Infectious Disease Pathology
Case 4 -
Primary Syphilis with Rectal Chancre
New Haven, CT
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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
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.
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.
Primary syphilis with rectal chancre.
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.
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.
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
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].
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.
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