Introduction
Late benign syphilis is rare in the antibiotic era. Even after 25 years of clinical reports of syphilis and human immunodeficiency virus (HIV) co-infection linked with possible increased progression and poorer treatment outcomes,Reference Zetola and Klausner1 there has been no report of gummatous syphilis in the HIV-infected population in 20 years,Reference Dawson, Evans and Lawrence2, Reference Hay, Tam, Kitchen, Horner, Bridger and Weber3 and few in the HIV-uninfected. We present a case of an HIV-infected man with chronic gummatous syphilis.
Case report
A 39-year-old man presented to the ENT department at the Chris Hani Baragwanath Hospital, Soweto, South Africa, with an ulcer on the face, covered by a handkerchief. The ulcer had been slowly progressive over a period of six years. It started as a small ulcer and gradually increased in size to involve the nose, the lips and ultimately the medial aspects of both cheeks. There was an associated dry cough. The patient denied any occupational exposure to heavy metals or use of illicit intranasal drugs. There were no other lesions anywhere else on the body and no rash.
The patient had recently been seen at a local clinic where a biopsy of the ulcer was performed. This showed ulceration, polymorphonuclear cell inflammatory infiltration, microabscess formation and secondary vasculitis. A Ziehl–Neelsen stain and Warthin–Starry silver stain were both negative. A diagnosis was not made.
Past medical history was non-contributory and travel history was negative. The patient drank alcohol occasionally and was a smoker, with a five pack-year history. There was no history of a genital ulcer.
Examination of the head and neck showed an ulcerative lesion of the midface involving the cheeks, and completely destroying the nose and the upper lip (Figures 1 and 2). The lower lip was destroyed completely on the right side; both the teeth and the gums were exposed. The palate was intact. The lesion had a moist, purulent base with rolled edges (Figure 1).
Frontal view of the patient with the rare benign syphilitic gumma, prior to treatment.
Side view of the patient with the syphilitic gumma, prior to treatment.
The differential diagnosis included all the midline granulomatous conditions: T-cell lymphoma, Wegener's granulomatosis, sarcoidosis, tuberculosis, deep fungal infection, Churg–Strauss syndrome and lethal midline granulomatosis disease.
Skull X-rays showed the destructive nature of the lesion, with absent nasal bones (Figures 3 and 4).
Frontal skull X-ray, demonstrating the destructive nature of the lesion.
Lateral skull X-ray (note that the nasal bones are completely destroyed by the disease).
Blood test results for full blood count, urea and electrolytes, and liver function, were normal. The erythrocyte sedimentation rate was 114 mm per hour. The angiotensin-converting enzyme level was normal. An HIV enzyme-linked immunosorbent assay was reactive, with a cluster of differentiation 4 count of 641 cells per µl. The rapid plasma reagin test result was positive, with a titre of 1:1024. This finding was supported by a positive Treponema pallidum haemagglutination assay result.
A biopsy of the lesion was performed and this showed non-necrotising granulomatous inflammation. The detailed report showed: ulceration, polymorph inflammatory infiltration, microabscess formation, secondary vasculitis, negative Ziehl–Neelsen results and negative results for spirochaetes on Warthin–Starry silver stain (Figure 5).
Photomicrograph showing non-necrotising granulomata. ( H & E stain, 10×) Courtesy of Prof. M Hale , Dept. of Histopathology
Tests for tuberculosis were negative. The patient refused to undergo a lumbar puncture to exclude neurosyphilis. (This possibility was considered because the patient had mood swings.) An audiogram showed normal hearing bilaterally.
A diagnosis of a syphilitic gumma of late benign tertiary syphilis was made. The patient was treated with 24 million units per day (administered intravenously) of aqueous crystalline penicillin (penicillin G) for 21 days. This treatment was chosen in order to cover for possible neurosyphilis.Reference Lynn and Lightman4
Over the course of treatment, the lesions on the face improved dramatically as they dried, and were reduced in size (Figures 6 and 7). The Figure 6 photograph was taken 10 days after the initiation of penicillin. The patient was assessed by plastic surgeons for possible reconstruction of the facial defect, but the patient refused cosmetic surgery and was subsequently lost to follow up.
Frontal view of the patient at day 10 of high-dose intravenous penicillin G.
Side view of the patient at day 10 of high-dose intravenous penicillin G.
Discussion
Syphilis is an infectious venereal disease caused by the spirochaete bacterium Treponema pallidum. If left untreated, 30 per cent of patients with latent syphilis will go on to develop tertiary syphilis.Reference Harrison5, Reference Rockwell, Yobs and Moore6 Tertiary syphilis can be subdivided into late benign syphilis, cardiovascular syphilis and neurosyphilis. However, it was revealed by Nnoruka and Ezeoke that a mucocutaneous gummatous lesion of tertiary syphilis and advanced secondary syphilis can be seen simultaneously,Reference Nnoruka and Ezeoke7 indicating a rapid progression of syphilitic disease within a very short time.Reference Zetola and Klausner1, Reference Nnoruka and Ezeoke7 This supports Gonzalez and Rhodes’ statement (as cited in Nnoruka and EzeokeReference Nnoruka and Ezeoke7) that patients can progress from primary to tertiary syphilis in a matter of weeks if there is co-infection with HIV.
In the Oslo study of the natural history of syphilis, conducted prior to the discovery of antibiotic treatment, late benign syphilis occurred in approximately 17 per cent of 1147 syphilis patients and was the commonest manifestation of tertiary syphilis.Reference Harrison5 In that study, the condition mostly affected skin (70 per cent), followed by involvement of bone (10 per cent) and mucosa (10 per cent). Upper respiratory tract involvement was not uncommon. Gummas were seen 1 to 46 years after infection, but usually in the first 15 years, and could remit and recur later. In the antibiotic era, late benign gummatous syphilis is an unusual finding.
The gumma represents a maximal inflammatory response to a few organisms. It is not infectious and it is very rare to find spirochaetes. Syphilitic inflammation is generally mild, but chronic destruction of tissue leading to fibrosis can occur. The early lesion is granulomatous and resembles tuberculosis. The gummatous lesion is usually nodular, ranging from a couple of millimetres to a few centimetres in diameter. The lesions are called gummas as the necrotic material is of a gummy consistency. On histology, these lesions show obliterative endarteritis, with central avascular necrosis; the inner lining of the artery is surrounded by a fibrous capsule that contains plasma cells and lymphocytes. The gummas appear to arise in people untreated or inadequately treated, or occur with reinfection in previously treated individuals.
• Clinicians should consider syphilis in the differential diagnosis of patients with unusual lesions
• Syphilis can be difficult to diagnose in a human immunodeficiency virus (HIV) infected individual
• Biopsy and serology are important in making the diagnosis
• Development of tertiary syphilis can be hastened by HIV infection
• Sometimes primary lesions and tertiary lesions can present simultaneously
Cutaneous lesions present in two different ways and may either be a superficial nodulo-ulcerative type, or a deeper, more destructive gummatous type. After weeks or months the lesions may ulcerate, leaving an atrophic scar. Bony gummas appear radiographically as areas of bone lysis with a surrounding dense sclerotic reaction, as seen in the nasal bones of the patient described here.
Diagnosis is to a large extent dependent on the consideration of syphilis as part of the differential diagnosis.Reference Hicks, Benson, Lupton and Tramont8, Reference Taniguchi, Osato and Hamada9 Syphilis is known for good reason as being ‘the great imitator’.Reference Rodriguez, Teich, Weinman, Greene, Keroack and Apstein10 It should also be kept in mind that HIV makes it more likely for syphilis to present with atypical features and an unusual pattern of disease.Reference Zetola and Klausner1, Reference Lynn and Lightman4 Serological screening tests are usually reactive, and the non-specific tests may reveal high titres as in the current case study. Serology may be negative in solitary bone lesions.
Treatment generally involves benzathine penicillin G (Bicillin® L-A), 2.4 million units, administered intramuscularly on a weekly basis, for 3 weeks. There is a good response to treatment and this can be used to add certainty to the diagnosis.
The patient in this case study had a gumma that involved the nasal bones, cheeks and lips, implicating the upper respiratory tract. The gummas in the four documented patients with co-infection were on the legs in two individuals, in the groin in one and on the penis in the other.Reference Dawson, Evans and Lawrence2, Reference Hay, Tam, Kitchen, Horner, Bridger and Weber3 The two documented cluster of differentiation 4 counts were 642 and 426 cells per µl.
Although the patient in the current study was HIV-infected, he had a preserved cluster of differentiation 4 cell count, and there was no evidence that his clinical presentation or response to treatment for late benign gummatous syphilis was influenced by his HIV status. Despite there being more than 25 years of clinical experience with co-infected patients, the interaction between syphilis and HIV remains unclear.Reference Zetola and Klausner1 More aggressive and unusual presentations occur in a few people and may represent usual variant presentations rather than being specifically HIV-related. The fact that there are so few reports of late benign syphilis related to HIV infection suggests that there is no interaction for this form of syphilis. Cerebral gummas have been reported in 11 HIV-infected people but are considered to belong to the neurosyphilis group and are also rare.Reference Fargen, Alvernia, Lin and Melgar11 As pointed out by other researchers, all HIV-positive patients co-infected with syphilis should be treated as if they had neurosyphilis, regardless of the stage at which they present.Reference Lynn and Lightman4
Conclusion
This case study serves to remind clinicians of the need to consider syphilis in the differential diagnosis of unusual presentations involving skin and bone, and other organs of the body. Furthermore, in patients co-infected with HIV, there is a need to keep testing for syphilis even if initial serological test results are negative.
