Exposing the Great Imitator: Proposal for a Holistic Diagnosis of Oral Secondary Syphilis in People Living with HIV

Abstract

Oral secondary syphilis may mimic various infectious, neoplastic, or immune-mediated processes; hence, its diagnosis may represent a challenge. Early diagnosis of syphilis, a disease that has increased in recent decades, is essential for adequate management, particularly in people living with HIV (PLWH). This study aimed to comprehensively characterize oral secondary syphilis in a group of 47 PLWH. A group of PLWH with oral secondary syphilis attending four HIV-referral centers in Mexico City was included (2004–2021). Clinical and laboratory data were retrieved, and an exhaustive oral examination was performed following the established criteria. Demographic, clinicopathological, immunohistochemical, and serological features of the patients were analyzed. Approximately 11% of PLWH with oral secondary syphilis demonstrated negative Venereal Disease Research Laboratory tests. A noticeable feature was the absence of symptoms in 95.7% of cases, despite the clinically evident appearance of the lesions. In contrast to previous results, 18% of ulcerations were detected to be deep, crateriform, and infiltrative, and 22% of the mucous patches were highly keratotic lesions. Most samples (77.3%) showed superficial lymphoplasmacytic infiltrates in the superficial lamina propria, with perivascular and perineural patterns, and immunohistochemistry was positive in 66.7% of the cases. The "great imitator" appears not only clinically but also histopathologically and immunohistochemically, where features may be comparable with those of chronic inflammatory processes, deep infections, or malignant processes. Although not recommended as a routine assay, IHC could be a critical tool, particularly in PLWH with atypical clinical features or with negative and/or dubious serology.

Introduction

Syphilis is a systemic sexually transmitted disease caused by Treponema pallidum that affects humans, invades several organs, and evolves through four overlapping stages: primary, secondary, latent, and tertiary [1, 2]. This disease remains a relevant public health challenge, particularly as coinfection among people living with HIV/AIDS (PLWH), and in 2019, the incidence of syphilis in PLWH was as high as 46% [1].

Since primary oral syphilis is asymptomatic and resolves spontaneously, most oral syphilis cases correspond to the secondary stage in both HIV and non-HIV-infected people [3–8], with the grayish-white mucous patches and superficial ulcers being the most common lesions [3, 4, 8]. However, in PLWH, the clinical and histopathological characteristics can overlap between the primary and secondary stages [8, 9].

Oral secondary syphilis may mimic various infectious, neoplastic, or immune-mediated processes [10]; hence, its diagnosis may represent a challenge. A definitive diagnosis may be achieved through the combination of the clinicopathological characteristics and the results of serologic assays (non-treponemal [Venereal Disease Research Laboratory {VDRL}, rapid plasma regain {RPR}], and treponemal [fluorescent treponemal antibody {FTA-Abs}, rapid treponemal assays]) [1].

Considering the significant variability in the clinicopathological spectrum of oral syphilis in PLWH and their serological results, it is critical to provide information to guide the correct diagnostic and therapeutic clinical decisions. Early recognition of clinical and histopathological features is essential for its early diagnosis and adequate management; thus, this study aimed to fully characterize the oral syphilis manifestations in a group of 47 PLWH.

Materials and Methods

A group of HIV-infected individuals attended the Oral Pathology and Medicine Service (Metropolitan Autonomous University) at four HIV/AIDS referral centers in Mexico City from 2004 to 2021 were included. The referral centers are two highly specialized institutes (the National Institute of Medical Sciences and Nutrition “Salvador Zubirán” and the National Institute of Respiratory Diseases), and two primary care centers for PLWH (Specialized “Condesa” Clinics). The institutional review boards of the participating institutions approved the research protocol, and each participant provided written informed consent before their enrollment.

Clinical and laboratory data (age, sex, HIV clinical stage, tobacco, and alcohol consumption, CD4 + lymphocyte counts, plasma HIV-RNA levels, current type and time of combined antiretroviral therapy [cART]) were retrieved from the medical charts.

Oral pathology and medicine specialists performed comprehensive oral examinations, following established definitions for oral syphilis diagnosis. In agreement with previous criteria [8, 11], oral lesions were classified and registered as erythematous maculae/plaques (flat-to-slightly raised, firm, red lesions), papular/nodular lesions (red, raised, firm round papules and/or nodules), mucous patches (slightly raised and covered by a grayish or white pseudomembrane, surrounded by erythema), and ulcers (oval erosions or shallow ulcerations of approximately 1 cm in diameter, covered by a grey mucoid exudate with an erythematous border).

In cases exhibiting erythematous macules, erythematous candidiasis was ruled out by the identification of Candida spp. hyphae in cytological smears stained with periodic acid-Schiff and/or the lack of antifungal treatment response. Likewise, herpesvirus infection was excluded in ulcers localized in keratinized oral mucosa, based on the absence of virus-infected cells in Pap-stained cytological smears and/or lack of clinical response to systemic antiviral therapy with acyclovir.

The VDRL test was performed to confirm syphilis diagnosis in most individuals, and FTA-Abs were completed in a few of them. Due to the differences in the facilities of each institution and the ease of monitoring patients, it was only possible to obtain a biopsy in 23 individuals. According to previous criteria [12–14], two oral pathologists (GAS and ICG) evaluated the histopathological features of 23 hematoxylin and eosin-stained slides. The parameters assessed included epithelium characteristics (hyperkeratosis, psoriasiform hyperplasia, poorly defined rete ridges, acanthosis, ulceration, micro-abscesses, neutrophils in stratum corneous, apoptotic keratinocytes, and exocytosis); inflammatory infiltrate pattern (lichenoid, superficial or deep lamina propria, perivascular, and perineural), the predominant type of inflammatory cells (lymphoplasmacytic and plasmacytic), and vascular structures (endarteritis and dilated vessels).

Immunohistochemical detection of T. pallidum was performed using a rabbit polyclonal antibody (BSB 3236, Bio SB, Santa Barbara, CA, USA) at a 1:2500 dilution. Endogenous peroxidase blocking was performed (Bio SB Santa Barbara, CA, USA). All slides were washed and treated with a diaminobenzidine substrate chromogen solution (DAB, Bio SB Santa Barbara, CA, USA) and counterstained with Harris' hematoxylin.

The information obtained was captured in a database using the SPSS v.25 software (IBM Corporation, Armonk, NY, USA). Descriptive statistics were used for the frequency distribution, and measures of central tendency (medians) and dispersion (interquartile intervals) were calculated. Bivariate analysis was performed using the chi-squared or Fisher's statistical tests.

Results

Here, we assessed 47 consecutive PLWHs with oral syphilis manifestations: 97.9% were men (n = 46), with a median age of 31 (Q₁–Q₃: 26–41) years; of these, 24 (51%) were smokers, and 47.6% (20/42) were alcohol consumers. As demonstrated in Table 1, 31 (65.9%) individuals were in the AIDS stage, and 74.5% (35/47) were using cART, with a median time of use of 27.5 (Q₁–Q₃: 7.7–61.7) months. Twenty-six (55.3%) individuals had undetectable levels of HIV viral load, with a median CD4 cells count of 372 (Q₁–Q₃: 190–631) cells/mm³. At the time of the oral examination, the included individuals also presented oral candidiasis (8/17.0%), recurrent aphthous stomatitis (3/6.4%), hairy leukoplakia (2/4.2%), and intraoral herpes simplex (2/4.2%).

Table 1.

Clinical characteristics of 47 HIV-infected individuals with oral syphilis manifestations

Characteristics	n	(%)
Males	46	(97.9)
Median age (years) (Q1–Q3)	31	(26–41)
Tobacco use	24	(51.0)
Alcohol consumption (n = 42)	20	(47.6)
AIDS*	31	(65.9)
Median nadir lymphocyte CD4 + count (cells/mm3) (Q1–Q3)	200	(76–354)
cART use	35	(74.5)
Median cART use (months) (Q1–Q3)	27.5	(7.7–61.7)
Undetectable HIV-viral load (copies/mL)	26	(55.3)
Median HIV-viral load (copies/mL) (Q1-Q3) (n = 19)	47,011	(6310–239,146)
Median Log10 HIV-viral load (Q1–Q3)	4.67	(3.80–5.38)
Lymphocyte CD4 + count (cells/mm3) (n = 45)
≤ 200	12	(26.7)
201–499	16	(35.5)
≥ 500	17	(37.8)
Median lymphocyte CD4 count (cells/mm3) (Q1–Q3)	372	(190–631)
Positive VDRL test (n = 45)	40	(88.9)
Positive FTA-abs test (n = 14)	14	(100)

cART combined antiretroviral therapy

*Individuals with CD4 + T-lymphocyte count of < 200 cells/mm3 and/or documentation of an AIDS-defining condition (A3, B3, C1–3)

A combination of serological, clinical, and histological diagnoses of syphilis was performed in 16 (34%) individuals. In 24 (51.1%) of them, the diagnoses were based on a combination of clinical and serological characteristics, and in seven (14.9%), clinical, histological and immunohistochemical features were sufficient to render the diagnosis. Although the FTA-abs test is not a part of the routine serological tests used to diagnose syphilis at our referral centers, 14 individuals demonstrated positive results in this assay. Conversely, five (11.1%) of the 45 individuals with VDRL tests had negative results; in four of them the diagnosis was established through the immunohistochemical T. Pallidum demonstration. However, in one of them (2%) due to the unspecific histopathological and serological characteristics, the polymerase chain reaction had to be used (PCR) to identify genomic sequences of T. Pallidum.

Most of the patients presented a unique type of oral syphilitic lesion (33/47, 70.3%), 13 (27.7%) showed two different oral manifestations, and one (2.1%) presented three different types of oral lesions. Figures 1, 2, 3 show representative images of oral secondary syphilis. A noticeable feature was the absence of symptoms in 95.7% of the cases, despite the clinically evident appearance of the lesions. The most frequent presentation was the mucous patches (n = 23, 48.9%), followed by ulcerative lesions (n = 11, 23.4%), erythematous maculae/plaques (n = 9, 19.1%), and papular/nodular lesions (n = 4, 8.5%). Five of the 23 mucous patches corresponded to well-defined keratotic lesions, also known as leukoplakia-like lesions; one had a condyloma lata appearance (Fig. 1C), and two of the 11 patients with ulcers (18.2%) exhibited deep, crateriform, and infiltrative ulcerative lesions (Fig. 2E–H).

Fig. 1.

Clinical diversity of oral mucous patches. A Typical presentation of mucous plaque on the right side of soft palate; B Extensive presentation with color changes in a tobacco user; C Mucous patches in hard and soft palate resembling the condyloma lata; D Mucous patches on retrocomisural mucosa; E, F Patches on lateral edges of the tongue that should be distinguished from hairy leukoplakia; G, H Two different aspects of highly keratinized mucous plaques, in areas where frictional keratosis due to chronic trauma should be ruled out

Fig. 2.

Clinical aspects of shallow and deep ulcers. A–D Shallow and well-limited ulcerations on the hard palate, mimicking oral herpes simplex virus infection. E–H Ulcers in trauma areas (the buccal mucosa and lingual edges) lead to wound chronification, exhibiting deep and raised edges, with mild symptoms

Fig. 3.

Clinical aspects of maculae and nodules. Erythematous diffuse macular lesions located on the hard palate (A, B), dorsum of the tongue (C), and labial mucosa (D) should be differentiated from erythematous candidiasis, acute trauma, or hypersensitivity reactions. The nodules on the dorsum of the tongue (E, F) can present different shapes and sizes, are asymptomatic, and generally are accompanied by other oral secondary syphilis manifestations

The most frequently affected sites were the soft palate, uvula, and oropharynx (n = 21, 44.6%), followed by the dorsum of the tongue (n = 9, 19.1%), lateral sides of the tongue (n = 6, 12.7%), hard palate (n = 4, 8.5%), buccal mucosa (n = 5, 10.6%) and labial mucosa (n = 2, 4.2%). Although mucous patches were located predominantly on the soft palate, uvula, and oropharynx (15/23, 65.2%), other frequent sites were the lateral sides of the tongue (n = 4, 17.4%), followed by the labial and buccal mucosa, dorsum of the tongue and hard palate in one case each. Ulcers were observed on the buccal mucosa (n = 4, 36.4%), lateral borders of the tongue (n = 2, 18.2%), and hard and soft palates (n = 2, 18.2% each one). The most common location for erythematous macules was the dorsum of the tongue (n = 4, 44.4%); the other sites were the soft and hard palates. Nodular lesions were observed only on the dorsum of the tongue, one of which had a florid presentation (Fig. 3).

Although not statistically significant, it is intriguing that almost a half of the individuals (14/31, 25.2%) with a unique type of lesion demonstrated CD4 + levels higher than 500 cells/mm³, in contrast with 58.3% (7/12) of individuals with two or three different clinical presentations with CD4 counts below 200 cells/mm³ (p = 0.099). We did not detect any differences between the number of lesions and other clinical, laboratory, or histopathological characteristics.

Twelve (25.5%) individuals presented a maculopapular rash covering the trunk and/or palmar and plantar lesions; additionally, two (4.2%) demonstrated alopecia in the eyebrows and eyelashes. Moreover, nine out of 10 (90%) individuals with skin manifestations demonstrated mucous patches as the primary oral manifestation (p = 0.074).

Histopathological analysis was performed on 23 individuals, showing that acanthosis, hyperkeratosis, microabscesses, and lymphocytic exocytosis were prominent epithelial findings among all clinical presentations (Fig. 4). The most common type of inflammatory infiltrates were lymphoplasmacytic (77.3%), located on the superficial lamina propria (60.9%), and exhibiting perivascular and perineural patterns in 60.9% and 43.4% of the cases, respectively. Endarteritis was detected in approximately half of the patients (43.4%). Moreover, acanthosis was present in mucous patches and ulcers, whereas psoriasiform hyperplasia was the primary finding in erythematous maculae/plaques and lingual papular/nodules. No significant associations between the clinical and histopathological characteristics were detected (Table 2).

Fig. 4.

Histopathological and immunohistochemical representative images of oral syphilis. A Epithelial hyperplasia with psoriasiform changes (hematoxylin and eosin [H&E], × 200); B Prominent diffuse plasma cells infiltrates (H&E, × 400); C A proportion of cases showed mixed inflammatory including lymphocytes and eosinophils (H&E, × 400); D Endarderitis in a blood vessel surrounded by predominantly plasmacytic infiltrates (H&E, × 200; E, F Coiled spirochetes at the basal and parabasal strata (T. pallidum immunostain × 200), attached at the epithelial cell surface (F) (T. pallidum immunostain × 400); G In few cases spirochetes groups are found at the lamina propria, and into blood vessels; H (T. pallidum immunostain × 400)

Table 2.

Summary of histological characteristics in 23 biopsies from cases of secondary syphilis

	Erythematous maculae/plaques (n = 4)		Mucous patches (n = 11)		Ulcerative lesions (n = 6)		Lingual papular/nodules (n = 2)		P	Total (n = 23)
	n	(%)	n	(%)	n	(%)	n	(%)		n	(%)
Epithelial changes
Hyperkeratosis	2	(50.0)	6	(54.5)	3	(50.0)	1	(50.0)	0.977	12	(52.2)
Psoriasiform hyperplasia	3	(75.0)	4	(36.4)	2	(33.3)	2	(100)	0.217	11	(47.8)
Poor defined epithelial rete ridges	1	(25.0)	5	(45.5)	–	–	–	–	0.747	6	(26.1)
Elongated rete ridges	–	–	2	(18.2)	1	(16.7)	–	–	0.174	3	(13.0)
Acanthosis	1	(25.0)	8	(72.7)	4	(66.7)	–	–	0.130	13	(56.5)
Micro abscesses	2	(50.0)	5	(45.5)	2	(33.3)	1	(50.0)	0.946	10	(43.4)
Neutrophils in stratum corneum	1	(25.0)	3	(27.3)	–	–	1	(50.0)	0.419	5	(21.7)
Apoptotic keratinocytes	–	–	2	(18.2)	2	(33.3)	–	–	0.507	4	(17.4)
Lymphocytic exocytosis	3	(75.0)	9	(81.8)	5	(83.3)	2	(100)	0.899	19	(82.6)
Type of inflammatory infiltrate
Lymphoplasmacytic	4	(100)	8	(72.7)	4	(66.7)	1	(50.0)	0.484	17	(77.3)
Plasmacytic	–	–	2	(18.2)	2	(33.3)	1	(50.0)		5	(22.7)
Pattern of inflammation
Lichenoid	1	(25.0)	2	(18.2)	2	(33.3)	1	(50.0)		6	(26.1)
Superficial lamina propria	2	(50.0)	9	(81.8)	2	(33.3)	1	(50.0)	0.237	14	(60.9)
Deep lamina propria	2	(50.0)	3	(27.3)	3	(50.0)	1	(50.0)	0.742	9	(39.1)
Perivascular	1	(25.0)	8	(72.7)	4	(66.7)	1	(50.0)	0.393	14	(60.9)
Perineural	–	–	5	(45.5)	4	(66.7)	1	(50.0)	0.218	10	(43.4)
Endarteritis	2	(50.0)	6	(60.0)	3	(50.0)	–	–	0.355	10	(43.4)
Dilated vessels	1	(25.0)	3	(30.0)	2	(33.3)	–	–	0.823	6	(26.1)

IHC was performed on 18 biopsies, with a positivity rate of 66.7% (n = 12). Ten samples (83%) exhibited the immunostaining predominantly on the epithelia, mostly (n = 7) on the basal and parabasal strata (Fig. 4), and two samples (17%) demonstrated a high quantity of spirochetes in the superficial lamina propria. In the six cases with negative IHC, the diagnosis of syphilis was made through the concoction of clinical, serological, and histopathological characteristics.

Discussion

This study illustrates the diversity of clinical and histopathological manifestations in PLWH, which is highly relevant because of the increase in the incidence of syphilis in recent years. Furthermore, since syphilis may go unnoticed by health personnel, the delayed diagnosis affects the progression in the individuals, causing severe systemic damage and leading to more syphilis cases as the individuals are not aware of their condition.

Our study population primarily comprised men (97.9%) like other studies (92–97%), in which PLWH accounted for 37–42% [5, 15]. However, in most studies on non-HIV-infected individuals with oral syphilis, the proportion of men varied from 51 to 60% [3, 6, 7], while in others, the proportion of non-HIV females accounted for 42%-57% [16–18]. These data support the rise in rates of acquired syphilis among women observed since 2012 [1, 19, 20], either in high-risk (transgender and sex workers) or non-high-risk populations of Latin American countries such as Argentina, Guatemala, and Brazil [21].

Moreover, the median age of the individuals included in this study (31 years) is comparable to that reported in both PLWH (31–32 years) [8, 22] and to the mean age of non-HIV-infected individuals (33–34 years) in the Latin American studies [3, 22]. Nevertheless, it differs from the mean age of 42 years observed in HIV-infected individuals from France [5] and in a series from the United States of America [10].

Regarding the clinical appearance of oral syphilis, mucous patches, described as white/pink lesions with a serpentine or snail-track pattern [3, 7, 10, 11, 17], represent the most common clinical appearance in this study as has been described in HIV-infected and non-HIV-infected individuals. In a previous study [4] of 105 non-HIV-infected individuals with oral syphilis, 80.9% had mucous patches, followed by erosive/ulcerative lesions (31.4%). Furthermore, other short case series in both PLWH and non-HIV individuals [16, 17] reported mucous patches as the only or primary clinical presentation. We found that the appearance of the mucous patches could be highly variable, with erosive or ulcerated areas. Previous reports have reported a combination of mucous patches and ulceration in 67.5% of the cases [7].

A remarkable finding was prominent keratinization in some mucous patches, which warrants ruling out irritative or viral factors in the differential diagnosis. Since there is still a lack of uniform terms for the description of oral syphilis, some authors have used the term leukokeratotic or leukoplakia-like plaques for this appearance [5, 17, 23]. However, this term should be used with great caution, as it can be confused with oral leukoplakia or suggest the diagnostic or clinical management of a potentially malignant disorder.

Similar to our observations in two cases, mucous patches located at the lateral sides of the tongue could mimic hairy leukoplakia [8], which is of great importance for identifying HIV/AIDS new cases or immunocompromise in already diagnosed PLWH. Furthermore, the differential diagnoses included lichen planus, traumatic ulcers, pemphigus vulgaris, leukoplakia, geographic tongue, and hairy leukoplakia [4, 6, 7, 24].

In this regard, we propose to consider that not all oral syphilitic ulcers exhibit a superficial or shallow appearance. Although most of them are truly shallow, covered by a grey mucoid exudate and with an erythematous border [8], if persistent irritating factors are present, the ulcers can be more extensive, deep, and exhibit crateriform edges, which require the inclusion of other chronic entities in the differential diagnosis [25].

Moreover, there is an occasional presence (5–22%) of raised papillary gray/white mucous patches [11], also described as whitish verrucous plaques [26], resembling the descriptions of genital/anal areas, known as condyloma lata [27–29]. In these cases, the differential diagnosis may include condyloma acuminatum [10]. Thus, histopathological analysis is critical because treating these lesions with cryotherapy or surgery leads to potential infection dissemination.

Following our previous findings [8], the soft palate, uvula, and oropharynx were the most frequently affected sites, followed by the dorsum of the tongue, as reported by most authors [5, 10, 16]. Likewise, the tongue and lips were the most common locations in other cases series [3, 4, 7, 17, 30]. However, as reported in other studies on PLWH and non-HIV individuals [4, 7, 8, 10, 17], the oral presentation of our patients was primarily multicentric; thus, it was challenging to precisely locate the most common site.

Correspondingly, the histopathological description of oral syphilis is quite relevant since, in PLWH, the microscopic characteristics could also vary. The “great imitator” appears not only in the clinic but also in the histopathology setting, where specific features may be like those in chronic inflammatory processes, deep infections, or even malignant transformation of the epithelium.

Although plasmacytic infiltration has been described as a conspicuous characteristic of secondary syphilis [3, 12, 13, 15], 81% of the samples included in this study showed lymphoplasmacytic infiltration in the superficial lamina propria, with perivascular and perineural patterns. This feature has been previously reported [8, 10, 30, 31] and confirmed using IHC [15, 32]. An earlier study described mixed chronic infiltrates, with a high proportion of T cells (CD3 +) at the subepithelial level and plasma cells (CD138 +) located primarily in the deep lamina and perivascular [32]. This finding is particularly relevant considering that in skin biopsies, the predominance of plasma cells is a diagnostic key for syphilis [14], whereas, in the gingiva, these cells are commonly detected, which can lead to misdiagnosis, particularly by inexperienced oral pathologists.

Another significant histopathological feature is vascular involvement with obliterating endarteritis [8, 12, 13, 30, 32], which was identified in approximately half of our cases. In vitro studies have demonstrated that T. pallidum vasculotropism stimulates endothelial cells and vascular smooth muscle cells to produce cytokines (interleukin-6), chemokines (monocyte chemoattractant protein-1), and adhesion molecules (intercellular adhesion molecule-1), thereby promoting inflammation [33].

At the epithelial level, the main features observed were hyperkeratosis, acanthosis, lymphocytic exocytosis, and microabscesses, which is consistent with previous studies [3, 9, 10, 12, 13, 30–32]. Exocytosis was a significant finding (86%) in all lesions. However, activated T cells and macrophages favoring epidermal inflammatory infiltration [32] over-infection by Candida spp. in the oral mucosa in PLWH could make this characteristic more prominent.

Moreover, psoriasiform epithelial proliferation [8, 9, 13, 30] and pseudoepitheliomatous hyperplasia (PEH) are common findings in oral syphilis biopsies [8, 25, 32]. Even when we did not detect cases showing PEH, it is essential to highlight the PEH could exhibit carcinoma-like features [34], particularly adjacent to ulcerated areas with a significant underlying inflammatory component. To exclude malignant epithelial transformation, minimal or no cellular atypia and lack of atypical mitotic activity should be cautiously identified.

False-negative serological tests are frequently associated with HIV-infected patients owing to prozone phenomena [35]. This finding appears in 0.83–2% of patients, and it causes an abnormal B-cell activation leading to excess antibody production [36], in addition to an atypical synthesis of IL-17 by γδ T cells in response to T. pallidum presence [37].

In agreement with our cases, the IHC sensitivity has been reported to range from 49 to 92% [38], being high in early primary and secondary syphilis and diminishing in later stages due to a decrease in the number of microorganisms in the lesions [38, 39]. Although not recommended as a routine assay, IHC is a critical tool, particularly in PLWH with atypical clinical features or negative and/or dubious serology.

As shown in Fig. 5, the diagnosis of syphilis may require confirmatory tests. Besides clinical, histopathological, immunohistochemical, and serological results, the use of additional tools such as IHC and PCR will allow reliable diagnoses in some challenging cases. All the methods acknowledged have an important role in various stages of syphilis.

Fig. 5.

Diagnostic algorithm for syphilis’ suggestive oral manifestations

In summary, this 17-years report enhances our knowledge regarding oral syphilis, highlighting the need to standardize clinical descriptions. Expanding knowledge about the spectrum of oral syphilis is essential, including highly keratinized forms of mucous patches and deep ulcers, is essential. Furthermore, the significant increase in syphilis cases in recent years makes it imperative for health professionals to identify the signs and symptoms of oral lesions of syphilis for its early diagnosis and treatment.

Authors Contributions

All the authors contributed to the study conception and design of the study. Material preparation, data collection and analysis were performed by all authors. All the authors wrote, read, and approved the final manuscript.

Funding

No funds, grants, or other support was received for the submitted work.

Data Availability

The data that support the findings of this study are available on request from the corresponding author.

Code Availability

All the cases enrolled in the study were coded and the data is available.

Declarations

Conflict of interest

The authors have no conflict of interest to declare that are relevant to the content of this article.

Ethical Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was obtained from the Ethics Committee of the Metropolitan Autonomous University (March 2005, May 2006, March 2013, December 2021. Agreement 18/21.2.1).

Consent to Participate

Written informed consent was obtained from all the individuals included in the study.