 2000 [10–14]. However, during that time syphilis still mucosa or abraded skin, it enters the lymphatic and blood
remained a problem in the Southern States where the dis- stream and disseminates to various organs including the
ease used to spread especially among poor minority groups CNS [1–3]. The incubation time is directly proportional to
that did not have access to medical facilities [15–17]. In the the size of the inoculum and may vary from 3 to 90 days.
USA, the incidence of syphilis continued to cycle reaching In about 10–20% of cases the primary lesion is intrarectal,
an all time low in 2000, with 2.1 cases per 100.000 persons perianal or oral. At difference with other sexually trans-
[17]. During the last 8 years a significant resurgence of this mitted diseases (e.g. HIV) T. pallidum is easily transmis-
disease has been reported in several countries such as the sible by oral sex, kissing and close contact with an
USA, Canada, England, France, Spain, Ireland, Eastern infectious lesion [1–3, 6].
Europe, Russia and China [6–24]. Main epidemiology An important common mode of transmission is in utero
changes, at the basis of increasing prevalence, reflect sex transmission. In addition, transmission can occur at deliv-
industry, sexual promiscuity, decreasing use of barrier ery if the newborn comes in contact with a contagious
protection (i.e. condoms) due to a false sense of security lesion. Blood transfusion can be another mode of trans-
that today sexually transmitted disease are curable and lack mission although today quite rare. Healthcare workers and
of pertinent knowledge. laboratory personnel can acquire the infection if their
Today, more than 50–60% of new cases of syphilis unprotected hands come in contact with the spirochetes
occur in men who have sex with men (MSM) and are [2, 3, 6].
strongly associated with HIV coinfection and high risk The likelihood of a susceptible person who is exposed to
sexual behavior [6, 7, 25]. In the Russian Federation since an infected individual of developing syphilis is about 50%
the fall of the Soviet Union the incidence of syphilis has [1–3]. Spirochetes multiply locally at the site of entry and
shown a rapid and substantial increase. The reasons are some spread to lymph nodes and systemically through the
linked to changes in sexual behavior, drug abuse, increased bloodstream. T. pallidum has an innate capacity to evade
travel and migration which all have created the conditions the host’s immune system. Evaluations of the outer mem-
for a parallel epidemic of HIV infection [19]. Also in other brane show only a small number of integral proteins thus
European countries like Spain, syphilis has been linked in the immune system cannot mount, in the absence of proper
injecting drug users with high-risk sexual behavior [20]. In immunogenic targets, an efficient immune response capa-
China cases of syphilis have been recently observed in an ble of eradicating the infection. Serological tests detect
increasing number and in association with less education, antibodies to T. pallidum early in the primary stage which
alcohol use, unprotected anal sex with male partners and remain detectable during the infection and which are used
diagnosis of sexual transmitted diseases [8]. to monitor the response to treatment. Cellular immune
responses cause the resolution of both primary and sec-
ondary syphilis. However, despite these immune responses
Etiology and Mechanism of Infection and in absence of antibiotic therapy T. pallidum is able to
survive in the human host for decades [26–30].
The causative agent of syphilis is T. pallidum. There are The clinical manifestations of syphilis are quite protean
other organisms which belong to the genus Treponema that and can be recapitulated into four principal stages: primary,
are closely related antigenically to T. pallidum. Among secondary, latent and tertiary syphilis (see below). The
these spirochetes that are pathogenic to humans there are: pathologic changes associated with syphilis are character-
T. pallidum subsp. pertenue (causative of yaws); T. palli- ized by obliterative endarteritis that is found in all stages of
dum subsp. endemicum (causative of bejel, nonvenereal the disease. In the primary chancre an inflammatory infil-
endemic syphilis); and T. carateum (causative of pinta) trate formed by polymorphonuclear leucocytes and mac-
[2, 3]. rophages and rich of treponemes is the typical feature.
Treponema pallidum has a slender, coiled morphology Gummas are agranulomatous lesions formed by a necrotic
and when examined by dark field microscopy it moves with coagulated center and associated with small-vessels oblit-
a drifting rotary motion (corkscrew). T. pallidum cannot erative endarteritis. T. pallidum is difficult to demonstrate
survive outside its only known natural host (humans) in tissue albeit it can be revealed by special silver stains
because it has limited metabolic capacities in order to [1–3, 28]. An individual with active or latent syphilis is
synthesize its own bionutrients. Syphilis spirochetes like resistant to superinfection with T. pallidum. If the disease is
Head and Neck Pathol (2009) 3:195–206 197

eradicated by adequate antibiotic treatment, the individual 80% of cases about 7–10 days after the development of the
again becomes fully susceptible to infection [2]. genital chancre [1–3, 31].

Secondary Syphilis
Clinical Manifestations
The secondary stage develops after 2–12 weeks after the
Syphilis evolves through a series of four overlapping stages first contact with the organism. This stage is the result of a
commonly known as primary syphilis, secondary syphilis, hematogenous dissemination and the organism, in very
latent syphilis, and tertiary syphilis. Each stage has distinct high number, colonizes several organs giving constitutional
clinical characteristics and degree of infectivity (Table 1) and mucocutaneous manifestations (Table 2). A rash of
[1–3, 6]. Prenatal transmission may induce distinct clinical varying extension is the most common presenting symptom
manifestations. [1–3, 31, 32]. The rash typically does not cause pruritus
and develops as symmetrical 3–10 mm pink or red ma-
Primary Syphilis cules, which can progress to papular or pustular form
(Fig. 1). If untreated, the rash resolves over several weeks
The primary stage of infection is known as syphilis chan- without complications. Characteristic anatomical locations
cre, which occurs at the site of inoculation. Chancre starts are the arms, palms, flanks and soles (Fig. 2). Occasionally,
as a papule that may evolve into an indurated, painless, about 5–6% of patients may develop patchy hair loss of the
nonpurulent ulcer with clean base. The size varies from 0.3 beard, eyebrows and scalp localized alopecia (Fig. 3).
to 3 cm and the borders appear marginated. Chancres can Condyloma lata (white gray mucous patches) are mainly
be single or multiple and usually regress (without treat- found in the genital or anal area in 5–22% of patients; less
ment!) after 2–8 weeks. The majority of extragenital
chancres occur in the mouth (40–75%) although they can
Table 2 Constitutional and mucocutaneous manifestations of sec-
be observed in any body parts, including hands of health- ondary syphilis
care workers. Regional lymphadenopathy occurs in up to
Symptoms: fever, malaise, weight loss
Table 1 Syphilis: outline of stages and incubation times Skin rash (symmetrical and generalized), alopecia
EXPOSURE Condyloma latum in intertriginous areas
Primary incubation: 3 weeks (range 3-90 days) Lymphadenopathy
Oral involvement: multiple mucous patches covered by grayish, white
CNS invasion:25-60% of cases pseudomembranes and surrounded by erythema
PRIMARY SYPHILIS
Ocular involvement: uveitis, iritis, optic neuritis
Arthritis, periostitis
Early neurosyphilis
Secondary incubation : 4-10 weeks
Hepatitis
Glomerulonephritis
Neurologic involvement: headache, meningitis, cranial nerve
paralysis, cerebrovascular accident

SECONDARY SYPHILIS

EARLY LATENT SYPHILIS

(1 year or less postinfection)

LATE LATENT SYPHILIS Late neurosyphilis (4-25 years)

(greater than 1 year postinfection)

TERZIARY SYPHILIS
(gummatous syphilis: after 15 years; cardiovascular syphilis: after 10-30
years) Fig. 1 Secondary syphilis: maculopapular skin lesions of the neck
198 Head and Neck Pathol (2009) 3:195–206

Fig. 4 Macerated plaques (condylomata lata) of the toe webs

Fig. 2 Secondary syphilis: maculopapular and scaly lesions of the
plantar area
(which usually occurs within the first 6 months of infection
or during the secondary rash) or cranial nerve involvement.
Deafness and optic neuritis may develop as sequelae [3, 6].
Secondary syphilis is clinically the least difficult to
diagnose, although in some cases the clinical manifesta-
tions (especially the macular rash!) can be confused with a
variety of skin diseases. Eczema, psoriasis, drug eruption,
pityriasis, lichen planus and a syndrome with skin rash plus
reactive arthritis, urethritis and conjunctivitis can be
mimicked by syphilis [32, 34, 35]. In HIV infection things
can be even more complicated considering that secondary
syphilis may show totally unexpected features [3, 6].

Latent Syphilis

After the secondary stage, there is a latent period during

which the patient does not show any clinical sign of
infection. In this phase the diagnosis of syphilis can be
made only through a serologic test [1–3].

Tertiary Syphilis

Late syphilis or tertiary disease develops in one third of

untreated patients and is characterized by long-term com-
plications. Late syphilis is also called gummatous syphilis
with gummas that involve the skin, CNS, liver, spleen,
bones and other organs [1–3]. Gummas are granulomatous-
like lesions that are indolent and can range in size from tiny
Fig. 3 Moth-eaten alopecia in secondary syphilis deposits to large masses. Skin manifestations may range
from superficial tumefactive lesions to large granulomatous
frequently they may develop in the axilla, inframammary masses, which can be subjected to ulceration. Cardiovas-
folds, face, oral commissures and toe webs (Fig. 4). cular syphilis is today very rare and mainly represented by
Patients may also experience sore throats and hoarseness ascending aortitis. Neurosyphilis is caused by focal syph-
due to inflammatory involvement of the pharynx, larinx or ilitic endarteritis in the blood vessels of brain and spinal
the tonsils. Due to systemic hematogenous dissemination cord tissues. Clinical forms such as meningovascular
renal, ophthalmologic, hepatic, bone and joint diseases can syphilis and parenchymal neurosyphilis (tabes dorsalis)
be seen [2, 3, 32, 33]. During secondary syphilis CNS today are very rare due to the use of antibiotic treatment
involvement can be seen under the form of meningitis [1–3].
Head and Neck Pathol (2009) 3:195–206 199

Congenital Syphilis population mixing, reduction in safe sex in MSM who no

longer feared AIDS, risk behavior such as use of the
Congenital syphilis is observed when infection of the fetus internet to meet partners and, use of recreational drugs.
in utero occurs in any untreated mother but is most likely to Recent findings have stressed, considering the high inci-
occur during the early stages of the infection [1–3, 6]. dence of asymptomatic syphilis in HIV? MSM, the
Transmission to the fetus is usually via the placenta, but importance of frequent (at least annually) routine syphilis
may occur during delivery in the presence of maternal testing in this group of patients [43].
genital lesions. The risk of vertical transmission ranges Among MSM unprotected oral sex is considered a safe
from 70 to 100% for primary syphilis to 40% for early practice thus many of them acquire syphilis through oral
latent disease to 10% for late latent disease. The incidence sex. The fraction of syphilis transmission attributed to oral
of congenital syphilis has experienced a four to fivefold sex has been estimated between 20 and 46% in various
increase in the last 10 years. Worldwide the WHO esti- literature reports coming from the USA and Europe
mates that maternal syphilis is responsible for 713,600– (reviewed in Peterman and Furness [39]).
1,575,000 cases of congenital syphilis mainly in the Several differences have been observed in the mani-
developing world [36]. Recently, the WHO stated that the festations of syphilis in HIV? patients. Primary disease
magnitude of the congenital syphilis burden, globally, seems less common than secondary syphilis and the
equals that of HIV infection in neonates yet receives little infection shows a more aggressive behavior [40, 41, 44].
attention. In the past 2 years, a WHO initiative has been Furthermore, HIV itself or opportunistic infections may
implemented in order to eliminate congenital syphilis [37]. render problematic the interpretation of clinical and diag-
Depending on the severity of the disease, infection of the nostic findings. Primary syphilis in HIV? patients is often
fetus may result in abortion, stillbirth, neonatal death or symptomless and these patients frequently present with
disease. The clinical manifestations of neonatal syphilis are secondary or latent infection. It is relevant to mention that
quite variable and are a reflection of vasculitis. Congenital with the relative increase in importance of oral sex in
syphilis can be early or late with the early features that are transmission of syphilis the primary lesion may not be in
similar to the manifestations of secondary syphilis in adults. the genitals [39].
These include generalized lymphadenopathy, maculopap- In HIV? patients syphilis presents an atypical clinical
ular rash, hepatosplenomegaly, glomerulonephritis and course with severe constitutional symptoms and unusual
bone alterations of tibia, hands, feet, clavicles, and skull. necrotic skin rashes (Fig. 5), organ involvement and a
Late features of congenital syphilis include bone, teeth and greater tendency to develop neurosyphilis and ocular
nervous system alterations. A classic feature of congenital involvement [40, 41, 44–46]. The skin lesions of syphilis
syphilis is the Hutchison’ triad formed by deafness, notched show atypical features that may render the diagnosis dif-
incisors and ocular interstitial keratitis [1–3, 6, 38]. ficult. Things can also be complicated by the fact that
serology for syphilis in HIV infection can be falsely neg-
HIV Infection and Syphilis ative. Biopsy is commonly needed to establish the diag-
nosis but histology of secondary syphilis is highly variable
The interaction between HIV infection and syphilis is of even in the absence of HIV [47]. Course of syphilis may be
great interest for the epidemiological and clinical impli- more aggressive with increase frequency of lues maligna or
cations that apply to both heterosexuals and MSM [39–42].
In the USA the increase in the rate of syphilis, between
the years 1999–2005, has been mainly observed in men.
This increase in the rate ratio of male to female patients
was the result of a disproportionate number of cases among
MSM. Large metropolitan communities of MSM have been
particularly affected by concurrent epidemics of syphilis
and HIV infection not only in the USA but also in Europe.
In California more of 60% of MSM with syphilis are HIV
infected, and it is estimated that, in major cities, 20–50% of
MSM with syphilis have also HIV infection. Prevalence
rate of HIV infection among syphilis cases has shown to be
two or threefold higher than the prevalence of HIV infec-
tion in the general population of MSM in the USA [41].
The reasons underlying this upsurge are complex but
include migration of people from high-prevalence areas, Fig. 5 Ulceronodular skin lesion of lue maligna
200 Head and Neck Pathol (2009) 3:195–206

the ulceronodular type [40, 41, 47–49]. In regard to neu-

rosyphilis, this complication may present particular diag-
nostic and therapeutic challenges since both syphilis and
HIV infection can have neurological involvement, which
can be very variable (reviewed in Lynn and Lightman
[40]). The commonest manifestation of ocular involvement
is uveitis (intraocular inflammation) that, in these patients,
may be more severe. Papillitis, optic neuritis, and retro-
bulbar optic neuritis may be additional presenting symp-
toms/ signs of coinfection with HIV [46].

Oral Manifestations

Oral chancres are observed in about 4–12% of patients with

primary syphilis and occur at the site of penetration of the
organism into the mucosa. Anatomical sites commonly Fig. 7 Secondary oral syphilis: mucous patches covered by grayish,
white pseudomembranes of the lower vestibular mucosa
affected are especially the tongue, gingiva, soft palate and
lips (Fig. 6). Lesions appear as painless indurated ulcers
associated with enlargement of the submandibular and
cervical lymph nodes, lasting 3–7 weeks. The lesions are
asymptomatic but are teaming with the spirochetes and are
highly infectious. The lesion is usually single and heals
spontaneously without scarring [50–53].
In secondary syphilis the oral manifestations are quite
variable and may show highly aspecific features. The most
well-recognized and characteristic lesions are multiple
mucous patches that are slightly raised and covered by
grayish, white pseudomembranes and surrounded by ery-
thema. The typical sites are the soft palate and pillars,
tongue and vestibular mucosa (Fig. 7) [31, 50, 51]. The
cervical lymph nodes are usually enlarged and rubbery in
consistency. Oral lesions are often painful and snail track
Fig. 8 Secondary oral syphilis with lesions on the soft palate. The
ulcers result when multiple mucous patches become con- patient also had pharyngitis and laryngitis
fluent. Often nonspecific pharyngitis, tonsillitis and laryn-
gitis are associated (Fig. 8) [49–51, 53–55]. Syphilis
presenting as isolated cervical lymphadenopathy has been In HIV? patients unusual oral, perioral and skin ulcers
also described [56]. have been described under the term of lues maligna. In this
situation the cutaneous manifestations are more florid with
multiple large ulceronodular lesions localized on the face
or other body parts [31, 47–49].
Tertiary syphilis manifests itself in the oral cavity as
gumma localized mainly in the hard palate. Others sites
may be the tongue, lips and soft palate. Gummas start as
small ulcers that enlarge and may involve if left untreated
the adjacent structures. An additional feature (although
today of extremely rare observation!) is glossitis with
mucosal atrophy, which may have a malignant potential [3,
50–53]; however, this point has been challenged by the
consideration that instead tongue carcinomas in the past
have been caused by arsenical compounds (formerly used
to treat syphilis!) that notoriously are carcinogenetic.
Fig. 6 Oral chancre in a promiscuous woman who had unprotected
Congenital syphilis is mainly characterized by perma-
oral sex nent cranial bone deformities such as saddle nose, palatal
Head and Neck Pathol (2009) 3:195–206 201

For dark-field examination the surface of the lesion

should be gently cleaned with sterile gauze soaked in 0.9%
sterile saline avoiding bleeding as blood cells may mas-
querade the treponemes. The best result is obtained using
the serous exudate that accumulates on the surface after
squeezing the base of the lesion. The exudate is mixed with
one or two drops of saline on a glass slide and covered with
a plastic cover slip and then is examined under a dark-field
microscope [2, 3, 57].
The direct fluorescent antibody test is the most specific
test for the diagnosis of syphilis when lesions are present
[57, 58]. The lesional exudate, after it has been smeared on
a glass slide, is stained with fluorescein-labeled anti-
Fig. 9 Perioral fissuring (rhagades) in a 3 year-old patient with
T. pallidum immunoglobulin. In contrast to dark-field
congenital syphilis microscopic examination, this test is reliable for the eval-
uation of oral and anal lesions because only T. pallidum is
erosions, high- arched palate, protruding mandible and stained. However, this test does not differentiate between
fontal bossing. Other features are alterations of the for- T. pallidum and other pathogenic treponemes causing
mation of both anterior and posterior teeth. The incisors yaws, endemic syphilis and pinta [2, 3, 57, 58].
(called Hutchinson’s teeth) show an increase of their width New specific and sensitive methods that employ reverse
in the middle third of the crown and a central notch on the transcriptase PCR have been recently developed in order to
incisal edge. The molars (called mulberry molars) exhibit detect very low numbers of spirochetes in clinical samples
the occlusal surface with numerous small globular projec- [58]. Although these methods are not standardized, they
tions that resemble a mulberry. In some patients perioral have been found to be highly sensitive, because able to
fissuring (rhagades) can be seen (Fig. 9) [36, 53]. detect as low as 1–10 organisms per specimen with high
specificity. However, these methods have not yet reached
the stage of widespread clinical application [57–59].
Diagnosis
Serology
Laboratory Confirmation
The serological laboratory tests that are used diagnostically
Dark-Field Microscopy and Direct Fluorescence are referred to as serologic tests for syphilis. These tests
fall into two categories: nontreponemal tests for screening,
The best ways to identify T. pallidum from primary or and treponemal tests for confirmation [3, 6, 58]. The non-
secondary lesions are the dark field illumination that shows treponemal tests measure both IgG and IgM antiphospho-
the typical motile spirochetes and direct immunofluores- lipid antibodies formed by the host in response to lipoidal
cence, a method that uses a fluorescin-labeled antitrepo- material released by damaged host cells early in infection
neme serum [2, 3, 6, 57, 58]. Using these techniques it is and lipid from the cell surfaces of the treponeme itself.
possible to make the correct diagnosis in almost 100% of Instead, treponemal tests use T. pallidum or its components
untreated primary syphilitic chancre. With the exception of as the antigen. Despite their limitations and the complexity
macular lesions, all cutaneous and mucous membrane of interpretation, serological tests play a pivotal role in the
lesions of secondary syphilis contain treponemes. Thus, diagnosis and follow-up of syphilis [3, 6, 58].
material obtained from an eroded moist lesion will almost The nonspecific nontreponemal reaginic antibody tests
always yield positive results [3, 57]. Nevertheless, limita- (VDRL, RPR, ART) are inexpensive, rapid, and convenient
tions can be availability of a dark-field microscope and of a for screening large number of sera and are also quite
trained, experienced microscopist. Success is dependent on helpful as an indication of disease activity [1–3, 57, 58].
factors such as too little or too much fluid on the slide, These tests, developed as economical tests for mass
thickness of smear, slide and cover slip, presence of screening, are not specific for T. pallidum therefore a
refractile elements in the specimen, etc. The test lacks variety of acute or chronic ailments may result in biolog-
reliability in case of oral lesions because saprophytic ical false-positive reactions. Also, these tests are reactive in
treponemes that cannot be differentiated from T. pallidum almost all patients with secondary and latent disease but are
are common in the oral cavity [3, 57]. less sensitive in patients with primary syphilis.
202 Head and Neck Pathol (2009) 3:195–206

Table 3 Interpretative outline

Nontreponemal tests Treponemal tests Significance
of serological tests
? ? Syphilis, yaws or pinta
? - Absence of syphilis; false positivity
- ? Primary or latent syphilis; prior, treated or
untreated syphilis; yaws or pinta
- - Incubating syphilis; absence of syphilis

The treponemal tests are considered today the most spirochetes are usually identified at the dermal-epidermal
sensitive and specific [3, 58]. These tests are the fluorescent junction and around the capillaries [60, 61].
treponemal antibody (FTA-ABS) and the T. pallidum In secondary syphilis of the skin ulceration may be
hemagglutination (TPHA) and the MHA-TP which is a present and the surface epithelium often demonstrates
modified version of TPHA. The former is able to reveal hyperplasia with significant spongiosis and exocytosis. The
syphilis antibodies in the patient’s serum in the early stage, most common histologic changes of secondary syphilis are:
while the last two become positive somewhat later during (a) superficial and deep perivascular infiltrate containing
the course of infection. The MHA-TP test is highly specific plasma cells; (b) lichenoid infiltrate obscuring the epithe-
([98%) and sensitive in patients with secondary syphilis. lial-lamina propria junction; (c) lichenoid as well as
The T. pallidum immobilization (TPI) test reveals specific superficial and deep perivascular pattern; (d) epithelial
antibodies after the second week of infection but is rarely hyperplasia, and (e) thickening and/or dilatation of lamina
employed because it requires live treponemes and is propria blood vessels. Of interest, a perineural plasmacel-
expensive. lular infiltrate can be seen in about 2/3 of cases of skin or
The diagnosis of secondary syphilis remains largely mucosal lesions [53–56, 60, 61].
clinical with support by serologic methods. The RPR and The usual method for detecting spirochetes in tissue
VDRL are uniformly positive (with high dilution: at least sections is the silver stain (Fig. 10); however, they are
1:32) in secondary syphilis; thus a negative or non reactive often difficult to detect due to marked background staining
test in a patient with a suspect of syphilitic rash in reality frequently seen with this technique. Alternative methods
indicates the absence of the infection [3, 57, 58]. In Table 3 for tissue detection of spirochetes are immunofluorescence
is reported an interpretation scheme of the serological tests using both fresh and fixed paraffin-embedded tissue
for syphilis. [62–64]. Another method is the use of the immunoperox-
Neurosyphilis is diagnosed in cerebrospinal fluid using idase method [65]. Hoang et al. [62] have found that
the same methods [3, 58]. immunostaining with polyclonal or monoclonal antibodies
against T. pallidum is a more sensitive and specific method
in comparison to the silver stain method for detecting
Histopathology
spirochetes in formalin-fixed, paraffin-embedded tissue of
secondary syphilis. Organism demonstrated by this method
The diagnosis of syphilis is often based on clinical and
serological findings without the employment of biopsy.
However, because of the multiform clinical manifestations,
rarity of oral lesions and unusual presentation in HIV?
patients, histological examination may be pivotal to con-
firm the diagnosis [2, 3, 60–62].
In primary lesions, the epidermis shows changes such as
acanthosis, spongiosis and exocytosis of lymphocytes and
neutrophils. In the center of the chancre, the epidermis is
thinner or completely absent and, when present, shows per-
meation of inflammatory cells. The connective tissue
appears edematous with a dense perivascular and interstitial
lymphohistiocytic and plasmacellular infiltrate which
occupies the whole dermis. Also an obliterative endarteritis
characterized by endothelial swelling and mural edema is
observed [60, 61]. Most of the features described above are
comparable to those observed in lesions of secondary syph- Fig. 10 Silver stain of syphilis showing the corkscrew-shaped
ilis. By silver staining or immunofluorescent techniques, treponemes (940)
Head and Neck Pathol (2009) 3:195–206 203

Fig. 11 Immunohistochemical method: the spirochetes are visible in Fig. 13 Secondary oral syphilis. A perineural and perivascular
the lower epithelial lamina (940) plasmacellular infiltrate is visible in the deep lamina propria (EE,
940)
can be seen, due to the near absence of background
staining, in the epithelial lamina, at the junction or in the syphilis, particularly if there is a perivascular distribution
connective tissue around capillaries (Fig. 11). [61]. However, it should be stressed that plasma cells are
Regarding oral syphilis, few papers have reported common in oral biopsies then their significance must be
detailed studies of its histological features and this may be critically evaluated [60, 66]. The presence of a plasma cell
due to the rarity of the oral manifestations or that biopsy is infiltrate which extents deeply into the lamina propria and
rarely taken [60]. Several Authors [60, 66] have stressed on around the capillaries is a finding that should suggests the
the fact that a key microscopic feature is plasma cell diagnosis of syphilis. As for skin syphilis a perineural
infiltration and proliferative endarteritis, at least in primary plasmacellular infiltrate has also been described in oral
and secondary disease. Endothelial cells proliferate within lesions (Fig. 13) [60].
small arteries and arterioles, producing a concentric lay- Oral tertiary syphilis typically shows absence of the
ering of cells that result in a narrowed lumen. Plasma cell, epithelial lamina with peripheral hyperplasia of pseudo-
along with lymphocytes and macrophages can be found in epitheliomatous type. The lamina propria contains foci
a perivascular distribution or as a band-like infiltrate in the of granulomatous inflammation (large central zone of
lamina propria (Fig. 12). The presence of plasma cells in acellular necrosis) with well-circumscribed collections of
skin is unusual and immediately raises the possibility of histiocytes and multinucleated giant cells. Despite the use
of special stains, the spirochetes are not found in gummas
[3, 60, 66].
In conclusion, although there is no single microscopic
feature specific to syphilis if the clinical information are
matched with the microscopic features the combination of
the two can provide a logical basis for further laboratory
investigations able to rule out the infection.

Principles of Treatment

Drugs of Choice

Benzathine penicillin G or aqueous procaine penicillin G

remains the drug of choice for all forms of syphilis. A
concentration of penicillin above 0.018 mg/L is considered
treponemicidal. However, serum concentration equivalent
Fig. 12 Secondary oral syphilis. Plasma cell, along with lymphocytes
and macrophages are visible as a band-like infiltrate in the lamina to the maximally effective in vitro level (0.36 mg/L) is
propria and with a perivascular distribution (EE, 920) recommended for at least 7–10 days in early syphilis and
204 Head and Neck Pathol (2009) 3:195–206

longer in late stage [67]. This drug is very effective in early Syphilis in HIV? Patients
syphilis and less effective in late stages. The principal
contraindication is hypersensitivity to the penicillins [3, 6, Treatment of HIV? patients with primary and secondary
67]. syphilis is the same as for HIV-negative patients. However,
Oral tetracyclines are also effective in the treatment of because syphilis in HIV? patients has a more aggressive
syphilis for patients who are allergic to penicillin. Tetra- course and treatment failure with benzathine penicillin may
cycline, 500 mg orally four time daily for 14 days, or occur more commonly, some Authors recommend a more
doxycycline 100 mg orally twice for 14 days are effective aggressive treatment as 3 doses of 2.4 million units of
against T. pallidum. These regimens are valid for primary, benzathine penicillin intramuscularly at weekly intervals
secondary, and early latent syphilis. In syphilis of more instead of a single administration [68, 69]. In HIV?
than 1 year’s duration (or unknown duration), treatment is patients, accurate clinical and serologic follow-up should
given for 28 days in the same dosage. Recent data suggest be done at 3, 6, 9, 12, and 24 months [3, 6].
that both ceftriaxone and azithromycin are effective for the
treatment of early syphilis [2, 3]. A problem with azith-
romycin is increasing resistance of T. pallidum [6, 67]. Comment

In recent years, syphilis outbreaks have been reported in

Primary Syphilis several parts of the world. The current epidemic in the US
and Europe has largely involved HIV? MSM. Since a
Benzathine penicillin G, 2, 4 million units intramuscularly misdiagnosis can have serious consequences for the patients
in the gluteal area, is given once. In penicillin-allergic clinicians should be aware of the protean manifestations of
patients: tetracycline, 500 mg orally four time daily for syphilis and difficulties in the diagnosis of the disease.
14 days, or doxycycline 100 mg orally twice for 14 days. Young clinicians in particular are no longer familiar with
the variable clinical symptoms and signs of syphilis.
Secondary Syphilis
Acknowledgement The authors thank Prof. Oslei Paes de Almeida,
FOP-UNICAMP, Brazil, for performing the immunohistochemistry
Therapy is as for primary syphilis. If neurosyphilis is reactions in Fig. 11.
present then treatment must be more aggressive (see
below).
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