Secondary syphilis presenting with elevated CA19-9: A report of two cases

Introduction

Syphilis, known as “the great imitator,” presents with diverse clinical features that mimic many diseases, ¹ leading to frequent misdiagnoses.^2–4 Despite numerous reports on its varied manifestations, the relationship between syphilis and elevated tumor markers, particularly carbohydrate antigen 19-9 (CA19-9), has not been well explored. CA19-9 is typically associated with pancreatic and biliary cancers but can also rise in benign conditions.^5,6 Here, we report two cases of secondary syphilis with elevated CA19-9 levels — both of which were measured inappropriately in the context of liver dysfunction as part of a malignancy workup — that normalized after treatment.

Case presentation

Case 1

A 64-year-old man presented with a 2-week history of low-grade fever and malaise, followed by a pruritic maculopapular rash and right upper quadrant pain. He had a history of unprotected sex with a non-marital partner 3–5 months prior. One year earlier, CA19-9 had been measured during a routine health checkup and was 8.7 U/mL. On admission, he was stable, with a rash on the trunk and back but no lesions on palms/soles, and no lymphadenopathy. Blood tests showed elevated CA19-9 of 2583 U/mL (reference, <37 U/mL) and liver enzymes (Table 1). Serologies for hepatitis virus, human immunodeficiency virus (HIV), and autoimmune diseases were negative. Magnetic resonance cholangiopancreatography (MRCP) revealed no obstructive or neoplastic lesions.

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Table 1.

Blood test findings on admission.

Laboratory findings	Case 1	Case 2	Reference
Aspartate aminotransferase (U/L)	69	62	13–30
Alanine aminotransferase (U/L)	88	57	10–42
Alkaline phosphatase (U/L)	788	1214	115–359
γ-glutamyl transferase (U/L)	803	577	8–38
Total bilirubin (mg/dL)	0.8	1.5	0.1–1.2
Carbohydrate antigen 19-9 (U/mL)	2,583	171	<37
Carcinoembryonic antigen (ng/mL)	-	3.3	<5
Rapid plasma reagin titer	1:64	1:132	-
T. pallidum hemagglutination titer	1:2560	-	-
T. pallidum antibody a (U/mL)	-	1796	<10
Hepatitis B surface antigen	Negative	Negative	Negative
Hepatitis C antibody	Negative	Negative	Negative
Human immunodeficiency virus antibody	Negative	Negative	Negative
Antinuclear antibody	Negative	Negative	Negative

^aLatex agglutination test.

Due to the rash and liver enzyme pattern, syphilitic hepatitis was suspected. Rapid plasma reagin (RPR) and Treponema pallidum hemagglutination (TPHA) tests were 1:64 and 1:2560, respectively, confirming secondary syphilis. He was treated with intramuscular benzathine penicillin G (2.4 million units). ⁷ After transient fever, likely a Jarisch–Herxheimer reaction, his symptoms resolved. CA19-9 and liver enzymes gradually normalized, with CA19-9 falling to 28.3 U/mL in 4 weeks. At 3 months, he remained well.

Discussion

We present two cases of elevated CA19-9 associated with secondary syphilis, in which no structural abnormalities were found and levels normalized after treatment, indicating a reactive elevation due to the infection.

Although CA19-9 elevation is primarily observed in pancreatic and biliary malignancies,^8,9 recent studies have shown that it can also occur in various benign, non-tumorous conditions. Proposed mechanisms for false-positive CA19-9 elevations in non-neoplastic diseases include inflammation, tissue regeneration, and epithelial injury. For example, in benign pulmonary diseases, CA19-9 elevation was observed in 81.3% of patients with idiopathic pulmonary fibrosis and 61.5% of those with healed tuberculosis. ¹⁰ Furthermore, in liver cirrhosis, 47.1% of patients had elevated CA19-9 levels, which were significantly correlated with liver enzyme levels, suggesting a possible link to hepatocellular injury and subsequent regenerative activity. ¹¹ Elevated CA19-9 has also been reported in other non-tumorous conditions such as autoimmune pancreatitis, diabetes mellitus, and post-vaccination inflammatory states, highlighting the non-specific nature of this marker.^12,13 Additionally, CA19-9 has been shown to correlate with inflammatory markers such as erythrocyte sedimentation rate and disease activity indices, further supporting the role of inflammation in these false-positive cases. ¹⁴

Secondary syphilis is a systemic inflammatory disease caused by the dissemination of T. pallidum, affecting multiple organs including the skin, mucous membranes, and lymph nodes, and syphilitic hepatitis is observed in about 3% of cases. ¹⁵ In our cases, three possible mechanisms may explain the elevated CA19-9 levels. First is an inflammatory response: as with other inflammatory diseases, secondary syphilis induces a systemic immune response involving cytokine release and activation of mucosal immunity, which may stimulate CA19-9 production even in non-malignant epithelial tissues. Second is tissue regeneration: in our cases, liver enzyme elevation was observed, suggesting hepatocellular damage and subsequent regeneration, which may have contributed to elevated CA19-9 levels in a manner similar to that seen in patients with liver cirrhosis. Third is epithelial changes: damage to the biliary epithelium due to syphilitic hepatitis may have caused the release of CA19-9 from epithelial cells, leading to elevated levels.

In conclusion, our cases highlight that secondary syphilis can cause transient CA19-9 elevation. These findings underscore the importance of considering infectious causes—especially in patients with relevant medical history or physical findings—when interpreting elevated tumor markers.