Syphilis: a re-emerging disease. An update for the dental practitioner

Syphilis is a chronic infection caused by the anaerobic filamentous spirochete, Treponema pallidum, with sexual contact the primary mode of transmission.¹ There has been a dramatic increase in the prevalence of syphilis in the Western world.² The incidence of syphilis in England has tripled in the last 10 years, rising from 2648 in 2010 to 7982 in 2019.³ Women and men of Black ethnic backgrounds experience the highest rate of diagnoses; however, most infectious syphilis diagnoses are made among those of white ethnicity.³ Although men who have sex with men (MSM) account for 78.4% of new diagnoses, there has also been a dramatic increase among heterosexuals. The increase in cases is clustered around large urban centres, primarily London, Brighton and Hove, Blackpool and Manchester.³ Of MSM infected with syphilis, approximately 40% have co-infection with HIV-1.⁴ Although syphilis is usually diagnosed by specialist sexual health services, initial presentation may present in other settings including dental practices. Oral manifestations of syphilis can mimic other diseases, including recurrent aphthous stomatitis, traumatic ulceration and, less commonly, vesiculobullous disorders. Therefore, establishing the diagnosis can be challenging. Dental practitioners should enquire about sexual history if the diagnosis is suspected. This avoids a delay in diagnosis and subsequent treatment, without which can lead to severe cardiovascular, ocular and neurological complications.⁵

As a result of the continued increase in cases with the associated morbidity from the disease, preventive measures were outlined by Public Health England's Action plan paper in 2019.⁵ The pillars addressed in this action plan include early detection and diagnosis, facilitated by maintaining professional awareness and knowledge of syphilis. The aim of this article is to raise awareness of the oral manifestations of syphilis to facilitate early diagnosis and referral for treatment. The variation in oral presentations of five cases seen between 2016 and 2021 in secondary care is illustrated (Table 1).

Case 1

A 34-year-old male attended with a 3-month history of persistent multiple painful ulcers involving the tongue. There were no systemic symptoms. The patient had a history of recurrent aphthous stomatitis and had previously been prescribed betamethasone tablets 500 µg to use as a mouthwash four times daily. The ulceration persisted despite topical corticosteroids. On presentation, there was a dense homogeneous white plaque involving the tongue, with a central ulcer. Owing to the persistent nature of the ulcer, an incisional biopsy was undertaken. Histopathology demonstrated ulceration with acute on chronic inflammation with distinct perivascular inflammation, suspicious of syphilis. Immunostaining was then carried out, which was positive for Treponema antibody-positive spirochetes. The patient was referred to the sexual health clinic for confirmation of syphilis and treatment.

Case 2

A 51-year-old male presented with a history of ulceration of the tongue and a wart involving the right lip, present for a number of weeks. There were no systemic symptoms. Medical history included gastro-oesophageal reflux disease and hypertension. Recent STI screen performed with his general medical practitioner (GMP) was negative. The patient was a smoker with a 30-year pack history. On examination, there was no lymphadenopathy. Intra-orally, there was a papillomatous lump involving the right commissure of the lip and a 2-cm round well-defined ulcer on the tongue. Owing to the persistent nature of the ulcer and smoking history, a biopsy was performed. This confirmed a squamous papilloma involving the lip. The ulcer was suspicious for syphilis owing to positive immunohistochemistry staining for Treponema antibody-positive spirochetes. One week following presentation, the patient developed lymphadenopathy. The patient was referred to a local sexual health clinic.

Case 3

A 47-year-old male was referred under the 2 week-wait pathway with multiple painless slow-growing lumps involving the dorsum tongue of 2 months' duration and a 6-week history of palatal lesions. There was no background medical history of note. On examination, well-circumscribed raised tender sessile lumps were noted on the dorsum tongue and soft/hard palate (Figure 1). Biopsy demonstrated epithelial hyperplasia, dense plasma cell infiltrate and invasive spirochete infection compatible with syphilitic mucositis following immunohistochemistry staining (Figure 2). Serology screen for syphilis was positive for Treponema antibodies (rapid plasma reagin) with a raised erythrocyte sedimentation rate of 42 mm/hour(reference range 0–10 mm/hour). The patient was referred to the sexual health clinic for treatment.

Case 4

A 56-year-old male was referred with a 3-week history of painless ulceration on the dorsum of tongue. The patient had a background of HIV with undetectable viral load. Current medications included antiretroviral therapy (Triumeq). On examination, there was generalized lymphadenopathy. Intra-orally, there was a 2-cm irregular ragged ulcer involving the dorsum of the tongue with no induration. Histopathology showed non-specific ulceration without malignancy. Following positive serological antibodies to T pallidum, further immunostaining performed at the request of the clinical team showed spirochetes in the epithelium and subepithelial tissue, supporting the diagnosis of syphilitic ulceration. The patient was referred to the sexual health clinic.

Case 5

A 49-year-old male was referred with a 2-month history of soreness and oral ulceration. The patient reported generally malaise, night sweats and unintentional weight loss over a 2-month period. The ulceration failed to respond to nystatin oral suspension, hydrocortisone pellets and fluconazole prescribed by the GMP. The patient had a history of HIV with undetectable viral load and hepatitis B. STI screen undertaken by the GMP was negative. On examination, there were multiple areas of ragged irregular ulceration involving the right and left lateral tongue, right buccal mucosa, right retromolar pad and anterior buccal commissures (Figure 3) suggestive of recurrent aphthous stomatitis. Owing to the persistent nature of the ulcers, biopsy was undertaken and showed ulcerated mucosa with a dense intra- and subepithelial plasma-cell inflammation. Immunohistochemistry showed numerous spirochetes in the epithelium. At review, the patient developed lymphadenopathy. Repeat serology confirmed Treponema antibodies and the patient was treated with intramuscular benzathine penicillin in the local sexual health clinic.

Discussion

Syphilis is primarily an acquired disease with sexual contact the most common mode of transmission. Treponema pallidum penetrates through the mucosa at the site of inoculation and continues to spread through the lympho-vascular system if left untreated.⁶ The incubation period varies between 3 and 90 days.⁷ The likelihood of developing syphilis following first exposure to an infected person is approximately 50%.¹ Unlike other sexually transmitted diseases, T pallidum is easily transmitted by oral sex, kissing and close contact with an infectious lesion.⁸ Transplacental transmission can also occur.¹ Less commonly, healthcare workers can acquire the infection if unprotected hands come in contact with infected areas.⁵ The age of presentation can vary, and in our cohort, the average age was 47 years. The majority of cases in heterosexual women occurs between the ages of 25 and 34 years, whereas in MSM and heterosexual men, it occurs later, between the ages of 35 and 64 years.³

Patients with syphilis progress through four characteristic stages, each with distinct clinical characteristics and rates of infectivity, although occasionally, the stages can overlap.

Primary syphilis

Primary syphilis is characterized by the chancre at site of inoculation, primarily genital, but can present intra-orally starting as a papule, which then ulcerates. HIV-1 co-infection is associated with reduced healing of the chancre.⁴ The majority of extra-genital chancres occur in the oral cavity, 40–75%.⁹ Oral manifestations are commonly seen on the lip, but can present on the buccal mucosa, tongue, palate, gingiva and tonsils. Regional lymphadenopathy is a common finding in 80% of patients and develops 7–10 days after development of the chancre. In our case series, Cases 2 and 5 both developed lymphadenopathy shortly after undergoing a biopsy procedure. If left untreated, the chancre heals within 3–8 weeks, but the infection continues to spread through the lympho-vascular system.⁶

Secondary syphilis

Developing 4–6 weeks after initial contact, if untreated, 25% of those infected develop secondary syphilis with non-specific symptoms – giving syphilis the title of ‘the great imitator’.¹⁰ Patients commonly present with fatigue, sore throat, malaise, fever and musculoskeletal pain. A distinct feature of secondary syphilis is a mucocutaneous rash with multiple red macules progressing into papules or pustules. If left untreated, the rash resolves over a few weeks.⁴

Approximately 30% of patients have focal white mucosal patches in the oral cavity. Less commonly, patients present with raised nodules in the mouth, known as condyloma lata, as seen in Case 3 (Figure 1).⁵ Although some studies have suggested an increased risk of oral squamous cell carcinoma (OSCC) in patients with syphilis, particularly on the tongue, links between syphilis and OSCC remain controversial. It is unclear whether any risk is a direct consequence of the disease, related to its treatment or related to the known causative risk factors for OSCC.¹²

Latent syphilis

After the secondary stage of infection, there is a latent period during which the patient does not show any clinical signs of infection. This can be divided further into early latent (<1 year) and late latent. Patients may still be infectious during the early latent phase.⁶

Tertiary syphilis

One-third of patients with untreated syphilis progress to tertiary disease, which can lead to irreversible damage.¹¹ Arising as early as 1 year, or up to 30 years after initial infection, this late syphilis is divided into gummatous, cardiovascular and neurosyphilis.^4,6,13 Gummas are granulomatous-like swellings of variable size, with a tendency to affect the hard palate and tongue.⁶ Initially developing as painless swellings, they progress into areas of ulceration that break down. There may be bone destruction with palatal perforation and oro-nasal fistula formation. Cardiovascular syphilis is rare with the ascending aorta the predominant site of damage resulting in dilation and aortic valve regurgitation. Neurosyphilis is caused by focal syphilitic endarteritis in the blood vessels of brain and spinal cord tissue leading to ischaemic stroke, cranial nerve palsies (trigeminal and facial) and progressive dementia.⁴

Congenital syphilis

Worldwide, the prevalence of congenital syphilis has increased four-fold in the last 10 years.⁷ Congenital syphilis is the second leading cause of preventable stillbirth globally, preceded only by malaria.¹⁰ In the UK, antenatal screening is carried out as part of infectious disease in pregnancy screening.⁴ Fetal mortality stands at approximately 40% due to late abortion, stillbirth or neonatal death.¹⁵T pallidum crosses the placenta after the 16th week in utero, hence, depending on the time of infection, the effects on facial structures vary.¹² The presence of signs at the time of delivery is dependent on duration of maternal infection and timing of treatment. Infants born with syphilis display signs within 2 weeks to 3 months.¹⁷

In 1858, Sir Jonathan Hutchinson described the pathognomonic changes found in congenital syphilis, also known as Hutchinson's triad: Hutchinson teeth, ocular interstitial keratitis and 8th nerve deafness.¹⁶ These changes are often described as late changes. Few patients have all these features. The dental changes alter the morphology of the anterior teeth, described as Hutchinson incisors, and the posterior dentition, described as mulberry molars. These anomalies only affect teeth mineralizing in the first year of life, with the incisors and first molars affected. Hutchinson incisors exhibit their greatest mesiodistal width in the middle third of their crown with teeth described as ‘screw driver’ with a characteristic notch in the incisal edge. Mulberry molars have distinct globular projections on the occlusal surface.⁸

We have summarized the most common oral manifestations in the larger case series published to date (Table 2). The largest series of 85 cases presenting to an oral medicine department in Brazil showed a slight male predilection, with a peak in the third and fourth decade. Most cases presented with oral ulceration or white patches, most commonly affecting the lips and tongue.¹⁹ A series of 12 cases showed the primary presentation as ulceration involving the tongue and palate and, less commonly, as white patches. They also described two cases presenting with rare hard palate gummas.²¹ The findings in the literature correlate closely to our cohort.^19,20,21 Patients presenting with oral syphilis are most likely to be middle aged and have ulcers or white patches, primarily on the tongue, lips and occasionally the palate.

The diagnosis of syphilis is usually based on a combination of clinical finding and serology. The serological laboratory tests for syphilis can be classed as non-treponemal tests for screening, and treponemal tests for confirmation. The non-treponemal screening tests (NTT) measure both IgG and IgM antibodies to antigens from T pallidum and include venereal disease research laboratory (VDRL) and rapid plasma reagin (RPR).¹⁸ The tests can either be used as a screening tool or as quantitative assays to monitor response to treatment.²² They do, however, detect IgM and IgG antibodies as early as 6 days post-infection.²³ However, they are not specific for syphilis, can produce false-positive results and alone, are insufficient for diagnosis.²⁴Treponemal tests look specifically for T pallidum or its components as antigens and are required for diagnosis.⁷ These qualitative tests include T pallidum haemagglutination assay (TPHA) and fluorescent treponemal antibody absorbed assay (FTA-Abs).¹⁶ More recently, Western blotting (WB) and the line immunoassay (LIA) have been added used as treponemal tests. Antibodies detected by treponemal assays appear earlier than those detected by NTT and typically remain detectable for life, even after successful treatment.²³

While the diagnosis of syphilis is often based on clinical and serological findings alone, histopathology is often necessary to exclude other oral pathology. The features of syphilis histologically on mucosa stained with haematoxylin and eosin are non-specific. The surface epithelium typically demonstrates hyperplasia; however, when ulceration is present, the epithelium is lost. A deep perivascular infiltrate containing plasma cells and endothelial cell infiltration is suspicious of syphilis, but is not diagnostic for the disease. Lichenoid band-like inflammation hugging the basement membrane can also be seen. Immunohistochemistry staining is essential to highlight and confirm Treponema antibody-positive spirochetes owing to the non-specific features seen on the mucosa stained with haematoxylin and eosin (Figure 2). Raising any clinical suspicions for syphilis in the clinical information to the pathologist is essential to ensure special Treponema-specific staining is undertaken.

Patients with syphilis are referred to a sexual health clinic and treated with stat intramuscular benzathine penicillin G 2.4 million units. High treatment success rates of 90–100% following IM benzathine penicillin G have been reported.²⁵ Late and late-latent infection is treated with 3-weekly injections of benzathine penicillin G 2.4 million units. Successful treatment of neurosyphilis requires the presence of adequate prolonged cerebrospinal fluid (CSF) concentrations of a treponemicidal antimicrobial with aqueous crystalline penicillin G being the treatment of choice.²⁵ Doxycycline 100 mg twice a day has also been recommended as an alternative in early syphilis, particularly for patients allergic to penicillin.⁴ Current treatment guidance is largely driven by clinical experience and expert opinion because there are limited data from clinical trials.²³

Partner notification, or contact tracing, is also essential to identify and treat new syphilis cases among sexual contacts of all individuals diagnosed with syphilis.^3,4 Treatment is more effective during the early stages, emphasizing the importance of early diagnosis. Additionally, testing for HIV status is also recommended.^4,18

The oral manifestations of early syphilis are managed using topical treatment. Treatment is usually only required for short-term use as oral manifestations resolve rapidly following systemic treatment. Benzydamine hydrochloride spray or mouthwash (0.15% w/v) used every 1.5–3 hours as required, and lidocaine hydrochloride gel (2%) applied as required on affected areas may be helpful for symptom relief. Patients with persistent oral ulceration may benefit from topical ‘triple’ mouthwash treatment (Cases 4 and 5 in our series) consisting of combined betamethasone 500 µg, nystatin 1 ml and/or doxycycline 100 mg up to four times daily.

Conclusion

Early detection of syphilis is essential to commence treatment quickly and avoid progression to later stages of disease with more serious implications. Dentists should be aware of the oral manifestations and know when to direct patients to appropriate services. While discussing sexual history may be not routine practice in a dental setting, with the increasing prevalence of syphilis in the UK, it is important to enquire about sexual practices if oral manifestations are suggestive of syphilis.