When Syphilis Imitates Cancer: A Case of Misdiagnosed Cutaneous T-Cell Lymphoma and Literature Review

1. Introduction

Syphilis, caused by Treponema pallidum, has long been known as “the great imitator,” owing to its complex presentations across dermatologic, neurologic, cardiovascular, and hematologic systems [1]. In its secondary stage, syphilis frequently manifests with mucocutaneous lesions and generalized lymphadenopathy, but in atypical cases, its features overlap with malignant or autoimmune diseases [2,3]. This diagnostic challenge is compounded by the nonspecificity of modern imaging, such as FDG-PET-CT, which may show hypermetabolic lymph nodes in both malignant lymphoma and reactive infections [4,5].

Unusual presentations of syphilis have been reported, including pulmonary nodules, gastric masses, cervical ulcerations, skin rash, and widespread lymphadenopathy, often leading to an initial misdiagnosis of lymphoma or carcinoma [5,6,7,8,9,10,11], as presented in Table 1. Malignant syphilis, particularly in immunocompromised individuals such as those with HIV, may histologically and clinically resemble cutaneous T-cell lymphomas (CTCL) [7].

Given its rising incidence globally, especially among at-risk populations, syphilis should remain an essential part of differential diagnoses when assessing patients with systemic symptoms, lymphadenopathy, and cutaneous lesions suspicious for malignancy [2,12]. Herein, we present a patient initially suspected of CTCL, ultimately diagnosed with secondary syphilis, provide a review of similar cases from the literature, and propose a diagnostic algorithm.

2. Case Report

A 27-year-old male suffering from ankylosing spondylitis (HLA-B27 positive) was suspected of being affected by CTCL. The initial manifestation in June 2022 included progressive right cervical lymphadenopathy with a non-healing ulceration of the overlying skin. Also, the patient experienced an unintentional weight loss of 8 kg within 1.5 months (from 80 kg to 72 kg) without night sweats or fever. Laboratory tests revealed a mild, new-onset anemia (drop of hemoglobin concentration from 16 g/dL to 12.8 g/dL (N: 14-18 g/dL) in the observation period). In September 2022, an excisional biopsy of head and neck lesions and involved skin revealed an infiltration of pleomorphic CTCL (CD3 +++,CD20 +, Ki67 + in 10% of cells, Melan A -, HMB-45 +/-, MITF -, SOX10 -). At that time, a FDG-PET-CT scan showed active proliferative disease involving lymph nodes above and below the diaphragm with cutaneous involvement. Additional tests were carried out in October 2022, including:

Biopsy of the ulcerated skin - abundant infiltration of plasmocytes and lymphocytes in the dermis proper without neoplastic lesions (Fig. 1A-D);

Bone marrow biopsy - medium-density marrow, without the presence of abnormal cells, with changes in granulocytes and platelets consistent with vitamin B12 deficiency;

Bone marrow cells flow cytometry - no evidence of abnormal clonal T-lymphocytes;

Cytogenetics - no detectable TCRβ or TCRαδ gene rearrangements;

Trephine biopsy - no presence of lymphoproliferative disease, consistent with reactive or inflammatory changes;

Testing for infectious or autoimmune diseases (negative for HBV, HCV, HIV, HSV 1/2, VZV, HTLV I/II, EBV, CMV, antinuclear, intrinsic factor and gastric parietal cell antibodies).

With these results, in March 2023, the patient was admitted to our ward in order to continue the diagnostic workup. He was in good general condition, with persistent left cervical and bilateral inguinal lymphadenopathy (lymph nodes up to 1.5 cm and 1 cm, respectively). Cutaneous involvement was present as infiltrative skin lesions including the scar after lymph node biopsy on the neck, chest, trunk, back, and scrotum, without pruritus or scaling (Figure 1E, 1F). Further testing revealed an IgG4 level within normal ranges with, however, a positive result of the Waaler-Rose, fluorescent treponemal antibody absorption (antibody titre 1/4000), treponema pallidum hemagglutination assay (antibody titre 1/10240), and venereal disease research laboratory (antibody titre 1/128) tests. Considering the positive treponema pallidum tests, and results of trephine and ulcerated skin biopsy (Figure 1A-D) suggesting the occurrence of an inflammatory process, a suspected syphilis diagnosis with skin involvement was made. The higher lymph node metabolic activity both above and below the diaphragm in the PET-CT scan from October 2022 was deemed secondary to the ongoing inflammatory process. As a consequence, in April 2023, the patient was referred to the Infectious Disease Department for treatment continuation.

4. Case Report

Syphilis continues to present significant diagnostic challenges due to its ability to mimic both hematologic and solid malignancies. In our case, the initial constellation of cervical lymphadenopathy, systemic weight loss, ulcerative cutaneous lesions, and FDG-PET-CT findings raised a strong suspicion of CTCL. Histopathology revealed pleomorphic lymphoid infiltration, while FDG-PET-CT demonstrated widespread hypermetabolic lymph nodes, further supporting this suspicion. However, repeated biopsies showed reactive plasmacytic infiltration without clonality, and subsequent treponemal serologies confirmed secondary syphilis. This illustrates the remarkable ability of syphilis to imitate lymphoma at multiple diagnostic levels [6,13].

The histopathological features of syphilitic lymphadenitis - including follicular hyperplasia, non-necrotizing granulomas, and polytypic plasma-cell infiltrates - may closely resemble those seen in lymphoma or IgG4-related disease [5,12,14]. Immunophenotyping often reveals a mixture of T- and B-lymphocytes without clear clonality, which can be interpreted as an early lymphoproliferative disorder unless molecular studies exclude it [6]. Similarly, FDG-PET-CT imaging, while highly sensitive for malignant lymphoma, lacks specificity; syphilitic lymphadenitis can demonstrate marked FDG uptake indistinguishable from aggressive lymphoma [4,5,8]. Thus, reliance solely on histology or imaging may perpetuate misdiagnosis.

Several case reports highlight this dilemma, as demonstrated in Table 1. Ohta et al. described generalized lymphadenopathy with pulmonary lesions mimicking lymphoma, ultimately diagnosed as syphilis after treponemal serology [4]. Cerchione et al. reported a patient with FDG-PET-CT hypermetabolic nodes initially misdiagnosed as lymphoma until a late syphilis diagnosis was established [6]. Yamashita et al. presented malignant syphilis in an HIV-positive patient, clinically and histologically resembling CTCL but lacking T-cell receptor clonality [7]. Other reports document gastric syphilis mimicking adenocarcinoma or lymphoma [5], skin manifestations initially diagnosed as drug eruption after antifungal therapy and primary cutaneous marginal zone lymphoma [9]. Cervical lymph node involvement with pulmonary nodules has also been misinterpreted as lymphoma [8,10].

Common diagnostic pitfalls across these cases include reliance on imaging suggestive of malignancy, nonspecific histology, and failure to consider syphilis serology early in the workup. Ultimately, serological testing, confirmatory immunohistochemistry or PCR for T. pallidum, and clinical resolution following penicillin therapy provide the final diagnostic confirmation. Our case adds to the already present scientific reports that polytypic plasma-cell infiltration without clonality and FDG-PET-CT findings of widespread hypermetabolism should always prompt consideration of syphilis, particularly in young patients or those with risk factors. Based on our expertise and on previous scientific reports, we propose a diagnostic algorithm that may be of use to clinicians in their daily clinical practice (Figure 2).

5. Conclusions

This case and reviewed literature emphasize that syphilis remains an important imitator of hematologic and non-hematologic malignancies. When patients present with lymphadenopathy, systemic symptoms, and cutaneous lesions suspicious for lymphoma, syphilis should be included early in the differential diagnosis, especially in patients at risk. Serologic testing is widely available, hence its implementation may prevent invasive diagnostics and inadequate therapies. Histopathology showing reactive plasmacytic infiltration without clonality, or a positive FDG-PET-CT with tracer uptake not proportionate to clinical presentation, should especially incline towards considering syphilis. A multidisciplinary approach is essential to avoid delays in diagnosis and, eventually, reduce patient morbidity. Ultimately, systematic inclusion of syphilis in diagnostic workups can avert misdiagnosis and unnecessary treatment, underscoring its relevance as “the great imitator” in modern hematology and internal medicine [1,2,12].