Primary syphilis with a tongue ulcer mimicking tongue cancer: a case report

Introduction

Syphilis is a systemic infectious disease caused by Treponema pallidum (T. pallidum) and a major sexually transmitted disease (STD). ¹ The main symptom in primary syphilis is a small, painless, sore or ulcer called a chancre on the penis, vagina, or around the anus, although lesions can sometimes appear in the mouth or on the lips, fingers, or buttocks. In late-stage syphilis, various symptoms in different organs, including rash, warts, white patches in the mouth, flu-like symptoms, swollen glands, patchy hair loss, and ocular, vascular, and neurological symptoms occur. ¹ Thus, syphilis is likely to be misdiagnosed as other diseases owing to the nonspecific symptoms, and the disease is referred to as the “great imitator”. ² Symptoms caused by syphilis are similar to those of other infectious diseases and non-communicable diseases, including autoimmune diseases and malignant tumors. ² Recent global trends have shown an increase in syphilis cases in high-income countries among men who have sex with men (MSM).^3–5 Furthermore, increasing rates among women, although still relatively low, have been observed in a number of countries, leading to concerns regarding mother-to-child transmission of syphilis and congenital syphilis. ⁴

Here, we present the case of a man in his early 60 s with a chief complaint of a painful tongue ulcer. We initially misdiagnosed his disease as tongue cancer; however, during a subsequent detailed examination for a malignant tumor, his disease was finally identified as primary syphilis.

Case report

A man in his early 60 s visited our hospital with a chief complaint of pain on the left edge of his tongue. He had a history of type 2 diabetes and took oral ipragliflozin L-proline. He had no particular family history and did not drink alcohol. He had a smoking history of 60 cigarettes/day for 37 years from age 20, but had used e-cigarettes for the previous 3 years. He had visited a nearby dental clinic owing to a painful ulcer on the left margin of his tongue approximately 1.5 months earlier, and had been diagnosed with aphthous stomatitis. He was treated with topical steroid ointment for 1 month, but the ulcer did not heal.

Subsequently, the patient was referred to our hospital. At the initial visit, he was 164 cm tall, weighed 65 kg, and had good nutritional status. His face was asymmetrical, with left submental swelling (Figure 1a) and no facial nerve palsy or mandibular nerve hypoesthesia. Palpation of the left submandibular area identified several abnormal cervical lymph nodes; one was the size of the tip of the index finger with elastic firmness, mobility, and tenderness, and two further back were the size of a soybean, with elastic firmness, mobility, and no tenderness. In the right submental area, a lymph node the size of the tip of the index finger was palpated, with elastic firmness, mobility, and tenderness. An ulcerated lesion (23 × 14 mm) was found on the ventral surface of the tongue, near the oral floor, with indurated and hemorrhagic surrounding tissues (Figure 1b).

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Figure 1.

Clinical findings at the initial visit. (a) The patient had facial asymmetry with left submental swelling, with no facial nerve palsy or mandibular nerve hypoesthesia and (b) An ulcerated lesion (23 × 14 mm) was found on the ventral tongue surface near the oral floor, with indurated and hemorrhagic surrounding tissues.

Blood tests revealed mild anemia (hemoglobin (Hb): 122 g/L), liver dysfunction (gamma glutamyl transpeptidase (GGT): 142 U/L), blood glucose: 8.6 mmol/L, C-reactive protein (CRP): 50.1 mg/L, and HbA1c: 68 mmol/mol (Table 1). Panoramic radiography revealed vertical bone resorption in the mesial side of the left mandibular second molar. Caries were detected in multiple teeth, with no other abnormal findings in the jaw bones (Figure 2a). Tongue cancer with cervical lymph node metastasis was suspected on the basis of the clinical findings, and an immediate biopsy of the left margin of the tongue was performed at the initial visit.

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Table 1.

Laboratory test results at the initial visit.

Parameter	Value	Parameter	Value
White blood cell count	6.1 × 109/L	Total bilirubin	10.2 µmol/L
Red blood cell count	3.97 × 1012/L	Direct bilirubin	3.4 µmol/L
Hemoglobin	122 g/L	Indirect bilirubin	6.8 µmol/L
Hematocrit	38.3 L/L	Total protein	83 g/L
Mean corpuscular volume	96.5 fL	Albumin	37 g/L
Mean corpuscular hemoglobin	30.7 pg	Cholinesterase	284 U/L
Mean corpuscular hemoglobin concentration	319 g/L	Urea	6.0 mmol/L
Red cell distribution width	13.4 fL	Sodium	140 mmol/L
Platelet count	360 × 109/μL	Potassium	4.3 mmol/L
Neutrophils	65.6%	Chloride	105 mmol/L
Eosinophils	2.5%	Creatinine	60 µmol/L
Basophils	0.7%	Estimated glomerular filtration rate	89.1 mL/min
Monocytes	6.8%	Glucose	8.6 mmol/L
Lymphocytes	24.4%	C-reactive protein	50.1 mg/L
Aspartate aminotransferase	23 U/L	Hemoglobin A1c	68 mmol/mol
Alanine aminotransferase	28 U/L	Qualitative rapid plasma reagin	4.0 RU
Alkaline phosphatase	479 U/L	Qualitative T. pallidum antibody	140.0 TU
Lactate dehydrogenase	150 U/L	Hepatitis B surface antigen	(−)
γ-Glutamyl transpeptidase	142 U/L	Hepatitis C virus antibody	(−)

T. pallidum, Treponema pallidum.

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Figure 2.

Imaging findings. (a) Panoramic radiograph showing vertical bone resorption on the mesial side of the left mandibular second molar. Caries was detected in multiple teeth, with no other abnormal findings in the jaw bones. (b) Contrast-enhanced computed tomography (CECT) imaging showing no marked changes in the left tongue or bone destruction in the mandible. Lymph node swelling (minor axis: 2–19 mm) is visible bilaterally in several submandibular lymph nodes and the upper internal jugular lymph nodes, without rim enhancement. (c) Contrast-enhanced magnetic resonance image (eMRI) showing a contrast-enhanced area from the left margin of the tongue to the mylohyoid muscle and (d) ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) image showing mild accumulation in the left margin of the tongue, The standardized uptake value (SUVmax) was 3.6, and accumulation was evident bilaterally in several swollen submandibular lymph nodes (SUVmax: 2.8–5.2).

Further imaging examination was performed before a histopathological diagnosis was obtained. Contrast-enhanced computed tomography (CECT) revealed no marked changes in the left tongue or bone destruction in the mandible. Lymph node swelling (minor axis: 2–19 mm) was found widely in bilateral submandibular lymph nodes and the upper internal jugular lymph nodes (Figure 2b), with no rim enhancement. Contrast-enhanced magnetic resonance imaging (eMRI) revealed an enhanced area from the left margin of the tongue to the mylohyoid muscle, swelling of different degrees in the right and left submandibular nodes and superior internal jugular nodes, and lymph nodes with heterogeneous inner regions and rim enhancement (Figure 2c). ¹⁸F-Fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) showed mild accumulation in the left margin of the tongue. The maximum standardized uptake value (SUVmax) was 3.6, and accumulation was evident in several swollen submandibular lymph nodes bilaterally (SUVmax: 2.8–5.2) (Figure 2d). No abnormal accumulation was detected in other organs. On the basis of these findings, the tongue lesion was clinically diagnosed as tongue cancer with cervical lymph node metastases (T2N2cM0).

Blood tests on admission were performed in preparation for immediate surgery while awaiting the biopsy result. High titers of 4.0 RU in a qualitative rapid plasma reagin (RPR) test and 140.0 TU in a qualitative T. pallidum antibody test were obtained. On the basis of these results, the tongue lesion was suspected to be hard chancre, and the lymph node swelling was considered lymphadenitis caused by syphilis, rather than tongue cancer and lymph node metastasis. Consequently, the patient was interviewed again about his behavior and lifestyle, which revealed that he had engaged in sexual intercourse that might have led to infection with syphilis 49 days before the first visit. There were no abnormal findings on the patient’s penis or at sites other than the oral cavity and cervical lymph nodes.

Histopathological examination showed no atypical cells in the epithelium and interstitium; however, slightly swollen nuclei were seen in epithelial cells, with spongiosis and epithelial detachment. Mild infiltration of plasma cells and lymphocytes was found in intraepithelial and subepithelial connective tissues (Figure 3). These pathological results excluded malignant tumor. Thus, the final diagnosis was primary syphilis on the basis of clinical findings, blood test results, imaging findings, and the history of sexual intercourse.

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Figure 3.

Histopathological image showing no atypical cells in the epithelium and interstitium, but slightly swollen nuclei in epithelial cells, as well as spongiosis and epithelial detachment. Mild infiltration of plasma cells and lymphocytes is visible in the intraepithelial and subepithelial connective tissues (hematoxylin and eosin, ×40).

The patient was examined in the Department of Diagnostic and Generalist Medicine as well as the departments of Dermatology and Ophthalmology, and was confirmed not to have syphilis-related rash or uveitis. Additionally, polymerase chain reaction testing for gonococcal and chlamydial organisms in samples from the oral cavity, and serum human immunodeficiency virus (HIV) antibody test results were negative. Treatment with oral amoxicillin (2.0 g/day) and probenecid (2.0 g/day) was started in the Department of Diagnostic and Generalist Medicine, and after 14 days, there was partial reduction in the swelling in the submandibular lymph nodes, size of the ulcer on the left margin of the tongue, and extent of the induration on the oral floor. After 1 month of treatment, the tongue ulcer and oral floor induration had disappeared (Figure 4), and oral amoxicillin and probenecid were stopped. No findings indicating relapse have occurred in the 1-year follow-up.

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Figure 4.

After 1 month of treatment, the tongue ulcer and induration on the oral floor had disappeared.

Discussion

The lesion in our patient was diagnosed as tongue cancer owing to the refractory tongue ulcer and surrounding induration, with lymph node swelling found by inspection and palpation during the first physical examination. The cervical lymph node swelling was suspected cervical lymph node metastasis. However, swelling in multiple cervical lymph nodes bilaterally and moderate FDG accumulation in these lymph nodes suggested that this was not typical for cervical lymph node metastasis of tongue cancer. Therefore, specific inflammation was considered in the differential diagnosis. At this point, T. pallidum infection was detected on blood examination.

Patients with primary syphilis develop hard chancre at the infected site 2 to 6 weeks after infection; however, patients usually have no subjective symptoms, including pain, and seldom visit a hospital because hard chancre disappears spontaneously 4 to 10 weeks later.^2,6–11 After symptoms of primary syphilis disappear, the disease transitions to a secondary stage through a latent period of 4 to 10 weeks.^2,6–11 The patient in this case visited our hospital 49 days after the sexual intercourse, which was likely during the latent period of the infection, and this made it difficult to differentiate primary syphilis from secondary syphilis. Because no systemic symptoms and signs except those in the oral cavity and cervical lymph nodes were found after the identification of syphilis infection in our hospital, the most reasonable diagnosis was primary syphilis contracted orally.

The number of patients with syphilis in Japan increased by eight times from 875 cases (0.7 per 100,000) in 2012 to 7007 cases (5.5 per 100,000) in 2018. ¹ A similar trend occurred in China, with an increase from 135,210 cases in 2005 to 441,818 cases in 2014, and the rates were 6.1 per 100,000 in 2016 in the European Union (EU) ³ and 9.5 per 100,000 in 2018 in the United States. ⁴ Worldwide, the numbers of patients with syphilis have increased among MSM in high-income countries, ⁴ and there might be many patients with syphilis as endemic disease in low-income countries, despite the absence of official statistics.

Syphilis is sometimes diagnosed as another disease owing to its nonspecific symptoms, and, as a result, it is referred to as the “great imitator”. ² Differential diagnosis is required for infectious lesions, namely, STDs, such as gonorrhea, Chlamydia, HIV, and herpesvirus infection; tuberculosis, and some nonspecific viral, bacterial, and fungal infections; ⁵ non-communicable diseases, including autoimmune diseases, such as Behcet’s disease, sarcoidosis, systemic lupus erythematosus (SLE), and dermatomyositis; and malignant tumors, such as squamous cell carcinoma and malignant lymphoma. ⁶ Cases of a rectal mass as a presentation of primary syphilis misdiagnosed as rectal cancer have been reported. ⁷ Primary syphilis, which is the early phase of the infection, develops as an indolent ulcer (referred to as hard chancre) in infected areas and is sometimes accompanied by indolent lymphadenopathy. ⁸

Li et al. reported a case of secondary syphilis misdiagnosed as sarcoidosis on the basis of eruptions on the face, bilateral upper thighs, and scrotum. ⁹ The case involved a heterosexual man in his 20 s with a diagnosis of HIV infection with generalized eruption as the primary symptom. Biopsy of a skin lesion at another facility revealed non-necrotizing granulomatous inflammation consistent with sarcoidosis; however, the lesion did not improve despite steroid therapy. The attending physicians performed RPR testing as a routine test for newly HIV-infected patients and identified a high titer. Therefore, immunohistochemical staining and PCR for T. pallidum were performed on existing biopsy specimens, and a definitive diagnosis of secondary syphilis was obtained.

There are also case reports of syphilis misdiagnosed as malignant tumors. Cerchione et al. suspected disseminated lymphadenopathy of malignant lymphoma in a male patient in his 50 s, on the basis of the results of FDG PET/computed tomography (CT). ¹⁰ The patient had hepatosplenomegaly, fever, nocturnal sweats, and weight loss. A biopsy was performed, but the results showed only nonspecific reactive hyperplasia. The patient developed a non-pruritic skin rash 4 months later, and additional investigation revealed a history of high-risk sexual intercourse. Serological testing for syphilis was repeated, which showed high titers (the initial screening was negative), and a late diagnosis of secondary syphilis was made.

Saito et al. performed a close examination of a dorsal mass on the tongue with cervical lymphadenopathy in a man in his 80 s, considering the possibility of cervical lymph node metastasis from tongue cancer. ¹¹ However, as in our case, the authors considered that the findings were atypical for tongue cancer; therefore, they biopsied the tongue and cervical lymph nodes. The authors also considered the possibility that the cervical lymph node swelling indicated malignant lymphoma unrelated to the tongue mass. The biopsy results showed only inflammatory cell infiltration, mainly immune cells, in both the tongue and lymph node specimens. On the basis of these results, the authors considered the possibility of oral syphilis and diagnosed oral primary syphilis on the basis of the blood test results.

These three “misdiagnosis” reports^9–11 were case reports in high-income countries (United States, Europe, and Japan, respectively). As we did, one of the reasons the authors of these reports struggled to diagnose their cases may be that syphilis is still poorly recognized, as the “great imitator”.

Conclusions

There has recently been a marked increase in the number of patients with syphilis in Japan. Thus, syphilis should not be considered a forgotten disease, but instead, should be diagnosed using serological tests in suspected cases. We suggest that dentists consider syphilis as a differential diagnosis for oral refractory ulcers with induration and obtain a detailed patient history.

Research Data