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Primary Anal Canal Syphilis in Men: The Clinicopathologic Spectrum of an Easily Overlooked Diagnosis.

While rates of primary and secondary syphilis in the United States reached a low in the 1990s and 2000, (1) there has been a steady increase of syphilis in the male population since 2001, particularly in men who are human immunodeficiency virus (HIV) positive ([HIV.sup.+]) and men who have sex with men (MSM). (1-3) Syphilis is a well-known venereal disease caused by the bacterium Treponema pallidum, which may progress through multiple stages starting with a symptomatic phase that includes primary and secondary syphilis. A painless sore/ulcer (chancre) at the site where syphilis first affects the body characterizes primary syphilis, (4) while secondary syphilis is characterized by mucosal sores in the anus, vagina, and or/mouth with or without skin rashes. Sometimes at the secondary stage of syphilis, condyloma lata, moist papules that are extremely infectious, can be present in the anogenital area, as well as other parts of the body where there are 2 areas of skin closely apposed to one another. If the primary infection is untreated, the patient enters a latent stage that can last for 10 to 30 years. A late symptomatic stage can then take place in approximately 15% of patients, manifesting as neurologic symptoms, damage to internal organs, and potentially death. (3) For that reason, early detection and treatment of syphilis with appropriate antibiotic therapy is imperative to prevent progression to the late stages of syphilis.

Although syphilis can present at any entry site in the body, including the anus, there is little detail in the pathology literature regarding the morphology of syphilis presenting specifically as an ulcer or mass in the anal canal. However, it is important for pathologists to consider syphilis as a part of their differential diagnosis for biopsy specimens taken from isolated anal canal ulcers or inflammatory anal mass lesions when certain histologic features are recognized. Herein, we present a series of 4 cases of primary syphilis of the anal canal to characterize the morphology and increase pathologist awareness of the presentation of syphilis in this location.

MATERIALS AND METHODS

The tissue samples in all cases were fixed in 10% neutral buffered formalin and processed for routine histologic examination by light microscopy. Briefly, paraffin-embedded, formalin-fixed tissues were sectioned at 4 [micro]m. Immunohistochemical (IHC) staining was performed on a BenchMark XT automated stainer (Ventana Medical System Inc, Tuscon, Arizona). The slides were stained by using the ultraView (Ventana) detection kits with the standard cell conditioning (CC1) antigen retrieval method for 30 minutes. CC1 is a prediluted Tris-based buffer with slightly basic pH. Slides were then incubated with prediluted ready-to-use anti-T pallidum (spirochete) rabbit polyclonal antibody (Biocare, Concord, California) for 32 minutes at room temperature. Reaction of Tpallidum organisms was visualized with a peroxidase-based brown detection or alkaline phosphatase-based red detection technique (ultraView Universal DAB Detection Kit and Universal Alkaline Phosphate Red Detection Kit, Ventana). The slides were counterstained with hematoxylin I. Appropriate positive and negative controls were used.

RESULTS

The clinicopathologic characteristics of 4 cases of primary syphilis involving the anal canal are described in the Table.

Case 1

A 52-year-old [HIV.sup.+] man, MSM, presented for evaluation of an anal canal ulcer. In this case, clinical suspicion for syphilis was high; therefore, serologic testing (rapid plasma reagin [RPR] and fluorescent treponemal antibody absorption [FTAABS]) was ordered at his initial visit. A biopsy sample for histologic evaluation and perianal swab for T pallidum polymerase chain reaction (PCR) were also taken. The RPR test result was nonreactive while the FTA-ABS test result was reactive. T pallidum qualitative real-time PCR from the perianal swab sample detected T pallidum DNA. The anal biopsy specimen had ulcer and adjacent nonulcerated areas with a bandlike chronic inflammatory infiltrate at the junction of the squamous epithelium and lamina propria, composed of lymphocytes and plasma cells (Figure 1, A). There was an underlying prominent mixed chronic inflammatory infiltrate rich in plasma cells, lymphocytes, and histiocytes (Figure 1, B) with rare, poorly formed granulomas (Figure 1, C). Treponema pallidum IHC stain highlighted characteristic "corkscrew" organisms near the basal layer of the squamous epithelium (Figure 2, A), and deeper in the lamina propria, sometimes in a perivascular pattern (Figure 2, B).

Case 2

A 44-year-old man presented with a nonhealing anal ulcer. Biopsy analysis of the lesion showed ulceration with a plasma cell-rich chronic inflammatory infiltrate and plasma cell-rich inflammation in a bandlike pattern at the junction of squamous epithelium and lamina propria. Treponema pallidum IHC stain also highlighted organisms deeper in the lamina propria and around vessels. Syphilis was not initially clinically suspected. After receiving the biopsy results, further evaluation was performed, and RPR and FTA-ABS test results for syphilis were positive.

Case 3

A 51-year-old man presented with an anal ulcer. The lesion was biopsied and histologic findings included ulceration composed of a chronic plasma cell-rich inflammatory infiltrate with rare, poorly formed granulomas. Treponema pallidum IHC stain highlighted organisms predominantly in the lamina propria, under the squamous epithelium, and concentrated around vessels. Syphilis was not initially clinically suspected; however, further evaluation was performed after the clinician received the biopsy results. The RPR test result was reactive at a dilution of 1:16, and a T pallidum particle agglutination confirmatory test result was reactive.

Case 4

A 31-year-old man, MSM, presented to the emergency department with bright red blood per rectum. Evaluation for HIV and other sexually transmitted infections (STIs) was performed. The patient was found to be [HTV.sup.+], the treponemal antibody test result was positive, and the RPR test result was reactive at a dilution of 1:256. An anal mass was palpated on physical examination, so the patient underwent endoscopic evaluation, which confirmed a large ulcerated, multilobular anal canal mass and also documented concomitant proctitis. The gastroenterology and surgery teams had high clinical suspicion for malignancy based on the endoscopy and computed tomography scan results both of which showed an anal mass lesion and rectal thickening. Biopsy specimens from the anal mass revealed fragments of polypoid granulation tissue with a prominent chronic inflammatory infiltrate with scattered plasma cells (Figure 2, C). The adjacent nonulcerated squamous epithelium had an underlying bandlike chronic inflammatory infiltrate with more prominent plasma cells than the granulation tissue (Figure 3, A). Concomitant rectal biopsy samples showed increased lymphoplasmacytosis of the lamina propria with minimal crypt distortion and focal cryptitis (Figure 3, B). Treponema pallidum IHC stain highlighted a patchy distribution of organisms within the granulation tissue taken from the anal mass, in some areas with a perivascular pattern, with rare organisms identified in the rectal mucosal biopsy samples. Subsequent resection of the anal mass revealed an ulcer with exuberant, deep underlying chronic inflammatory infiltrate composed of a lymphoplasmacytic and histiocytic infiltrate with cytologically atypical lymphocytes. Immunohistochemical workup confirmed the lymphoid infiltrate was reactive.

COMMENT

Increasing rates of syphilis, particularly among [HIV.sup.+] patients and MSM, have been reported internationally. (5,6) We revisit syphilis and report 4 cases of syphilis of the anal canal to bring pathologists' attention to syphilis in this location. All 4 patients were male, and 2 were [HIV.sup.+] MSM. The HIV status and whether the other 2 patients in our study were MSM were unknown at the time of biopsy. Three of our patients presented with an anal canal ulcer and one presented with an ulcerated anal mass. The lesions were likely the primary sites of infection in our patients, as compared to the papular, moist, and papillary condylomata lata of secondary syphilis, which can commonly be seen in the anogenital region. (7)

Syphilis involving the anal canal was clinically suspected in 1 of the known [HIV.sup.+] patients (case 1) but unsuspected in the other 3 cases. Of interest, RPR test results in case 1 were negative, although the FTA-ABS test result returned positive, which supported the diagnosis of syphilis in conjunction with the biopsy and PCR results. The negative RPR finding could be explained by a rare prozone phenomenon in which patients, particularly those with high antibody titers, have falsely negative RPR findings in undiluted specimens. (8) Some have proposed this phenomenon may be more prevalent in [HIV.sup.+] patients. (9)

In cases 2 and 3, syphilis was not clinically suspected such that a confirmatory clinical workup and treatment were only prompted by the biopsy findings. In case 4, the patient presented with an ulcerated anal mass. In this case, there was a prominent reactive inflammatory infiltrate along with inflammation-related changes in the surrounding soft tissue (ie, edema) that likely contributed to the masslike appearance clinically. In addition, syphilis involving squamous mucosa/epithelium can sometimes cause intense pseudoepitheliomatous hyperplasia, possibly mimicking a squamous cell carcinoma histologically, and producing a masslike appearance, although this was not seen in our case. Although the positive syphilis laboratory test result was known in case 4, and T pallidum IHC staining was reported as positive on the initial biopsy samples, the endoscopic and CT impressions still favored malignancy until the resection results were received. In cases 2, 3, and 4, the pathologist's suspicion of syphilis was paramount to making a timely diagnosis and prompting appropriate treatment.

Histologic features of primary syphilis involving the site of contact in the skin have been well characterized and include (1) a prominent bandlike inflammatory infiltrate, often rich in plasma cells and mixed with lymphocytes and histiocytes at the dermoepidermal junction; (2) a dermal and perivascular chronic inflammatory infiltrate, often rich in plasma cells and mixed with lymphocytes and histiocytes; and (3) sometimes poorly formed granulomas. (10-13) The patterns of inflammation in all 3 of our anal canal ulcer cases were very similar to what is described in skin, with a bandlike chronic inflammatory infiltrate rich in plasma cells, beneath the squamous epithelium, with prominent perivascular inflammation. Two of our cases had poorly formed granulomas. The biopsy samples taken from the anal mass also had prominent chronic inflammation within the granulation tissue, and the adjacent nonulcerated squamous epithelium had an underlying bandlike chronic inflammatory infiltrate similar to our other cases. There were more plasma cells in the subepithelial infiltrate as compared to the granulation tissue component of the mass, demonstrating that the presence of plasma cells, although helpful in suspecting a diagnosis of syphilis, can be variable in biopsy samples. (10) The patient with an anal mass case also had concurrent rectal biopsy samples that were taken at the time of anal biopsy, in which the rectal mucosa also had a chronic lymphoplasmacytic inflammatory infiltrate expanding the lamina propria, and mild cryptitis that could mimic inflammatory bowel disease. In our case, other features of chronicity, such as prominent crypt architectural distortion, were not well established in the rectal biopsy samples. However, we would like to highlight that distinction of syphilitic proctitis from inflammatory bowel disease can be difficult, as more prominent crypt distortion, and sometimes granulomas or Paneth cell metaplasia, may also be present in syphilitic proctitis. Recognition of the pattern of inflammation in the anal canal mucosa, similar to what is seen in skin, as well as the pattern of inflammation in rectal mucosa if concurrent rectal biopsy samples are provided, is critical to raise the pathologist's suspicion of syphilis when examining biopsy samples taken from the squamous zone of the anal canal and should prompt ancillary studies to further characterize the cause of the inflammation.

Historically, silver stains, including modified Steiner or Warthin-Starry stains, have been used to highlight spirochetes in cases of suspected syphilis (Figure 3, C); however, these stains have suboptimal sensitivity and specificity. In the skin, histochemical silver stains are limited by the presence of melanin in the epidermis, staining of reticulin fibers in the dermis, and high levels of background staining, particularly in cases with few organisms. (10,11,13-15) Melanin/melanocytes can also be present in the squamous zone of the anal canal, limiting the utility of histochemical silver stains in this region. Treponema pallidum IHC stain has improved the accuracy of the histologic diagnosis of syphilis, with higher sensitivity and specificity than histochemical stains alone. (13,14) Use of a red chromogen in place of a brown chromogen to highlight T pallidum organisms can also be helpful in anal canal lesions to distinguish the organisms from brown melanin pigment (10,16) (Figure 3, D). In our 3 anal canal ulcer cases the T pallidum IHC stain highlighted organisms in a characteristic pattern, which included concentration of organisms at the junction of the squamous epithelium and lamina propria, and in a perivascular pattern, with a relatively high concentration of organisms. In the case with the anal mass, T pallidum IHC stain highlighted organisms in the granulation tissue, with organisms concentrated around vessels, but in a patchy distribution.

Although T pallidum immunohistochemistry has been shown to have a high sensitivity and specificity, the organisms are occasionally not detected, possibly owing to a variable distribution of organisms, previous treatment, and/or sampling error. Some suggest that in cases where there is high suspicion for syphilis either clinically or histologically, it may be worthwhile to examine multiple levels of the immunostained slides under high magnification/oil immersion, allowing for detection of rare organisms. (17) In addition, T pallidum immunohistochemical monoclonal or polyclonal antibodies can cross-react with Borrelia burgdorferi and other spirochetes, sometimes resulting in false-positive staining. Correlation of positive T pallidum immunohistochemistry findings with the patient's clinical and laboratory findings should resolve the issue, given that the clinical presentations of syphilitic infection and Lyme disease are relatively different. (18) Finally, negative T pallidum immunohistochemistry findings do not entirely rule out the possibility of syphilis or other STIs. For example, the histologic features of syphilitic infection and lymphogranuloma venereum in the anorectal mucosa have very similar histologic features including a chronic inflammatory infiltrate rich in plasma cells. Therefore, despite a negative T pallidum IHC result, if there is high suspicion for syphilis/STI, based on the pattern of inflammation and/or clinical presentation, a biopsy can be signed out descriptively, with a comment suggesting clinical follow-up with appropriate laboratory tests to rule out STI including syphilis or lymphogranuloma venereum. (16)

In summary, we demonstrate that the histologic findings of syphilis of the anal canal can resemble those of syphilitic skin lesions. However, the diagnosis may be missed because of its presentation in the anal canal location. If clinical suspicion for syphilis is not high, the pathologist could attribute the anal chronic inflammation and ulceration to another etiology such as mechanical trauma, prolapse, other types of infection, or anal fissures (either idiopathic or related to Crohn disease, particularly if granulomas are present). In addition, it is important to highlight that syphilis can also present in the anal canal as an inflammatory mass lesion, clinically and possibly histologically mimicking malignancy, which has been described in other locations, (16,19,20) most recently in the liver. (21) Finally, rectal involvement by syphilis can be misinterpreted as nonspecific proctitis or inflammatory bowel disease. It is especially important to consider syphilis in MSM, and in [HIV.sup.+] and other immunosuppressed patient populations in which false-negative serologic test results have been reported. (8,14,15) Ancillary studies, including T pallidum IHC staining performed on the paraffin-embedded tissue, provide critical clues to help confirm the diagnosis and avoid a delayed or missed diagnosis of syphilis that may progress to late-stage disease, with longstanding complications.

Please Note: Illustration(s) are not available due to copyright restrictions.

The authors would like to thank Mark Smith, AAS, for his help with formatting the images in this manuscript.

References

(1.) Peterman TA, Furness BW. The resurgence of syphilis among men who have sex with men. Curr Opin Infect Dis. 2007; 20(1):54-59.

(2.) Su JR, Beltrami JF, Zaidi AA, Weinstock HS. Primary and secondary syphilis among black and Hispanic men who have sex with men: case report data from 27 states. Ann Intern Med. 2011; 155(3):145-151.

(3.) Center for Disease Control and Prevention (CDC). Syphilis: CDC fact sheet. 2012. www.cdc.gov/std/syphilis/STDFact-Syphilis-detailed.htm. Accessed May 21, 2014.

(4.) Ho EL, Lukehart SA. Syphilis: using modern approaches to understand an old disease. J Clin Invest. 2011; 121(12):4584-4592.

(5.) Weerakoon AP, Fairley CK, Read TR, et al. Syphilis infection among homosexual men reporting contact with syphilis: a case control study. BMJ Open. 2012; 2(4):e001339.

(6.) Heffelfinger JD, Swint EB, Berman SM, Weinstock HS. Trends in primary and secondary syphilis among men who have sex with men in the United States. Am J Public Health. 2007; 97(6):1076-1083.

(7.) Deshpande DJ, Nayak CS, Mishra SN, Dhurat RS. Verrucous condyloma lata mimicking condyloma acuminata: an unusual presentation. Indian J Sex Transm Dis. 2009; 30(2):100-102.

(8.) Liu L, Lin L, Tong M, et al. Incidence and risk factors for the prozone phenomenon in serologic testing for syphilis in a large cohort. Clin Infect Dis. 2014; 59(3):384-389.

(9.) Jurado RL, Campbell J, Martin PD. Prozone phenomenon in secondary syphilis, has its time arrived? Arch Intern Med. 1993; 153(21):2496-2498.

(10.) Quatresooz P, Pierard GE. Skin homing of Treponema pallidum in early syphilis: an immunohistochemical study. Appl Immunohistochem Mol Morphol. 2009; 17(1):47-50.

(11.) Quatresooz P, Pierard GE. Perivascular cuff and spread of Treponema pallidum. Dermatology. 2009; 219(3): 259-262.

(12.) Engelkens HJ, ten Kate FJ, Judanarso J, et al. The localisation of treponemes and characterization of the inflammatory infiltrate in skin biopsies from patients with primary or secondary syphilis, or early infectious yaws. Genitourin Med. 1993; 69(2):102-107.

(13.) Hoang MP, High WA, Molberg KH. Secondary syphilis: a histologic and immunohistochemical evaluation. J Cutan Pathol. 2004; 31(9):595-599.

(14.) Phelps RG, Knispel J, Tu ES, et al. Immunoperoxidase technique for detecting spirochetes in tissue sections: comparison with other methods. Int J Dermatol. 2000; 39(8):609-613.

(15.) Lee WS, Lee MG, Chung KY, Lee JB. Detection of Treponema pallidum in tissue: a comparative study of the avidin-biotin-peroxidase complex, indirect immunoperoxidase, FTA-ABs complement techniques, and the darkfield method. Yonsei Med J. 1991; 32(4):335-341.

(16.) Arnold CA, Limketkai BN, Illei PB, et al. Syphilitic and lymphogranuloma venereum (LGV) proctocolitis: clues to a frequently missed diagnosis. Am J Surg Pathol. 2013; 37(1):38-46.

(17.) Putri I, Mercer SE, Phelps RG, Levitt JO. False-negative anti-treponemal immunohistochemistry in secondary syphilis. Int J Dermatol. 2013; 52(2):172-176.

(18.) Buffet M, Grange PA, Gerhardt P, et al. Diagnosing Treponema pallidum in secondary syphilis by PCR and immunohistochemistry. J Invest Dermatol. 2007; 127(10):2345-2350.

(19.) Alrajab S, Payne K, Areno J, et al. A 40-year-old man with a nodular lung disease and skin rash. Chest. 2012; 141(6):1611-1617.

(20.) Adachi K. Syphilitic gastritis mimicking gastric neoplasms. Dig Liver Dis. 2011; 43(9):748.

(21.) Hagen CE, Kamionek M, McKinsey DS, Misdraji J. Syphilis presenting as inflammatory tumors of the liver in HIV-positive homosexual men. Am J Surg Pathol. 2014; 38(12):1636-1643.

Purva Gopal, MD, MS; Rajal B. Shah, MD

Accepted for publication December 11, 2014.

From the Department of Pathology, University of Texas Southwestern Medical Center, Dallas (Dr Gopal); and Miraca Life Sciences, Miraca Life Sciences Research Institute, Irving, Texas (Dr Shah).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Purva Gopal, MD, MS, Department of Pathology, University of Texas Southwestern Medical Center, 5959 Harry Hines Blvd, POB-1, Suite 310, Dallas, TX 75390 (e-mail: purva.gopal@ utsouthwestern.edu)

Caption: Figure 1. A, Bandlike chronic inflammatory infiltrate at the junction of squamous epithelium and lamina propria. B, Plasma cell-rich inflammatory infiltrate. C, Poorly formed granulomas (hematoxylin-eosin, original magnifications X200 [A], X600 [B], and X400 [C]).

Caption: Figure 2. A, Treponema pallidum immunohistochemical stain highlighting characteristic "corkscrew" organisms at the junction of squamous epithelium and lamina propria. B, Treponema pallidum immunohistochemical stain highlighting characteristic "corkscrew" organisms in a perivascular pattern. C, Granulation tissue from the anal canal mass with chronic inflammatory infiltrate and scattered plasma cells (original magnification X600 [A and B]; hematoxylin-eosin, original magnification X400 [C]).

Caption: Figure 3. A, Squamous epithelium adjacent to ulcerated anal mass with underlying bandlike and deep chronic inflammatory infiltrate. B, Rectal mucosa with increased lymphoplasmacytosis of the lamina propria with minimal crypt distortion and mild cryptitis. C, Warthin-Starry stain highlighting "corkscrew" organisms (solid arrows) and nonspecific staining (dotted arrow) in granulation tissue taken from the anal mass. D, Treponema pallidum immunohistochemical stain using red chromogen, highlighting organisms at the junction of squamous epithelium and lamina propria (hematoxylin-eosin, original magnifications X200 [A] and X400 [B]; original magnifications X600 [C] and X400 [D]).
Clinicopathologic Characteristics
of 4 Cases of Syphilis Presenting
as Anal Canal Lesions

Case             Sexual          Clinical
No.    y/Sex   Orientation     Presentation      Histologic Features

1      52/M    MSM           Anal canal ulcer   Bandlike chronic
                                                plasma cell-rich
                                                infiltrate at the
                                                junction of squamous
                                                epithelium and lamina
                                                propria with rare,
                                                poorly formed
                                                granulomas

2      44/M    Unknown       Nonhealing anal    Bandlike plasma
                             canal ulcer        cell-rich chronic
                                                inflammatory
                                                infiltrate at the
                                                junction of squamous
                                                epithelium and lamina
                                                propria

3      51/M    Unknown       Anal canal ulcer   Ulcer with chronic
                                                plasma cell- rich
                                                inflammatory
                                                infiltrate and rare,
                                                poorly formed
                                                granulomas; adjacent
                                                squamous epithelium
                                                with underlying
                                                bandlike chronic
                                                inflammatory
                                                infiltrate

4      31/M    MSM           Anal canal mass;   Granulation tissue
                             proctitis          with scattered plasma
                                                cells; adjacent
                                                squamous epithelium
                                                with underlying
                                                bandlike plasma
                                                cell-rich chronic
                                                inflammatory
                                                infiltrate; expansion
                                                of rectal lamina
                                                propria by
                                                lymphocytes and
                                                plasma cells; minimal
                                                crypt distortion;mild
                                                cryptitis

                                 Treponema
Case                             pallidum
No.      Laboratory Results     IHC Results

1      RPR test nonreactive      Positive
       FTA-ABS test reactive
       Tpallidum qualitative
       real-time PCR positive
       HIV test positive

2      RPR test reactive         Positive
       FTA-ABS test reactive
       HIV test unknown

3      RPR test reactive         Positive
       TP-PA test reactive
       HIV test unknown

4      RPR test reactive         Positive
       Syphilis treponemal
       antibody positive
       HIV test positive

Abbreviations: FTA-ABS, fluorescent
treponemal antibody absorption; HIV,
human immunodeficiency virus;IHC,
immunohistochemistry; MSM, men who
have sex with men; PCR, polymerase
chain reaction; RPR, rapid plasma
reagin; TP-PA, Treponema pallidum
particle agglutination.
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Author:Gopal, Purva; Shah, Rajal B.
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Date:Sep 1, 2015
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