Case Report

A 29-year-old homosexual male with no previous medical history was initially evaluated for nausea, vomiting, diarrhea, and weight loss. The patient’s symptoms started six months prior to presentation with watery diarrhea, 4–10 low-volume, and non-bloody bowel movements per day, associated with tenesmus and unintentional weight loss of 40 lb over the six-month period. A month before presentation, the patient had developed aching epigastric pain that was episodic, exacerbated by eating and was associated with postprandial nausea and vomiting ~ 10 min after food ingestion. The patient also reported that he started to experience diminished hearing in his left ear over the previous month. The patient was not taking any medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), but he smoked one marijuana cigarette 2–3 times per week for about a year. The patient is in a monogamous relationship with a male partner who is infected with human immunodeficiency virus (HIV) and admitted to having unprotected sex with him on a number of occasions. Although the exact HIV status and cluster of differentiation (CD)4 count of his partner was not known to the patient, he knew that his partner was receiving antiretroviral therapy. There was no history of recent travel or contact with animals. Family history was significant only for Crohn’s disease in his mother.

Physical examination was generally unremarkable with no icterus or skin changes. Pertinent findings included an axillary temperature of 36.1 °C, heart rate 90/min, blood pressure 122/87 mmHg, and respiratory rate of 16/min. Examination of his abdomen revealed mild localized epigastric tenderness on direct palpation, but no rebound tenderness. He had no hepatosplenomegaly or other masses. Bowel sounds were active, but there was no distension or ascites. There were no enlarged lymph nodes. There were no penile, perianal, or mucous membrane lesions. Neurologic, audiologic, and ophthalmic examinations were unremarkable.

Laboratory studies (normal ranges) revealed a white blood cell count of 7100/mm3 (4000–11,000/mm3), hematocrit of 43.4% (36–48%), platelet count of 363,000/mm3 (150,000–400,000/mm3), and serum concentrations of sodium 141 mmol/L (137–145 mmol/L), potassium 4.0 mmol/L (3.4–4.8 mmol/L), chloride 99 mmol/L (98–107 mmol/L), magnesium 2.1 mg/dL (1.6–2.3 mg/dL), bicarbonate 27 mmol/L (20–31 mmol/L), creatinine 0.86 mg/dL (0.66–1.25 mg/dL), and random glucose 105 mg/dL (74–140 mg/dL). Liver function tests showed a total serum protein of 8.8 g/dL (6.3–8.5 g/dL), albumin 4.4 g/dL (3.5–5.0 g/dL), alkaline phosphatase 108 U/L (38–126 U/L), aspartate aminotransferase 34 U/L (17–59 U/L), alanine aminotransferase 40 U/L (21–72 U/L), total bilirubin 0.7 mg/dL (0.2–1.3 mg/dL), and lipase 49 U/L (21–72 U/L). Other laboratory studies including Clostridium difficile toxin gene polymerase chain reaction (PCR) assay, enzyme-linked immunosorbent assay (ELISA) for Giardia antigen, anti-tissue transglutaminase antibody, fecal lactoferrin, fecal H. pylori antigen, stool bacterial cultures, and stool ova/parasites were all negative. Hepatitis C virus antibody (HCV-Ab), HIV 1/2 antibody, and PCR testing for HIV were also negative. Abdominal X-ray was normal, and computed tomography (CT) scan of the abdomen and pelvis showed irregular wall thickening in multiple areas of the wall of the stomach.

An esophagogastroduodenoscopy (EGD) showed diffuse mucosal erythema with thickening of folds in the antrum (Fig. 1, left). Colonoscopy revealed a small localized area of mucosal erythema in the distal sigmoid colon (Fig. 1, right). Biopsies were taken from the gastric and colonic mucosa. Microscopic examination showed prominent lymphoplasmacytic infiltrate to include lymphoid follicles with germinal centers (Fig. 2a, b) and heavy neutrophilic infiltrate within the lamina propria and glandular epithelium (Fig. 3). Though the findings were highly suggestive of H. pylori infection, no organisms were identified by Diff Quik® or immunoperoxidase stains. CD3 and CD20 stains showed only a normal mixture of T-cells and B-cells. No vasculitis was apparent, and there was no evidence of any kind of neoplasia present. A rapid plasma reagin test, obtained due to the presence of hyperacute gastritis, was positive at a titer of 1:32; serum Treponema pallidum antibody test was also reactive. With a high suspicion of syphilis, a spirochete immunoperoxidase stain was performed on both gastric and colonic biopsy specimens and revealed spirochete organisms in specimens from both organs. Staining of the gastric antral biopsy specimen for Treponema was also positive (Fig. 4a, b).

Fig. 1
figure 1

Upper endoscopic image showing antral wall erythema and irregular mucosal thickening (left). Small area of sigmoid erythema as seen on the colonoscopy (right)

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Fig. 2
figure 2

a Low-power view of antral mucosa with “follicular gastritis” (lymphoid follicle formation). b Medium-power view of antral mucosa with “follicular gastritis” (lymphoid follicle formation)

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Fig. 3
figure 3

High power of antral mucosa with active (acute) inflammation (active gastritis) showing abundant neutrophils

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Fig. 4
figure 4

Low (a) and high (b) power views of spirochete antibody stain of antral mucosa

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A formal auditory evaluation by an otorhinolaryngologist revealed that the patient had left-sided sensorineural hearing loss. Lumbar puncture showed a non-reactive cerebrospinal fluid venereal disease research laboratory (VDRL) test without pleocytosis. A diagnosis of tertiary syphilis (otosyphilis) with syphilitic gastritis and colitis was made; the patient was treated with intravenous penicillin G 24 million units per day for a total of 2 weeks. By the end of the therapy, the patient’s symptoms were completely resolved. An endoscopic evaluation performed 8 weeks after the therapy showed normal mucosa.

Discussion

Syphilis is a contagious sexually transmitted disease caused by Treponema pallidum, in which the agent penetrates the skin or mucous membrane after small abrasions. There are three phases of syphilis. Initially, the primary infection is characterized by a painless indurated chancre developing at the site of the inoculation. Soon afterward, there is hematogenous dissemination of the organism, at which point any organ may be affected by the disease including the gastrointestinal (GI) tract. This secondary syphilis, due to hematogenous spread, classically leads to a generalized copper-colored macular rash accompanied by generalized lymphadenopathy. After this overt secondary phase, the disease usually enters a latent stage that can manifest itself in the patient as a recrudescence of secondary syphilis anytime within the first 1–2 years. Up to one-third of patients with latent disease will develop neurosyphilis, cardiovascular syphilis, or gummatous syphilis [1]. In the USA, the rate of primary and secondary cases of syphilis has increased steadily from 2.1 per 100,000 in the year 2000 (the lowest reported incidence since 1941) to 7.5 per 100,000 in 2015. Until 2013, this increase was largely attributable to the increase in incidence among gay and bisexual men and other men who have sex with men (MSM) and often occurs in young patients who are dismissive of practicing “safe sex.” The West region of the USA, of which New Mexico is a part, has the highest rate of disease at 9.6 cases per 100,000 [2]. Gastric and colonic syphilis is caused by vasculitis in the mucosa that has usually occurred as a result of hematogenous dissemination of T. pallidum, and is not linked to oral ingestion of the organism. Although GI involvement can occur in any phase of syphilis, it is predominantly seen during the secondary phase (50%) and more rarely in the tertiary phase (6%) [3]. It is most important for clinicians to realize that the absence of cutaneous lesions from syphilis does not exclude gastrointestinal involvement [3].

Gastric syphilis is an uncommon manifestation of the disease. Some older autopsy series calculated a rate of 1/500 of patients with documented syphilitic infection. Medical literature from the beginning of the twentieth century attributed up to 10% of “peptic ulcers” to syphilis, but since the discovery of penicillin, upper gastrointestinal manifestations of syphilis have rarely been reported. With all stages of syphilis combined, gastric and colonic involvement occurs in < 1% of cases, with the gastric antrum and rectum being the sites most commonly affected. About 60% of those with gastric syphilis have a current or previous history of syphilis [4]. Nevertheless, clinical manifestations of gastrointestinal involvement are nonspecific and include epigastralgia, nausea and vomiting, weight loss, emaciation, early satiety, diarrhea, and tenesmus. Rare manifestations have also included gastric ulcer perforation and gastric outlet obstruction [2, 4]. Contrast radiography can highlight findings such as reduction in gastric distensibility, mucosal breaks or ulcerations, thickening of the gastric mucosa, and mucosal edema [5].

Upper GI endoscopic findings typically show mucosal erythema, friability, and multiple erosions or ulcers that typically involve the antrum, at times not unlike the injury typical of NSAID injury. Sizeable nodules or malignant-appearing masses have also been reported. These endoscopic findings can also mimic similar pathologies such as lymphoma, linitis plastica, tuberculosis, and proximal Crohn’s disease. In these other diseases, however, the lesions usually extend beyond the pylorus, whereas in syphilitic involvement of the stomach, there is usually abrupt cessation of lesions at the pylorus [6].

Histologically, an intense inflammatory infiltrate with lymphocytes and plasma cells often dominates the histologic appearance. Neutrophils may also be present which, when significantly infiltrating the gastric glandular epithelium, can result in a histologic appearance resembling H. pylori-associated gastritis [7]. Accordingly, we believe that syphilitic gastritis, although rare, is a valid consideration in the differential diagnosis of H. pylori-associated active gastritis. It is also important to distinguish Treponema pallidum from H. pylori and H. heilmannii due to similarities in appearance. Treponema pallidum is a Gram-negative spirochete bacterium measuring 8–15 µm in length and 0.1–0.2 µm in diameter, whereas Helicobacter pylori measures 1–3 µm in length and 0.5–1.0 mm in diameter and exhibits a spiral appearance on high magnification. Helicobacter heilmannii is longer and wider in appearance than H. pylori, but shorter and stouter than T. pallidum. T. pallidum might also be confused with abundant silver-staining fibers in the background tissue, but on closer examination T. pallidum manifests denser stainability and a more distinctly spiral outline than the fibrillary material in the background [8, 9].

The microscopic features of syphilitic gastritis and colitis are neither specific nor diagnostic. Therefore, additional histologic features, including vasculitis, granulomata, and microorganisms, should be meticulously sought and considered to exclude the possibility of Crohn’s disease or other infectious conditions including H. pylori and tuberculosis [10]. Also, because lymphoepithelial infiltrates and nuclear atypia of epithelial cells can be observed in syphilitic gastritis, the pathologists must be careful not to misdiagnose the presence of infiltrative gastric carcinoma or lymphoma [11, 12].

Immunohistochemical assessment, with polyclonal antibodies directed against Treponema pallidum, shows a higher diagnostic sensitivity than does assessment with the routine silver nitrate-based Warthin-Starry stain (80 vs. 50%) [13]. Cross-positive reactions were described only in Borrelia burgdorferi and other Brachyspira intestinal spirochetes [14]. Warthin-Starry silver stain can also demonstrate spirochetes and confirm the diagnosis. Nonetheless, the sensitivity of detecting spirochetes organisms can sometimes be compromised by artifactual background staining of tissue elements (i.e., reticulum fibers, melanin), which may contribute toward false-positive or false-negative results [9]. Therefore, T. pallidum immunostaining should always be considered for the evaluation of potential cases of syphilitic gastritis. Patients with suspected involvement of the central nervous system, as in this case, should always have a cerebrospinal fluid examination to assess for neurosyphilis prior to initiation of therapy.

The current treatment recommendation for syphilis is penicillin G benzathine 2.4 million units intramuscularly once for early syphilis and once weekly for 3 weeks for latent syphilis. Neurosyphilis should be treated with aqueous penicillin G, 3–4 million units IV every 4 h (or 18–24 million units continuous IV infusion) for 10–14 days [15].

Clinical symptoms usually disappear approximately 3–4 days after initiation of therapy, and upper endoscopic findings rapidly become normal by the end of the treatment [16, 17].

Learning Points

  1. 1.

    Syphilitic gastritis should be considered in patients at risk of sexually transmitted disease who present with nonspecific GI symptoms.

  2. 2.

    Absence of cutaneous lesions from syphilis does not exclude gastrointestinal involvement. Initial histologic changes may be nonspecific according to routine microscopy and often resemble those seen in H. pylori infection.

  3. 3.

    The commonest sites of GI involvement are the stomach and rectum.

  4. 4.

    Even though GI involvement typically occurs in the second phase of syphilis, it can also be seen in the tertiary stage.

  5. 5.

    T. pallidum immunostaining, being more specific than the traditional histochemical stains, should always be considered in evaluating potential cases of syphilitic gastritis.