Clinics in Dermatology (2014) 32, 196–208

Skin as an indicator for sexually transmitted infections Henry J.C. de Vries, MD, PhD ⁎ STI Outpatient Clinic, Cluster of Infectious diseases, Public Health Service Amsterdam, Amsterdam, The Netherlands Department of Dermatology, Academic Medical Center, Post Office Box 22700, 1100 DE, University of Amsterdam, Amsterdam, The Netherlands Centre for Infection and Immunity Amsterdam (CINIMA) Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands Centre for Infectious Diseases Control; National Institute for Public Health and the Environment (CIb/RIVM), Bilthoven, The Netherlands

Abstract Cutaneous signs and skin conditions associated with sexually transmitted infections (STIs) are discussed. Syphilis, condyloma acuminata, and scabies are well-known STIs with cutaneous manifestations. Chlamydia and gonorrhea can also cause specific muco-cutaneous signs and symptoms. HIV often manifests itself through skin conditions. Dermatologists are pivotal in the timely diagnosis of HIV infection and play an important role in the disease prognosis and ongoing transmission. Anal intra-epithelial neoplasia (AIN), an HPV related precursor of anal carcinoma affecting HIV positive men, is a relatively new condition that many dermatologists will face in the future. STIs should be involved in the differential diagnosis when dermatologists are confronted with anogenital dermatoses, especially in patients with an increased risk for STIs. © 2014 Elsevier Inc. All rights reserved.

Introduction Historically, dermatologists were the first modern specialists who studied sexually transmitted infections (STIs). Around the dawn of premodern dermatology in the second part of the 19th century, syphilography was an important subspecialty, which flourished in the first dermatologic schools in Paris followed by Vienna.1 As a consequence of this historical background, most dermatologist training programmes in continental European countries still incorporate venereology, the subspecialty involved with STI. This is not the case in the British medical tradition. In the United Kingdom and most Commonwealth territories, Sexual Health (previously Genito-Urinary Medicine) is the specialty dedicated to STI and in these countries dermatologists are much less involved with STI. In the United States, infectious diseases specialists and public health physicians have an ⁎ Corresponding author. Tel.: +31 20 566 2582; fax: +31 20 696 0076. E-mail address: [email protected] (H.J.C. de Vries). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.08.003

important role in the STI field; however, dermatologists continue to play a significant role in the diagnosis and treatment of these diseases. Signs and symptoms involving the skin and adjacent mucosal tissues accompany many STIs. It is important (and not only for dermatologists) to think of STI when a patient presents with the sudden onset of skin conditions, especially in the anogenital region. The a priori chance of a causative STI can be estimated by a detailed assessment of risk behavior: eg, previous STI episodes, number of sexual partners, and the use of condoms.

Cutaneous manifestations in bacterial STI Syphilis Syphilis is a disease with a highly variable clinical course. The disease is called “the great imitator,” because the various clinical manifestations of syphilis match many other diseases. Syphilis occurs worldwide. The incidence tends

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to increase during periods of social upheaval, as occurred in Eastern Europe after the collapse of communism in 1989,2 and in recent times in China during the economic boom.3 Syphilis affects special risk populations like men who have sex with men (MSM). In this group, a sharp rise in syphilis has occurred from the mid-1990s to date.4 The rise in syphilis prevalence among MSM has been attributed to the introduction of effective antiretroviral therapy for HIV infection. Because HIV infection is no longer considered a deadly disease, it is said to have permitted unsafe sexual behavior, a phenomenon sometimes called HIV optimism.5

Syphilis extra-genital primary inoculation Primary syphilis is characterized by a lesion at the inoculation site. Initially, a solid papule arises, which after a few days breaks in the center to form a painless indurated ulcer (ulcus durum). In 80% of cases, regional lymphadenopathy can be found. The external genitalia are the most frequent site of inoculation. In case of receptive anal or oral sex, primary lesions around and/or in the anal canal and mouth are not uncommon (Figure 1). Although spirochetes are said not to invade through squamous skin, infectious

Fig. 2 Primary syphilis affect on the clavicular region. Probably via contact of a pre-exsisting abrasion with genital fluids.

excreta can cause primary syphilitic lesions in unexpected sites, such as in the pubic area or the upper aspects of the trunk via abrasions due to for example the shaving of body hair (Figure 2). Primary syphilitic lesions contain spirochetes and are contagious through sexual contact. Spontaneous healing of the primary lesion occurs in 3 to 6 weeks by a cellmediated immune response, in which treponema are phagocytized by activated macrophages. Spirochetes are spread via lymphatic and blood vessels within several hours after acquisition; thus, syphilis is considered a systemic infection from the onset.6 The bacteria can infect virtually every organ, including the central nervous system.

Syphilis secondary stage The signs of secondary syphilis usually occur between six and twelve weeks (and sometimes up to 12 months) following the moment of acquisition. Around this time, treponema can be found in almost all organs. By definition, nontreponemal antibody tests (VDRL, RPR) are highly

Fig. 1 Panel a, peri-anal primary syphilis affect, panel b, intraoral primary syphilis affect on the hard palate.

Fig. 3 Maculo-papular eruption on the leg plus hyperkeratotoc plaques on the foot sole of a man with secondary syphilis.

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Fig. 4 Condyloma lata, a manifestation of secondary syphilis, in the peri-anal region. Hair growth in the lesion is not affected, in contrast to condyloma acuminata.

reactive (with titer results of ≥ 1:32). False negative nontreponemal can occur in case of an extremely high serum antibody titers, a phenomenon known as the prozone phenomenon.7 Vascular changes play an important role in the pathophysiology of secondary syphilis, and vascular precipitation of immune complexes in the skin and in the kidneys (glomerulonephritis) can be seen. Secondary syphilis occurs in 60% to 90% of infected patients and is characterized by one or more skin and/or mucosal abnormalities. Apart from the skin, other organs can be involved. Approximately four to eight weeks after the onset of the primary lesion (which sometimes is still present), the first signs of the secondary stage occur. Most prominent is a

Fig. 5

Moth eaten alopecia caused by secondary syphilis.

Fig. 6 mouth.

Typical annular secondary syphilitic lesions around the

maculo-papular, nonitchy eruption on the trunk and extremities, including the palms and soles (Figure 3). Sometimes, condylomata lata develop in the folds of the anus or genitals, appearing as elevated verrucous papules with a moist surface (Figure 4). They contain many spirochetes and are highly contagious. Such lesions are often mistaken for genital warts (condyloma acuminata). In contrast to genital warts, hair growth is not interfered within condyloma lata. Sudden alopecia is another remarkable sign of secondary syphilis (Figure 5). When multiple small alopecic spots are involved, it is often referred to as “moth-eaten” alopecia. Annular lesions around body orifices like the genital area, perianal area, and the mouth are typical of secondary stage syphilis (Figure 6). Malignant syphilis is a rare expression of secondary syphilis characterized by multiple disseminated ulcerative lesions, each resembling a primary lesion (Figure 7).8 Secondary syphilis is often accompanied by systemic symptoms, such as fever, malaise, headache, and muscle ache.9 Laboratory analysis sometimes reveals hepatic and renal impairment. Joint and bone pain caused by an infectious arthritis and periostitis can occur. Sudden unilateral facial paralysis, visual and/or auditory impairment, are signs of cranial nerve compression caused by syphilitic meningitis. These neurologic complications are also part of the secondary stage and can occur especially in HIV coinfected patients with low cellular immune parameters (CD4 T cell count b 350 x 106 cells/ml).10 Secondary syphilitic lesions contain spirochetes, but when they involve intact squamous skin (such as the

Fig. 7 Malignant syphilis at the forehead, a secondary stage phenomenon characterised by multiple disseminated ulcers.

Skin as an indicator for sexually transmitted infections palms) they are not infectious via daily interhuman contact. Mucosal secondary syphilitic lesions in contrast, are infectious during sexual intercourse.

Syphilis tertiary stage Progression to tertiary syphilis occurs years, even decades, after acquisition of the infection and is likely a result of waning immunity to T pallidum. The treponemas invade the central nervous system (and can cause syphilitic meningitis and parenchymatous neurosyphilis), cardiovascular structures, and other organs. A destructive inflammatory reaction results in irreversible, potentially lethal, organ damage. Since the introduction of penicillin and other antibiotics after World War II, tertiary stage syphilis has become increasingly rare.11 Granulomatous gummata, deep ulceration, and scarring are cutaneous signs of tertiary syphilis. Two to four years after infection, tertiary syphilis characteristic granulomatous, nodular, or ulcerative abnormalities (gummata), can occur in the skin, mucous membranes (Figure 8), bones, and virtually every internal organ. Histopathologically, they can be distinguished as a chronic proliferative inflammatory process with granuloma and giant cell formation (similar to mycobacterial infections).

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Urogenital chlamydia infection Chlamydia trachomatis is a gram-negative obligate intracellular bacterium of 0.2 micrometer. It is too small to detect via a light microscope, although indirectly intracellular inclusion bodies are suggestive for C trachomatis infected cells.12 In general, C trachomatis genotypes D to L3 are transmitted via sexual contact, but can be transferred from mother to child during delivery with the chance of neonatal eye or respiratory infections. C trachomatis serotypes A, B/Ba, and C cause trachoma, a nonsexual acquired eye infection endemic in tropical regions that eventually leads to blindness. C trachomatis can cause distinct sexually acquired syndromes; urogenital and anal chlamydia (caused by genovar D-K) and lymphogranuloma venereum (LGV; caused by genovar L). C trachomatis serotype D to K remain confined to mucosal lining without extensive inflammatory responses and therefore often cause little to no symptoms. In contrast, LGV is an invasive infection that often leads to severe inflammatory responses and symptomatic disease, as a result.13

Sexually acquired reactive arthritis C trachomatis infection rarely causes a reactive autoimmune syndrome, also known as sexually acquired reactive arthritis (SARA).14 The prevalence of reactive arthritis is estimated at 30 to 40 per 100,000, with the caveat that reactive arthritis can also be caused by pathogenic intestinal bacteria. Specific prevalence rates for SARA are not known. SARA can be accompanied by characteristic skin signs as keratoderma blenorrhagica (hyperkeratotic plaques in the palms and soles), balanitis circinata (gyrating erythematous lesions with marginal scaling on the penile glans), aphthous ulcers, and onychopathy (Figure 9). It is believed that pathogenic antigens ignite a plasmocellular immune response with the production of cross-reacting autoantibodies that recognize host structures. As a consequence, sterile inflammatory reactions, such as dermatitis, arthritis, conjunctivitis, and tenovitis, may occur. The combination of urethritis, conjunctivitis, and arthritis has also been known as Reiter's syndrome. This eponym is no longer used because it became widely known that the physician for whom the eponym was used, Reiter, committed serious war crimes during the World War II.15

Neonatal chlamydia conjunctivitis

Fig. 8 Panel a, Granulomatous plaque under the chin and, panel b, Gumma and destruction of the tongue in tertiary stage syphilis (from the collection of Jan and Titia Warndorff).

During delivery, a mother with an untreated urogenital chlamydia infection can infect her newborn. This is more common during a vaginal delivery (67%) than after a cesarean (8%).16 The overall risk for mother to child C trachomatis transmission is 50-75%.17 In case of a neonatal infection, watery eyes, discharge, redness, and/or

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Fig. 9 Manifestations of Sexually Aquired Reactive Arthritis (SARA) triggered by urogenital chlamydia infection. Panel a, Keratoderma blennorhagica on the foot soles, panel b, Balanitis circinata, c. Keratoderma blennorhagica and onycholysis, panel d, Reactive conjunctivitis (Panels a and c, and c from K.D. Quint, Leiden University Medical Center, Leiden, the Netherlands).

swelling of one or both eyes usually occur between the end of the first week and third month.18 Most infections resolve spontaneously and heal without serious complications, but untreated eye infection can persist subclinically for years and cause great discomfort, even during the neonatal period.19 The conjunctiva are a porte d’entrée for the upper and lower respiratory tract via the nasopharynx. At least 50% of newborns with C trachomatis conjunctivitis have concurrent nasopharyngeal infections or pneumonia (8%-22%).20 Direct colonization of the lungs, without conjunctivitis, can occur.

Chlamydial conjunctivitis in adults C trachomatis conjunctivitis with urogenital serotypes (D-K) can also occur in sexually active adults, usually via self inoculation, but also via contact with genital fluids (Figure 10). The incubation period is 4 to 12 days and the patient usually presents with unilateral or bilateral redness of the eye with photophobia, a “grain of sand” feeling and after

Fig. 10 Infectious chlamydia conjunctivitis with photophobia caused by autoinoculation in a patient with urogenital chlamydia.

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a few days also mucopurulent discharge. Large follicles in the lower fornix and pre-auricular lymphadenopathy are other signs of C trachomatis-conjunctivitis. Due to its aspecific nature, recognition can be considerably delayed. Untreated conjunctivitis can become chronic and persist for several months.21

Lymphogranuloma venereum Lymphogranuloma venereum (LGV) was considered an STI usually confined to equatorial regions until 2004, when an epidemic of LGV was unveiled among men who have sex with men (MSM) in major cities throughout the Western world.22 LGV is caused by C trachomatis-type L and is associated with a severe invasive, destructive inflammatory response. If left untreated, it can eventually lead to irreversible damage to the lymphatic system with strictures and chronic pain syndromes in the pelvic region.23 Depending on the progression of the infection, three stages can be distinguished in LGV.24 1. The inoculation stage: Characterized by an inconspicuous and short-lived ulcer at the inoculation site. If help is sought, it is usually at the external genitalia. If the inoculation occurs intra-anal or intra-vaginal, it is usually missed. 2. The regional stage: Subsequent invasion of C trachomatis in the submucosal tissue causes a violent inflammatory reaction with edema. In addition, C trachomatis spreads via the lymphatics to regional lymph nodes where lymphadenopathy occurs. Necrosis in lymph nodes can lead to fluctuating abscesses (bubo formation) that sometimes rupture and leave long-standing fistula. When the infection is no longer localized, many patients have malaise, fever, weight loss, and even joint pains, possibly caused by a reactive arthritis. 3. The late stage: Left untreated, LGV infection causes fibrosis and irreversible complications, such as urethral, tubal, and anal strictures (that can lead to bladder dysfunction, infertility, and megacolon, respectively). LGV can also cause the “frozen pelvis” syndrome characterized by chronic pain, intestinal passage disorders, and infertility due to adhesions around the organs in the lower pelvic region, including the bladder, intestines, uterus, and ovaries. Lastly, irreversible lymphatic edema of external genitalia (elephantiasis) can arise from lymphatic destruction. Esthiomene is a classic lymphatic obstructive syndrome in women with longstanding LGV infections characterized by vegetative lymphorroids of the external genitalia, reminiscent of hemorrhoids. Apart from the time lapse stages, the primary inoculation site of LGV can cause three specific syndromes: 1. Anorectal LGV: Most cases of LGV in the current epidemic in MSM involve anorectal infections.25 These men get infected via anal receptive intercourse. The

Fig. 11 a. Anorectal lymphogranuloma venereum (LGV) with perianal ulceration, b. intra anal discharge, mucosal inflammation and edema upon anoscopy in the same patient is depicted in a.

inoculation stage is mostly missed and help is sought when the regional stage of infection arises. It is characterized by a severe proctitis with a bloody purulent anal discharge, rectal pain, itch, and cramps (tenismus). Constipation due to submucosal edema is often reported (Figure 11). Ascending infections (proctocolitis) give rise to diarrhea. Anorectal LGV can easily be misdiagnosed as chronic colitis. 26 Lymphadenopathy is often absent upon physical examination since the draining lymph nodes of the anal canal reside retroperitoneal. Late stage complications, such as the formation of anal strictures and fistulas, have been reported.27 2. Inguinal LGV: Clinical manifestations due to the inoculation stage of LGV via the external genitalia are often inconspicuous and short lived. A genital ulcer may be noted, but most often inguinal LGV is diagnosed when regional lymph nodes get involved and cause painful and fluctuating abscessing inguinal tumors called bubo’s (Figure 12). Untreated inguinal LGV can lead to chronic genital inflammation with formation of fistulas (Figure 13) and local obstruction of lymphatic vessels, resulting in genital lymphedema (elephantiasis). 3. Pharyngeal LGV: Inoculation of the pharynx is rare but has been reported in the current LGV epidemic among

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H.J.C. de Vries first line treatment, modality, gonorrhea has the potential to become a problematic infection again.30 There is a risk that, in the future, extended spectrum cephalosporins will not be effective. To date, there is no empirically proven effective alternative available.

Gonorrhea systemic disease: Pustular dermatitis

Fig. 12 Inguinal lymphogranuloma venereum (LGV) with a bubo in the groin area.

MSM.28 It may cause mucosal abnormalities and cervical lymphadenopathy.

Most gonococci infections remain confined to the mucosal linings of the primary inoculation site; yet, N gonorrheae has the potency to enter the systemic circulation.31 In particular, strains resistant to the lytic action of (IgM) antibodies that can circumvent complement activation are known to cause bacteriemia.32 Disseminated gonococci infections can cause fever, a cutaneous eruption or pustular dermatosis, and a very painful (usually staggered) polyarthralgia or septic arthritis in the extremities, endocarditis, and meningitis. This occurs in between 0.6 and 3.0% of women and 0.4 and 0.7% of men.33 Disseminated gonococcemia should always be considered in a sick, sexually active patient with pustules in the palms and soles of the feet. In neonates, gonococcal conjunctivitis (ophthalmia neonatorum) can result from inoculation during vaginal delivery (Figure 14). This can lead to complications, such as corneal ulceration with a risk of perforation and eventual blindness.

Gonorrhea

Cutaneous manifestations in viral STI

Before the advent of antibiotics, gonorrhea was a difficult to threat STI and caused extensive morbidity with strictures, infertility, and destructive arthritis. With the recent introduction of multiresistant gonococci 29 and widely reported decreased susceptibility for the current

HIV

Fig. 13 Late stage inguinal lymphogranuloma venereum (LGV) with fistulas (from Dr. R. Hu, Dermatological Service, Paramaribo, Suriname).

In the early 1980s, a case series described a cluster of apparently healthy young homosexual men in New York with cutaneous Kaposi’s sarcoma (KS) who later proved severely immune-deficient.34 This was one of the first reports of AIDS patients in the medical literature. All cases had multiple STI episodes in the past, and Kaposi sarcoma was a rare skin malignancy, only known in middle-aged men of Mediterranean origin.

Fig. 14 A newborn with gonococcal ophthalmia neonatorum caused by a maternally transmitted gonococcal infection (from Centers for Disease Control and Prevention's Public Health Image Library).

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From the start of the HIV epidemic, it was apparent that sexually transmitted diseases and unusual skin manifestations were hallmarks in this new disease. Atypical (opportunistic) skin infections are often the first signs of an already advanced HIV infection and may be a first indication for an HIV test. In recurrent skin infections and cutaneous diseases poorly responsive to therapy, an underlying HIV infection could play a role.

athy can arise 3 to 6 weeks after acquisition (Figure 15).35 Ulceration and enanthema of the oral mucosa and anogenital ulceration can also be found in acute or primary HIV infection. Similar mucocutaneous findings can be found in syphilis, and the route of transmission of HIV and STI are alike; therefore, all prevalent STIs should be excluded when acute HIV is suspected. There are several reasons for correctly diagnosing and treating primary HIV infections. Temporary treatment of primary HIV infections defers the start of antiretroviral therapy required during the chronic phase of infection and has a positive impact on health-related quality of life.36–38 Disease progression toward immune suppression is quicker in those with a history of symptomatic primary HIV infection. In the early phase of the HIV infection, patients have high viral titers. As a consequence, they are more infectious and capable of transmitting the disease to their partners.36 Early detection and subsequent treatment is thus considered a public health tool to prevent ongoing transmission. Clinical manifestations, related to primary HIV infection, spontaneously resolve after several weeks, and an asymptomatic period of months to years can follow before the findings related to immune deficiency develop.

Acute HIV exanthema In 50% to 70% of the patients with a primary or recent HIV infection, general malaise with fever, a macular eruption, myalgia, diarrhea, and generalized lymphadenop-

HIV indicator diseases Of the approximately 2.3 million people living with HIV in the European region, it is estimated that one in three are unaware of their HIV status, resulting in significant levels of late diagnosis and transmission across the region.40,41 Late presentations of newly diagnosed HIV-positive patients (ie, with a CD4 count b 350 cells/μL) is associated with increased HIV-related morbidity and mortality, poorer response to treatment, increased health care costs, and increased transmission rates. Earlier diagnosis requires innovative approaches to improve testing among those most likely to be infected with HIV and who present late for care. People with undiagnosed Table 1

Fig. 15 Manifestations of a primary HIV infection. Panel a, Macular eruption, Panel b, Enanthema of the oral mucosa, Panel c, Peri-anal ulceration. Breakdown of the mucosal barrier plus a high viral load makes the early stage of HIV infection highly infectious for sexual partners.

HIV related indicator skin conditions ⁎

Kaposi’s sarcoma Herpes Simplex ulcer(s) Atypical disseminated leishmaniasis Penicilliosis, disseminated Seborrheic dermatitis/exanthema Herpes zoster Sexually transmitted infections Hepatitis B or C (acute or chronic) Severe or recalcitrant psoriasis Candidiasis Cutaneous lymphoma Anal cancer/Anal Intra-epithelial Neoplasia (AIN) Psoriasis Oral hairy leukoplakia ⁎ Adapted from: HIV Indicator Conditions: Guidance for Implementing HIV Testing in Adults in Health Care Settings Late diagnosis. HIV in Europe, freely downloadable from www.hiveurope.eu

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HIV may potentially present to any hospital, clinic, or primary care/general practice setting. HIV testing should be considered during any clinical contact when a person presents with an indicator condition. Multiple medical specialties are involved in the care of individuals presenting with HIV indicator conditions. Because HIV related pathology frequently involves the skin, dermatologists especially can be confronted with undiagnosed HIV patients and should offer HIV testing in case of dermatoses as outlined in Table 1, especially in case of unusual, therapy resistant and recurring presentations.

HPV related skin diseases Human papillomaviruses (HPV) Human papillomaviruses are small DNA viruses of about 55 to 60 nanometers, containing a double-stranded, circular DNA genome of approximately 8000 base pairs.37 There are more than 150 different HPV types known, of which at least 35 can infect the anogenital epithelium. HPV types can be divided into a cutaneous group, related to squamous skin lesions (eg, warts) and a mucosal group, related to, for example, anogenital pathology. In addition, a distinction is made between benign and oncogenic HPV types. Since the 1970s, it has become increasingly known that HPV infections can cause cellular changes and that HPV is linked to cervical cancer. 38,39 Some HPV types (eg, HPV 16 and 18) have oncogenic potential. Persistent oncogenic infections can cause solid malignancies in the anogenital area, such as the cervix and anal canal, especially in the transformation zone where squamous and columnar mucosal linings meet.

Fig. 16

Condyloma acuminata on the buccal mucosa.

per 100,000 person-years.40 This increase seems to be mainly concentrated in HIV-positive MSM; the pooled anal cancer incidence was 459 per 100 000 men.41 This is 4 to 5 times higher than the incidence of cervical cancer in women in the general population before the introduction of screening programs. The pathophysiology of anal cancer is very similar to that of cervical cancer. They share oncogenic human papillomavirus (HPV) as a causative link, mainly HPV 16.42 Anal intraepithelial neoplasia (AIN) is considered the precursor of anal cancer and graded 1 to 3 in increasing

Anogenital warts HPV 6 and 11 are regarded as benign types and the causative agents of anogenital warts. Anogenital warts or condyloma acuminata are one of the most common STIs and the most common viral STI. Normally, they can be found at the external genitals, perianal, intraanal, intravaginal, and the public area (sometimes, extensively if pubic hairs are shaved and the virus has been disseminated in the region via shaving abrasions). Typical condyloma acuminata have a comb or fig shape and consist of papillomatous papules and can be found on extra-genital locations, such as the oral cavity (Figure 16). Older lesions tend to develop a horny surface. Some warts may be flat topped (verrucae plana).

Anal intra-epithelial neoplasia (AIN) With the introduction of antiretroviral therapy, HIVinfected patients live longer, and new causes of morbidity and mortality have been noted. One of the most striking is anal cancer, whose incidence has increased from 20 to 78

Fig. 17 High resolution anoscopy (HRA) is required to screen for anal intra-epithelial neoplasia.

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Fig. 20 Fig. 18 Intra-anal intra-epithelial neoplasia (AIN) grade 2 in an HIV positive patient characterized by punctuation and acetowhitening located at 2 hours (10× magnification).

severity of neoplasia. AIN 1 is called low-grade (LGAIN), AIN 2 and 3 are called high-grade AIN (HGAIN). AIN can be visualized via high-resolution anoscopy (HRA), a combination of proctoscopy and a colposcope used in gynecology. With HRA the transformation zone in the anal canal is viewed under magnification (Figure 17). Acetic acid application is required to appreciate AIN lesions (Figure 18). Flat acetic white stained macules with punctuation, and aberrant vascularity are typical for AIN lesions.43 Perianal AIN lesions manifest as flat hyperkeratotic or hyperpigmented papules (Figure 19). Suspected lesions need to be biopsied to confirm the diagnosis. Electrocoagulation is considered the standard option of treatment but recurrences are frequent.44 Patients with AIN need to be screened regularly to monitor disease progression. When HGAIN progresses and becomes an invasive disease, anal cancer arises, characterized by exophytic tumorous lesions and chronic ulceration (Figure 20). The management of anal

Fig. 19 Peri-anal intra-epithelial neoplasia (AIN) in an HIV positive patient characterized by hyperpigmentend flat papules also known as Bowenoid papulosis (10× magnification).

Anal carcinoma in an HIV positive patient.

cancer falls beyond the scope of this overview. Apart from AIN, oncogenic HPV can also cause intraepithelial neoplasia in other locations like the vagina (VIN), and the penis (PIN; Figure 21).

Cutaneous manifestations in ectoparasitic STI Scabies Scabies is caused by the ectoparasite Sarcoptes scabiei (scabies mites).45 Transmission occurs during skin-skin contact lasting longer than 15 minutes, which is mostly the case during sexual contact and almost never the case in everyday human interactions, such as shaking hands. An exception to this rule is crusted scabies, a highly contagious form of scabies, characterized by numerous mites that can cause airborne transmission within institutions where the index case is being hospitalized. Outside the host, mite survival depends on the ambient

Fig. 21 Penile Intra-epithelial Neoplasia (PIN) in an HIV positive patient. Like AIN, PIN is caused by a persistent oncogenic HPV infection.

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Fig. 22 A burrow at the lateral side of the pinkie finger in a patient with a scabies infestation.

Fig. 24 Sclerosing lymphangitis in the penile sulcus of a patient with urethral gonorrhoea.

temperature and humidity. At room temperature mites lose their infectious potential after three days. The incubation period in a scabies naïve patient is two to six weeks; in case of repeat infections complaints can occur at an earlier notice (1–4 days) due to sensitization to the scabies antigens (via a delayed type hypersensitive T-cell mediated response). Itching is the main symptom. Typical “burrows” and excoriations can be found on the predilection locations, such as the external genitalia, buttocks and thighs, the interdigital space of the fingers, the lateral sides of the palms, the flexor side of the wrists, feet, armpits, and around the nipples. Burrows look like linear, narrow, tortuous, slightly elevated, up to 15 mm long, hyperpigmented or erythematous skin lesions (Figure 22). In the genital area, scabies normally presents with larger (about 0.5 to 1 cm) pruritic papules. Scratching is an effective method to reduce the number of mites. Sarcoptes scabiei can cause a hyperinfective condition called crusted scabies (formerly known as scabies norvegica or scabies greenlandica) in severely immunosuppressed (eg, AIDS), paraplegic and severely mentally disabled patients in a hospitalized setting. A reduced scratching reflex, caused respectively by anergy,

an inability to scratch, or a deranged itching sensation, leads to undisturbed propagation of mites, and their number may thus increase dramatically. Hyperkeratotic crust-like lesions can be found at the predilection sites and under the finger nails (Figure 23).

Fig. 23

Crusted scabies in a patient with AIDS.

Miscellaneous manifestations related with STIs Signs of inflammation in the genital area can be a clue for (possibly asymptomatic) STI. Non-STI related genital dermatoses are not covered, although sclerosing lymphangitis and Mondors’ disease need to be mentioned, because both are highly associated with infections and can arise as atypical charcteristics of an underlying STI. Sclerosing lymphangitis is characterized by a sudden appearance of a nonpainful subcutaneous fluctuating or fibrotic cord-like structure in the penile coronal sulcus (Figure 24).46 Although unproven, it is possibly a result of decompensation of lymphatic drainage caused by an inflammatory process. It is usually found in sexually active men in their 20s to 40s, following vigorous sexual intercourse or masturbation, probably resulting in mechanical trauma of the lymphatic apparatus. In two-thirds of the patients with sclerosing lymphangitis, an STI is diagnosed. Mondors’ disease is a rare condition, which is considered a thrombophlebitis of the subcutaneous veins.47 It commonly occurs on the anterolateral thoracoabdominal wall, but it can also occur on the penis, groin, antecubital fossa, and posterior cervical region. The clinical features are a sudden and typically asymptomatic onset of a cord-like induration, although some patients report a feeling of “strain.” It is a selflimiting process that lasts a short period of time, which may be the reason why there are few reports about its diagnosis and treatment. In the particular case of penile Mondors’ disease, it is essential to exclude sexually transmitted infections.48

Skin as an indicator for sexually transmitted infections

Conclusions STIs are often asymptomatic and can therefore easily be missed. Because STIs share the same route of transmission and many STIs cause a breakdown of the local immunity, exposed patients have a considerable risk of multiple infections. STI should be considered as a syndrome. When an infection is suspected, other endemic STI should be excluded as well. Apart from risk behavior, the aforementioned cutaneous manifestations and conditions form an indication for a full STI screening, including HIV.

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