Case 4 -

Primary Syphilis with Rectal Chancre Brian West Yale University New Haven, CT

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Clinical History A 53 year old gay man presented to his gastroenterologist complaining of rectal bleeding that he had noticed intermittently over a period of months and that he had attributed to hemorrhoids. He was HIV-positive, and on treatment with highly active anti-retroviral therapy. On questioning the bleeding proved to be low-volume spotting evident at defecation, and the patient admitted to increasingly severe proctalgia over several weeks. He denied recent anal intercourse. On colonoscopy he had a tubular adenoma at 50 cm and patchy moderately severe proctitis with focal ulceration. The large intestinal mucosa was otherwise normal. Multiple endoscopic biopsies of the rectum were taken. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 Rectal mucosa with mild architectural distortion and lymphoid infiltrate Case 4 - Figure 2 Distorted rectal mucosa with branched gland, and marked chronic inflammation extending into muscularis propria Case 4 - Figure 3 Prominent plasma cell component in lamina propria infiltrate. Plump endothelial cells are present in some capillaries Case 4 - Figure 4 Neutrophils are present in area of erosion. Plump endothelial cells are present also. Case 4 - Figure 5 Mild cryptitis. Note prominent plasma cells in lamina propria Case 4 - Figure 6 Tightly coiled spirochetes in lamina propria (Warthin-Starry, 100x) Case 4 - Figure 7 Immunostaining with polyclonal anti- T.pallidum antibody (40X; Stain by Dr R Cartun) Case 4 - Figure 8 Immunostaining with polyclonal anti- T.pallidum antibody (100x; Stain by Dr R Cartun) Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The rectal biopsies include areas of mucosa with normal architecture, areas of ulceration, and areas with loss and branching of glands indicative of regeneration. A lymphoid infiltrate with a focally prominent plasma cell component expands the lamina propria and extends into the muscularis mucosae. Neutrophils are present mainly in ulcerated areas, and there is mild cryptitis. Endothelial cells in lamina propria capillaries are prominent. Granulomas, vasculitis, thrombosis, viral cytopathic changes, pathogens and parasites are not seen in hematoxylin and eosin stains. Biopsies of endoscopically normal adjacent mucosa are normal. Differential Diagnoses: The differential diagnosis of rectal ulcer is large and includes infectious, inflammatory, traumatic, reactive, ischemic and neoplastic entities (Table). In view of the patient's history of HIV positivity and receptive anal intercourse, albeit several months earlier, sexually transmitted infection was suspected. Gram, Ziehl-Neelsen, Grocott and PAS stains were negative, as were immunostains for CMV, Herpes simplex and Adenovirus. A Warthin-Starry stain was positive for spirochetes in the area of ulceration, and an immunohistochemical stain for Treponema pallidum demonstrated numerous organisms. The diagnosis was confirmed by serology. Evidence of secondary syphilis was not detected. Final Diagnosis: Primary syphilis with rectal chancre. Case Discussion: Syphilis is a sexually transmitted disease caused by the spirochete Treponema pallidum subspecies pallidum, a thinly-coiled motile bacterium 6 to 15 µm long and 0.1 to 0.2 µm wide. Materno-fetal transmission occurs also. Humans are the only natural reservoir. In sexually transmitted disease the initial lesion occurs at the site of infection, most often on the vulva or penis, but in individuals who practice oral or anorectal sex, it may develop in the oral mucosa or anorectum. It begins as a papule or a mucosal patch. One or more of these lesions develop into painless indurated ulcers (chancres) in which the treponemes proliferate, and if this is accessible smears from the lesions may reveal motile spirochetes on microscopical examination with dark-ground illumination. The organisms spread through the lymphatics and an enlarged lymph node is commonly found in the drainage area of the chancre. The chancre heals slowly, sometimes taking several months, and systemic disease (secondary syphilis) may develop before or after it has healed. This usually takes the form of a maculo-papular rash, typically affecting the skin and mucous membranes (including the palms and the souls of the feet), and mild systemic flu-like symptoms. Condyloma latum, a raised smooth moist warty lesion in which spirochetes are abundant, may develop in the anogenital area in second stage syphilis: it is easily distinguished from the dryer, more keratinized lesions of condyloma accuminatum. Secondary syphilis fades away in time, and a latent period develops which may last for many years. Latent syphilis is divided into two categories, early if less than one year after infection occurred, late if more than that. In the majority of untreated patients the disease remains latent, but in about a third syphilitic lesions develop, often 20 years or more after infection. The protean manifestations of tertiary syphilis include neurosyphilis, cardiovascular syphilis and gummatous syphilis (in which granulomas can occur in any organ or tissue). Untreated, syphilis has a mortality of 8 to 58% [Kolker 1997, Kent 2008]. Humoral and cellular immune responses to syphilis begin to develop immediately after exposure to the organism, and during the primary stage resistance to new infection is established. The immune system fails to eradicate the primary infection, however, and rising titers of antibody are associated with increasing clinical manifestations of disease rather than clearing of the organisms. In the second stage, organisms are ubiquitous throughout the body. Following this, most of the organisms are eradicated and the patient is asymptomatic, but a subpopulation of organisms survive and continue to divide and provoke inflammatory changes that result ultimately in the manifestations of tertiary syphilis. T.pallidum has the ability to invade small blood vessels and bind to endothelial cells. This elicits a localized inflammatory reaction and lymphocytes and plasma cells infiltrate the walls of affected blood vessels resulting in perivascular cuffing and activation of perivascular fibroblasts. The endothelial cells also proliferate and hypertrophy, narrowing the lumen, resulting in vascular compromise, obliterative endarteritis and ischemic damage to multiple organs [Kolker 1997, Kent 2008]. Clinical Presentation: Anorectal syphilis occurs in individuals who practice receptive anal intercourse. When not visible at the anal verge, the primary chancre may be hidden from view and, as it is usually painless at least initially, it may go undetected for long periods. Anorectal syphilis is generally believed to be markedly underdiagnosed, partly for this reason. It is not always painless, however, and patients may present with pain that is sometimes associated with defecation, tenesmus, constipation, bleeding or anal discharge. On proctoscopy one or more indurated ulcers 1 to 2 cm in diameter with raised edges may be found, associated with focal inflammation. In the anal mucosa in particular these lesions may be mistaken for carcinoma, especially if sexually transmitted disease is not being entertained in the differential diagnosis. Inguinal lymphadenopathy is often present in patients with anorectal syphilis, and has been mistaken clinically for lymphoma [Drusin 1977]. Histologic features: The microscopic characteristics of syphilitic proctitis are well demonstrated in the present biopsies, although there can be considerable variation in histology of the primary lesions, as with their gross appearance [Kolker 1997, Chapel 1978, Akdamar 1977]. There is mild distortion of the rectal mucosal architecture, with abnormal gland spacing and gland branching, mild acute cryptitis with mucin depletion, and reactive changes in the surface epithelium. The lamina propria is expanded by a lymphoplasmacytic infiltrate that is unusually rich in plasma cells. This infiltrate extends into the muscularis mucosae at the deep margins of the endoscopic biopsies. Small blood vessels in the lamina propria have prominent plump endothelial cells, and, though not well represented in the present case, small vessel vasculitis is often present. These features, though typical, are by no means specific, and are difficult to distinguish from other infectious proctocolitides. One additional feature that helps to make this distinction is localization of pathology to a small defined area, and histologic normality of adjacent (endoscopically normal) mucosa. In primary anal syphilis there is ulceration of the anal squamous epithelium (chancre) with a lymphoplasmacytic infiltrate in the underlying tissue, abundant plasma cells, prominence of endothelial cells in small blood vessels, and small vessel vasculitis with lymphocytic cuffing. Inflammatory cells infiltrate the basal layers of the squamous epithelium, which is damaged with reactive changes. Warthin-Starry stains show the presence of spirochetes. By immunohistochemistry spirochetes are shown to be present in much greater numbers than is evident from the silver stains, with particular concentrations both in the basal layers of the squamous epithelium, where they infiltrate between the epithelial cells, and adherent to the endothelium of inflamed blood vessels. Review of the Literature/Treatment Options (if applicable): Epidemiologic aspects: In 1999, 12 million individuals were estimated to have syphilis, 90% of whom were in the developing world. Since syphilis infection increases the likelihood of HIV transmission 2 to 5 fold, syphilis is an important risk factor for HIV [Kent 2008]. In western countries the prevalence of syphilis declined during the 1980s and 1990s, but since 2000 the rates of syphilis have been increasing. This increase has been seen mainly among men who have sex with men [Dougan 2007], although from 2004 to 2007 in the United States there was a 38% increase in the rate of primary and secondary syphilis in women, followed by a 23% increase in the rate of congenital syphilis [Su 2010]. The increases in congenital syphilis and syphilis acquired in adolescence have serious implications for child health [Chakraborty 2008]. In Europe the increase of syphilis among men who have sex with men appears to the result of improved survival of HIV-positive individuals on HAART, coupled with serosorting (men choosing male partners of concordant HIV status for unprotected sex) and increased high-risk behavior, as exemplified by increased frequency of unprotected anal intercourse [Dougan 2007]. Pathologists can expect to see increasing numbers of cases of anorectal syphilis if these trends continue. Tissue diagnosis: In routine histological sections, spirochetes can be stained selectively by several silver stains, including Warthin-Starry, Steiner and Dieterle methods. The presence of spirochetes is not specific to T.pallidum, of course, and other spirochetes such as Borrelia burgdorferi, Leptospira and the organisms of intestinal spirochetosis (including Brachyspira aalborgi, B.pilosicoli and B.hyodysenteriae) will stain also, as will non-pathogenic spirochetes of the oral cavity and gastrointestinal tract. However, the location and histologic appearance of the lesion will usually limit the differential diagnosis. In any case, the diagnosis should be confirmed serologically. Immunohistochemistry may also be used as an aid to diagnosis. There are reports of the use of fluorescent antibodies for this purpose, including with monoclonal antibodies that do not cross-react with non-pathogenic spirochetes [Hunter 1984, Ito 1992, Chen 2006]. The immunostains presented here were prepared using a rabbit polyclonal antibody raised against highly purified T.pallidum [Beckett 1979]. This antibody cross-reacts with several other spirochetes, including Borrelia burgdorferi and the organisms of intestinal spirochetosis. It is very much more sensitive than the silver stains, possibly because it reacts with dead and degenerating organisms as well as with intact ones, and the stained organisms appear larger than in silver preparations because of the chromogen deposited on them. These features, together with the intense color contrast, make it highly suitable for screening for spirochetal infections. Serologic tests: In primary syphilis, dark-field microscopy, or direct fluorescent antibody staining, of swabs or scrapings of chancres can reveal numerous organisms and establish the diagnosis. Serological tests are highly reliable but there is a window period of several weeks after infection before they become positive. During this period patients with suspicious lesions and histories should be treated, despite the lack of a laboratory-based diagnosis. Non-treponemal serologic tests include the venereal Disease Research Laboratory (VDRL) assay (positive in 75% of cases of primary syphilis, 95% of patients with early latent syphilis, and 100% of those with secondary disease) and the Rapid Plasma Reagin (RPR) test. Both can result in false positives and false negatives, and should be confirmed with a treponemal assay such as the Fluorescent Treponemal Antibody (FTA) absorption test or the Treponema Pallidum Particle Agglutination assay (TPHA) which usually become positive about 6 weeks after infection [Kent 2008, Larson 2010]. Treatment: T.pallidum is sensitive to penicillin, which is the antibiotic of choice. Primary or secondary syphilis can be cured by a single intramuscular injection of penicillin G, but longer-standing disease may require three doses at weekly intervals, or if there is CNS involvement, large doses daily for 10 days. In patients with an allergic reaction to penicillin, tetracyclines or macrolides may be used [Kent 2008]. However, resistance to various antibiotics has recently emerged, including to macrolides, clindamycin and rifampin, although resistance to penicillin and tetracycline has not yet been reported [Stamm 2010]. Conclusion(s): In view of the increasing prevalence of syphilis in the community, and in particular among men who have sex with men, and because of the increasingly common pattern of unprotected anal intercourse, pathologists can expect to see biopsy specimens from patients with anorectal syphilis with increasing frequency. It is important, therefore, to have a high index of suspicion for this disease, and to employ appropriate diagnostic tests. Immunohistochemical stains for T.pallidum, as used here, may be much more sensitive than classical silver stains and can provide an excellent screening method, despite their non-specificity. Experience with other antibodies may, of course, be different. Histologic features that should alert the pathologist to the possibility of syphilis in ulcerated anorectal tissue include a prominent plasma cell component in the lymphoplasmacytic infiltrate, endothelial cell prominence and lymphocytic cuffing in small vessels, localization of the pathology to small well-defined areas of the mucosa, and lack of involvement of adjacent, endoscopically normal tissue. References: Akdamar K, Martin RJ, Ichinose H. Syphilitic proctitis. Dig Dis 1977;22:701-704. Beckett JH, Bigbee JW. Immunoperoxidase localization of Treponema pallidum: its use in formaldehyde-fixed and paraffin-embedded tissue sections. Arch Pathol Lab Med 1979;103(3):135-138 Chakraborty R, Luck S. Syphilis is on the increase: the implications for child health. Arch Dis Child 2008;93(2):105-109 Chapel TA. The variability of syphilitic chancres. Sex Trans Dis 1978;5:68-70 Chen C-Y, Chi K-H, George RW, et al. Diagnosis of gastric syphilis by direct immunofluorescence staining and real-time PCR testing. J Clin Microbiol 2006;44(9):3452-3456 Dougan S, Evans BG, Elford J. Sexually transmitted infections in Western Europe among HIV-positive men who have sex with men. Sex Transm Dis 2007;34(10):783-790 Drusin LM, Singer C, Valenti AJ, Armstrong D. Infectious syphilis mimicking neoplastic disease. Arch Intern Med 1977;137:156-160 Hunter EF, Greer PW, Swisher BL, et al. Immunofluorescent staining of Treponema in tissues fixed with formalin. Arch Pathol Lab Med 1984;108:878-80. Ito F, George RW, Hunter EF, Larsen SA, Pope V. Specific immunofluorescent staining of pathogenic treponemes with a monoclonal antibody. J Clin Microbiol 1992;30:831-8. Kent ME, Romanelli F. Reexamining syphilis: an update on epidemiology, clinical manifestations and management. Ann Pharmacother 2008;42(2):226-236 Kolker SE, Manz HJ, Schwartz DA. Syphilis. In Connor DH, Chandler FW, Schwartz DA, Manz HJ, Lack EE. "Pathology of Infectious Diseases", Appleton & Lange, Stamford, CT 1997: pp833-846 Larson SA, Pope V, Johnson RE, Kennedy EJ. Manual of Tests for Syphilis, 9th edition, on-line . Centers for Disease Control and Prevention, 2010 www.cdc.gov/std/syphilis/manual-1998/default.htm Stamm LV. Global challenge of antibiotic resistant Treponema pallidum. Antimicrob Agents Chemother 2010;54(2):583-589 Su JR, Berman SM, Davis D, et al. Congenital syphilis - United States, 2003-2008. MMWR 2010;59(14):413-417