Skin-Colored Disorders
Peter J. Lynch
SECTION A: SKIN-COLORED PAPULES
“Skin colored” refers to those disorders whose color is of the same hue as the patient’s surrounding normal tissue. Thus, in a darkly pigmented person, skin-colored lesions would be tan or brown, whereas in a lighter pigmented person, skin-colored lesions would be almost totally nonpigmented or white. Likewise, skin-colored lesions on a pink or red mucosal surface will be pink or red. Skin-colored lesions may be benign or malignant.
Genital Warts
Genital warts are caused by infection with human papillomavirus (HPV). These viruses cause common benign neoplasms and are significant because of (1) their transmissibility, (2) the association of some HPV types with the development of malignancy, and (3) our current inability to eradicate latent HPV from infected tissue. In contrast with herpes simplex virus (HSV) where there are just two viral types, HSV 1 and HSV 2, there are over 200 HPV types; about one-quarter of which can infect the anogenital region.1
Clinical Presentation
Most anogenital HPV infections occur at a subclinical and asymptomatic level, and only a small percentage (about 10%) of those infected will develop clinical lesions in the form of genital warts and precancerous lesions. Asymptomatic anogenital infection due to HPV is extremely common. Most (75%-90%) sexually active individuals will become infected in their lifetime making HPV the most commonly transmitted sexually transmitted disease (STD) agent in the world.1 Moreover, about 10%-20% of men and women in their 20s and 30s have evidence of HPV infection. This rate decreases with age, declining to about 5% in older persons. Not surprisingly, the rates are even higher in special groups such as prisoners, patients who attend an STD clinic, and men who have sex with men (MSM). On the other hand, the prevalence of symptomatic anogenital infection (anogenital warts and precancerous lesions) based on genital examination varies from country to country and is ˜0.1%-5% in men and women worldwide. Importantly, there is evidence that HPV vaccination is reducing these prevalence figures.2
Human papillomavirus infection is quite transmissible and the major risk factor for acquisition of the virus relates to sexual activity. Specifically, the risk of infection correlates best with age at first intercourse and the number of past sexual partners. Another important risk factor is that of immunosuppression due to HIV/AIDS and organ transplantation.1 Most HPV transmission occurs by way of vaginal and anal intercourse, but other forms of sexual activity with skin-to-skin contact also result in high transmission rates. In contrast, among children with anogenital warts, probably most transmission occurs through selfinoculation and innocent nonsexual contact. Though the evidence is not conclusive, condom use and male circumcision appear to decrease the risk of transmission.
There are four major morphologic variants of genital warts. Those found in persistently moist areas tend to be skin colored, filiform (eg, tall and narrow) with or without a brushlike tip (Fig. 7-1). This variant is appropriately
termed “condyloma acuminatum” (pl: condylomata acuminata) and, strictly speaking, is the only form of warts for which this term should be used. The second variant occurring in the anogenital area is verruca vulgaris (common warts) (Figs. 7-2 and 7-3). These are skin colored and similar in appearance to hand warts. They are about as wide (5-10 mm) as they are tall and typically have palpable, if not visible, surface roughness due to the presence of scale; there may also be a visible brushlike surface on the top of these lesions. They are located on the drier aspects of the anogenital tissue. The third variant is represented as smooth-surfaced, flat-topped, or dome-shaped papules that are wider than they are tall (Figs. 7-4 and 7-5). These are usually 3-15 mm in diameter and can occur on either moist or dry surfaces. While often skin colored, these flattopped warts may be pink, red, brown, or black. Finally, large globular warts, 2-4 cm in diameter, correspond to the fourth variant (Fig. 7-6). They have a smooth but often cauliflowerlike surface and are skin colored, pink, or red in hue. This type of lesion is often termed a giant condyloma or Buschke-Lowenstein tumor.
termed “condyloma acuminatum” (pl: condylomata acuminata) and, strictly speaking, is the only form of warts for which this term should be used. The second variant occurring in the anogenital area is verruca vulgaris (common warts) (Figs. 7-2 and 7-3). These are skin colored and similar in appearance to hand warts. They are about as wide (5-10 mm) as they are tall and typically have palpable, if not visible, surface roughness due to the presence of scale; there may also be a visible brushlike surface on the top of these lesions. They are located on the drier aspects of the anogenital tissue. The third variant is represented as smooth-surfaced, flat-topped, or dome-shaped papules that are wider than they are tall (Figs. 7-4 and 7-5). These are usually 3-15 mm in diameter and can occur on either moist or dry surfaces. While often skin colored, these flattopped warts may be pink, red, brown, or black. Finally, large globular warts, 2-4 cm in diameter, correspond to the fourth variant (Fig. 7-6). They have a smooth but often cauliflowerlike surface and are skin colored, pink, or red in hue. This type of lesion is often termed a giant condyloma or Buschke-Lowenstein tumor.
 Fig. 7-1. The acuminate, or spiky, shape of this genital wart give the name to the condyloma acuminatum morphology of external genital warts. |
 Fig. 7-2. This wart shows the morphology of a common wart; these are found on the dry, more keratinized skin and shows a very rough, keratotic surface. |
 Fig. 7-3. This wart is as tall as it is wide, as is typical of the morphology of a common wart. |
 Fig. 7-4. The proximal shaft shows an extensive shaft flat wart. |
 Fig. 7-5. These perianal warts are mostly wider than they are tall, with a smooth surface. |
 Fig. 7-6. Unusually large, globular warts are called giant condylomata or Buschke-Lowenstein tumors. |
Genital warts occur most often in individuals between the ages of 16 and 25 years. Although genital warts are usually asymptomatic, they occasionally produce itching and/or irritation. The number and size of lesions in an infected individual presumably depend on the immunologic resistance that the host can mount against the infecting virus. Thus, some individuals with very good immune response may have only a few small lesions that disappear spontaneously or respond readily to treatment. Other patients with lesser immune response exhibit numerous small and large lesions that can be resistant to most attempts at therapy.
In men, most genital warts occur on the shaft of the penis and, less frequently, the glans, foreskin, scrotum, groin, and periurethral or intraurethral area. Perianal and anal warts occur most commonly in men who have anal coitus with men but also can develop in heterosexual men who do not have anal intercourse. In women, genital warts occur most commonly around the vaginal introitus, the vulvar vestibule, and the surrounding anogenital skin. Approximately half of women with vulvar warts have evidence of cervical HPV infection. Women may develop perianal warts, and, not surprisingly, their presence at this site is especially likely in those who participate in receptive anal intercourse.
Diagnosis
A diagnosis of anogenital warts is generally made on a clinical basis. However, biopsy is required for two types of warts, described as the third and fourth variants above. These are the flat-topped, smooth-surfaced lesions and the giant condylomata. Histological examination is necessary in these two variants because in situ or invasive squamous cell carcinoma (SCC) may be present in these otherwise clinically normal-appearing HPV infections. In an attempt to better identify genital warts, some clinicians apply 5% acetic acid (common vinegar) to the anogenital area for several minutes prior to visual examination. Whitening suggests where warts are present, but we believe that neither the specificity nor sensitivity of this procedure is high enough for this technique to be recommended. Low-power magnification, usually with a lamp containing a centrally mounted magnifying glass surrounded by a circular fluorescent bulb, can be helpful in detecting small lesions. Gynecologists and dermatologists sometimes examine the anogenital area with high magnification using a colposcope or a dermatoscope. Dermoscopic findings have been described as showing a fingerlike appearance with highly vascular-patterned features surrounded by whitish halos.3 Colposcopy, along with scraping for a cytological specimen, as is true for cervical HPV infection, is especially useful for identifying anal HPV infection. This is particularly true for HIV-positive women who participate in anal intercourse and MSM.4 I believe, that with this one exception, such highly magnified approach has little usefulness and greatly increases the duration and cost of the examination.
Biopsy can confirm a clinical diagnosis of genital warts, and it is highly recommended under certain circumstances such as for individuals with the third or fourth variants of genital warts. The histologic hallmarks include variable acanthosis often with elongation of the rete ridges. The presence of koilocytosis (vacuolated cells with dark pyknotic nuclei) is particularly helpful. True koilocytosis occurs throughout most layers of the epidermis. Pathologists who are not expert in cutaneous pathology often overcall this feature, failing to realize that scattered vacuolated cells (usually without nuclear change) are normally present in anogenital tissue. About 250 molecular tests for determining the specific HPV type or types are commercially available.5 Because of the identification of low-risk and high-risk HPV types, there has been slowly increasing enthusiasm over the use of HPV typing. However, at the current time, we believe that treatment and follow-up of patients can largely still be based on the degree of dysplasia, if any, identified on biopsy. Viral cultures cannot be carried out as HPV does not grow in artificial media.
Many conditions must be considered in the list of differential diagnoses for genital warts. In women, vestibular papillomatosis can easily be confused with genital warts. Patients with this condition have closely set, minute, hemispherical papules, arranged in a cobblestonelike pattern, within the vulvar vestibule (Fig. 7-7). This is a normal physiologic variant that needs no therapy. The equivalent disorder in men, pearly penile papules (PPP), consists of one or two rows of minute papules encircling the corona of the glans penis (Fig. 7-8). Other conditions to be considered include molluscum contagiosum, common
skin tags, lymphangiectasia, elephantiasis from chronic edema, and enlarged sebaceous glands (Fordyce spots) (Figs. 7-9, 7-10, 7-11, 7-12). As indicated above, both in situ and invasive HPV-related SCC may have an identical appearance in the third and fourth variants of warts, flat-topped papules, and plaques or large globular lesions.
skin tags, lymphangiectasia, elephantiasis from chronic edema, and enlarged sebaceous glands (Fordyce spots) (Figs. 7-9, 7-10, 7-11, 7-12). As indicated above, both in situ and invasive HPV-related SCC may have an identical appearance in the third and fourth variants of warts, flat-topped papules, and plaques or large globular lesions.
 Fig. 7-7. Vulvar papillae resemble genital warts but are differentiated by their rounded rather than spiky tips, and the fact that each papilla is discrete to the base rather than fused as is common with warts. |
Pathophysiology
Human papillomaviruses are grouped into five genera of which only the alpha and beta genera are important to clinicians. Viruses of both the alpha and beta genera can cause latent (asymptomatic) infections. On the other hand, it is primarily viruses from the alpha genus that are responsible for the vast majority of benign and malignant mucosal and cutaneous lesions (symptomatic infections) in the anogenital region.1 These alpha papilloma viruses are further divided into “high-risk,” “uncertain risk,” and “low-risk” categories. Anogenital infection may occur with viruses from any one of these three categories. The average incubation period is about 3 months. Approximately 90% of clinically recognizable infections are due to four HPV types. The vast majority of these are caused by low-risk types HPV 6 and 11, and the remainder are mostly due to high-risk types HPV 16 and 18. It is not possible clinically to determine which of these HPV types represents the cause of genital lesions. Coinfection with multiple HPV types happens fairly often.
 Fig. 7-8. Pearly penile papules are monomorphous skin-colored or white papules arranged in one or more rows around the corona, and seen almost exclusively in uncircumcised men. |
 Fig. 7-9. This patient has lymphangiectasias (also called secondary lymphangioma circumscriptum) extruding through the surface of the skin due to chronic edema resulting from pelvic surgery. |
 Fig. 7-10. Elephantiasis is a peculiar skin reaction to chronic edema, consisting of firm nodules that can mimic genital warts; this patient had only modest edema on the basis of erosive lichen planus. |
 Fig. 7-11. Fordyce spots are ectopic sebaceous glands that are found on the modified mucous membranes of the vulva, here on the medial left labium minus. Although these are regularly found in premenopausal women, this patient has unusually prominent lesions that can be confused with flat warts. |
GENITAL WARTS Diagnosis
Most commonly occur in sexually active individuals 15-30 years of age.
Four clinical variants: (1) filiform warts, (2) verruca vulgaris, (3) flat-topped papules/plaques, and (4) large globular nodules.
Lesions may be skin colored, pink, red, brown, or black.
Biopsy, especially for the third and fourth variants, is necessary to confirm diagnosis and to rule out malignancy.
Consider the possibility of cervical involvement in women and anal involvement in both sexes.
Prognosis
Information on the duration of asymptomatic HPV infections in which no visible lesions are present (by far the most common type of infection) is based mostly on older serological data that involve the detection of antibodies to the HPV L1 protein. Unfortunately, since the virus exists only in epidermal cells above the basement membrane (where only limited antigen processing can occur), these data are highly suspect. However, they do suggest that immune clearance occurs in a matter of a few months for most infections with low-risk virus types and a little longer (about a year) for most high-risk types. But it is also recognized that latency, with a persistent very low viral load, occurs in an unknown percentage of cases. Presumably the likelihood of latency is higher with high-risk virus types and is also higher in those who have some degree of immunosuppression. Clearance also occurs more rapidly in younger individuals than in those who are older, probably based on more robust immune response in young people.
 Fig. 7-12. Ectopic sebaceous glands occur on the shaft of the penis as well, seen here as discrete small light papules; he also has hyperpigmented flat warts on the proximal shaft. |
Spontaneous resolution of visible warts occurs when an HPV-specific cell-mediated immune (CMI) response develops. Resolution without treatment, if it is to occur, takes on average several months. Unfortunately, those warts containing high-risk HPV types and those occurring in immunosuppressed patients are likely to remain in place longer or even indefinitely. This CMI response, rather than humoral immunity, appears to be much more important for lesion resolution. This belief is based on four observations. First, the titer and timing of antibody response do not correlate well with resolution of warts; second, many patients with visible lesions are not seropositive; third, many patients who are seropositive do not currently have clinically detectable infection; and fourth, individuals with significantly depressed CMI, notably those with HIV-AIDS, are more easily infected, have larger numbers of lesions, and rarely clear their lesions spontaneously.
Management
In spite of the potential for resolution, most anogenital warts should be treated to reduce contagion occurring through sexual activity and other skin-to-skin contact. This is particularly important because it is not possible to determine clinically which warts contain foci of dysplastic change. However, it is extremely important to note that treatment only eradicates visible lesions; latent virus can remain in place indefinitely. This leads to high recurrences rates regardless of the type of treatment used.
Before considering treatment options, clinicians should consider whether or not biopsy of one or more lesions should be undertaken. As indicated above, flat-topped warts (regardless of color) and large globular warts should be biopsied because of the possibility that in situ or invasive SCC may be present. Shave biopsy is acceptable for flattopped warts. On the other hand, local excision is preferred for large globular warts for three reasons: deeper penetration (even when there is no dermal invasion); risk of missing true dermal invasion; risk of sampling error in these large lesions. Filiform lesions and those mimicking hand warts (see above) may be treated without biopsy due to the very low likelihood that dysplasia will be present.
Multiple approaches to treatment are available.6,7,8 Treatment needs to be individualized for each patient as no single therapy is universally preferable. One of the first priorities in the treatment process is the education of patients regarding the contagious aspects of the viral infection, the likelihood of recurrence after therapy, and, in some instances, the potential for malignant transformation. After this has been accomplished, input from the patient should be sought as to whether the treatment is to be undertaken by the patient (patient-based therapy) or by the clinician (clinician-based therapy). Cost and, in the United States, insurance coverage also should be taken into consideration. Lastly, for clinicianbased therapy, availability of equipment and the provider experience will influence the choice of therapy.
Patient-based therapy. There are four medications, all requiring a prescription, available for patient-based therapy: 0.5% podophyllotoxin (Condylox), 3.75% imiquimod (Zyclara) or 5% imiquimod (Aldara), and 15% sinecatechins (Veregen). Podophyllotoxin solution or cream is applied to the warts twice daily for 3 days followed by 4 days without treatment. This is usually carried out for 4 or 5 weeks, and note that podophyllotoxin is contraindicated for use during pregnancy. Imiquimod 3.75% or 5% cream is applied once daily two or three times per week (on alternate days) for up to 16 weeks. Sinecatechins 15% ointment (Veregen) is applied three times per day for up to 16 weeks. Adverse effects of redness, burning, pain, and erosion occur with all four of these products. Clearance rates (about 50%-75%) are slightly better with podophyllotoxin; recurrence rates (about 25%-35%) are approximately similar for all four medications.6,8
Clinician-based therapy can be either medical or procedural. The medical approach consists of the application of trichloroacetic acid (80%-90%) carried out very carefully in the office at 2- or 3-week intervals. Clearance rates of 70%-80% have been reported, but recurrence rates are similar to those with patient-based therapy as described above.7 Burning on application is troublesome for patients, and ulcer formation is possible if too much is applied. Nevertheless, it is a reasonable approach when the warts are relatively nonkeratotic and the number and size of the lesions are small. It has the advantage of not requiring specialized equipment. Another medical approach, the application of 25% podophyllin, is no longer recommended.
Clinician-based procedural therapy includes cryotherapy, electrosurgical destruction, laser destruction, and surgical excision.6 With cryotherapy, liquid nitrogen is sprayed (or is applied by probe or with cotton-tipped applicators) at 2- to 3-week intervals. Electrosurgical destruction (electrofulguration, electrodessication) is carried out under local anesthesia. Other electrosurgical approaches using loop excision or a bipolar Bovie-type apparatus can also be used. Laser therapy, generally with a CO2 laser, can also be considered, but the cost of this equipment, and thus the cost of treatment, is quite high. Surgical excision is most often accomplished with a tangential shave or scissors-snip technique; rarely elliptical excision might be considered. All three of these ablative approaches result in clearance rates of close to 90%, but recurrence rates remain high. Drawbacks to procedural therapy include the possibility of secondary infection, potentially long healing time, scarring, and, with all but cryotherapy, the necessity for local anesthesia.
The choice of which medical or procedural approach is taken depends on patient preference and on the experience level of the clinician. For most patients, I (PJL) prefer either electrosurgical destruction or removal with scissors “snip” or tangential shave excision. If bleeding persists, it can be stopped with very light electrosurgery to the base. These two approaches are time honored, inexpensive, and do not depend on patient compliance. Moreover, only a single clinic visit is generally necessary, and the patient leaves the clinic with the knowledge that he or she is free of most or even all of the visible lesions. Of course, if the number and size of the warts are large, staged eradication at monthly intervals may be necessary.
Anogenital warts in children present a special problem because of the concern that sexual abuse may have taken place. However, for children under the age of 2, it is not likely that the transmission occurred through sexual contact.1 Anogenital warts in these very young children may have arisen through normal parental contact, autoinoculation, or by way of contagion from an infected birth canal. A greater level of concern about sexual abuse exists for those over the age of 4, and in any case, inquiry by an experienced clinician or by other skilled interviewers must be carried for all children with anogenital warts.
Vaccination
The best approach for HPV infection (and lesions associated with this infection) is to prevent it from occurring in the first place. During the last two decades, three HPV vaccines have been approved in most countries.9 These include Cervarix, Gardasil, and Gardasil 9. All three vaccines are directed against the HPV L1 structural protein and do not contain any part of the HPV that would allow for viral replication following vaccination.9
Cervarix is a bivalent vaccine that is directed toward HPV 16 and 18, the two HPV types that are associated with the development of about 70% of anogenital malignancies. Gardasil is a quadrivalent vaccine that offers the same protection against HPV 16 and 18 as well as against HPV 6 and 11, the two low-risk types that cause about 90% of benign anogenital warts. Gardasil 9 is a nonavalent vaccine that is designed to prevent infection from HPV types 6, 11, 16, 18, 31, 33, 45, 53, and 58 thus covering the risk of ˜90% of cervical and other anogenital malignancies. Interestingly, though all three of these vaccines were originally approved by the U.S. FDA, Gardasil 9 is the only one currently available in the United States.
Cervarix is a bivalent vaccine that is directed toward HPV 16 and 18, the two HPV types that are associated with the development of about 70% of anogenital malignancies. Gardasil is a quadrivalent vaccine that offers the same protection against HPV 16 and 18 as well as against HPV 6 and 11, the two low-risk types that cause about 90% of benign anogenital warts. Gardasil 9 is a nonavalent vaccine that is designed to prevent infection from HPV types 6, 11, 16, 18, 31, 33, 45, 53, and 58 thus covering the risk of ˜90% of cervical and other anogenital malignancies. Interestingly, though all three of these vaccines were originally approved by the U.S. FDA, Gardasil 9 is the only one currently available in the United States.
All three vaccines are administered by way of three intramuscular injections administered over a 6-month period of time with the second injection given 1-2 months after the first. The third injection is administered at about the 6th month. Although three doses are recommended for adults, there is evidence that for children two doses are sufficient. All three vaccines are preferably given before sexual debut (usually at age 9-11) because the vaccines have no efficacy against their HPV types once infection with them has occurred. Catch-up vaccination (to offer protection against those HPV types that have not as yet been acquired) is recommended for those teenagers and adults who have not been vaccinated earlier.
Safety of these vaccines is excellent with no serious safety concerns having so far been detected.9 Vaccination is not specifically recommended for pregnant women but appears to be safe when it is administered. The efficacy of HPV vaccination is also excellent. When vaccines are given to those with no evidence of previous HPV infection (HPV-naive group), there is at least 90% prevention of HPV-related anogenital malignancy.9 And when the quadrivalent vaccine is administered to the HPV-naive group, there is almost complete protection against the development of anogenital warts.9 Studies have shown that this protection lasts for at least 6-10 years. Unfortunately, in the real world, the prevalence of vaccination, and the lateness in life with which vaccines are often administered, limits the efficacy to appreciably lower protection rates. Female vaccination rates are higher than for men, but fortunately, there is some evidence of “herd immunity” for heterosexual men as the rate of vaccination for women rises.
GENITAL WARTS Management
Home therapy with imiquimod or podophyllotoxin
Office therapy with liquid nitrogen or trichloroacetic acid
Office therapy with electrosurgery, excision, or laser ablation
Follow-up for recurrences and development of new warts
Check for sexual abuse in children with anogenital warts
Prevent infection with vaccination before sexual debut
Molluscum Contagiosum
Infection with molluscum contagiosum virus (MCV) is common, benign and self-limited. It can be viewed as more of a nuisance than a threat to health or well-being. A review of the subject was published in 2019 and many of the points that follow are related to that review.10
Clinical Presentation
Molluscum contagiosum (MC) is a common infection that occurs primarily in children, and less often, in sexually active older individuals and in those who are immunologically compromised. In children ages 1-4 years, the incidence rates in the United Kingdom and North America appear to be about 0.1%-1.5% per year. The point prevalence rate for children worldwide averages <3% or 4%. Though controversial today, historically, it has been believed that children with atopic dermatitis (“eczema”) and those who are frequent swimmers may be predisposed to acquire the infection.10 Sexual abuse as a cause of MC essentially does not occur. Spread (hetero-inoculation) among children in families is possible but occurs infrequently. Auto-inoculation is also possible. Adults account for only a small portion of all MC infections. The majority of such infections occur in those sexually active young adults and in those who compete in close skin-to-skin contact sports such as wrestling. In addition, individuals who are immunosuppressed either by illness or through immunosuppressive therapy are predisposed to infection together with more numerous and somewhat larger lesions. Infection rates are similar between males and females. Transmission occurs primarily by skin-to-skin contact and is facilitated by damage to the epidermal barrier layer.
The lesions of molluscum contagiosum are skin colored, pink, white, or, occasionally, translucent (“water warts”) hemispherical papules 3-8 mm in diameter (Figs. 7-13 and 7-14). Uncommonly, a light red halo forms
around the molluscum papule.10 Rarely, and mostly in immunocompromised patients, giant lesions are encountered. Patients with intact immunity generally have 15-50 lesions at any one time; some of these may appear in a clustered group. Most of the lesions develop on keratinizing epithelial skin, but they rarely also occur on mucous membranes. The skin surrounding lesions is usually normal in appearance, but redness and eczematous changes may occur circumferentially.10 Sometimes early during the resolution stage (“the beginning of the end”), individual MC develop brisk, red inflammation (Fig. 7-15).
around the molluscum papule.10 Rarely, and mostly in immunocompromised patients, giant lesions are encountered. Patients with intact immunity generally have 15-50 lesions at any one time; some of these may appear in a clustered group. Most of the lesions develop on keratinizing epithelial skin, but they rarely also occur on mucous membranes. The skin surrounding lesions is usually normal in appearance, but redness and eczematous changes may occur circumferentially.10 Sometimes early during the resolution stage (“the beginning of the end”), individual MC develop brisk, red inflammation (Fig. 7-15).
 Fig. 7-13. These dome-shaped shiny discrete papules are typical for mollusca contagiosa. |
 Fig. 7-14. Although providers look for a central dell as a diagnostic sign on lesions of mollusca contagiosa, most lesions do not show this useful hint. |
The fully developed papules of molluscum contagiosum characteristically have a central depression or umbilication. However, many lesions, especially early and small lesions, lack this feature (Fig. 7-16). Although this umbilication may not be seen in every lesion, a careful examination, especially with magnification, usually allows one to find at least a few of these characteristic umbilicated lesions. Molluscum contagiosum is typically asymptomatic, but some patients may experience low-grade pruritus. Lesions in children may be found anywhere on the skin but occur most often on the trunk. In sexually active women, MC are commonly located on the mons, the medial thighs, and the buttocks. In both genders, they may develop on the genitalia.
 Fig. 7-15. Mollusca contagiosa are not a sign of sexual abuse in children, and the inflamed lesions here suggest that her lesions are entering a resolution phase. |
 Fig. 7-16. These mollusca contagiosa all show the central umbilication, cinching the diagnosis. |
Diagnosis
The diagnosis, especially when umbilicated lesions are present, is usually made on a clinical basis. Sometimes, the diagnosis can be confusing, and dermoscopy is useful. Magnification enhances the central umbilication and shows polylobular white-to-yellow amorphous structures and peripheral crown vessels.10 Otherwise, confirmation of a clinical diagnosis is possible through removal of a lesion by curettage with subsequently “mashing” and spreading it out on a microscope slide; this reveals a typical small white “molluscum body.” A shave biopsy submitted for microscopic observation may be appropriate if the clinical appearance is atypical. The histologic findings include pathognomonic features of intracytoplasmic inclusion bodies (“Henderson-Patterson” bodies) made up of globular viral proteins.
The list of differential diagnoses includes HPV infection (genital warts), scabies, hidradenoma papilliferum, lymphangiectasia, and, in men, PPP and lichen nitidus. Genital warts are not usually hemispherical and often
have a rough, rather than smooth, surface. The lesions of scabies occur in a characteristic distribution pattern (web spaces, axillary folds, areolae, and penis), and small linear burrows can usually be found. The small papules and vesicles of lymphangiectasia contain fluid when pierced with a needle. The lesions in lichen nitidus are more numerous, mostly flat-topped, and more morphologically homogenous. PPP occur only on the corona and sometimes coronal sulcus of the glans penis.
have a rough, rather than smooth, surface. The lesions of scabies occur in a characteristic distribution pattern (web spaces, axillary folds, areolae, and penis), and small linear burrows can usually be found. The small papules and vesicles of lymphangiectasia contain fluid when pierced with a needle. The lesions in lichen nitidus are more numerous, mostly flat-topped, and more morphologically homogenous. PPP occur only on the corona and sometimes coronal sulcus of the glans penis.
MOLLUSCUM CONTAGIOSUM Diagnosis
Small, smooth, dome-shaped papules.
White, pink, translucent, or skin colored.
Umbilication at the summit is characteristic.
Bright red color may occur when lesions undergo resolution.
Confirm by curettage and microscopic examination for a molluscum body.
Pathophysiology
Molluscum contagiosum is caused by the MCV, which is a very large DNA poxvirus. There are four MCV virus types (c.f. two for HSV and 200 plus for HPV).10 Most infections are caused by MCV 1; some by MCV 2. Infection due to MCV 3 and 4 is quite rare. There are no significant differences in appearance or distribution for infections caused by the four MCV types. MC infection only involves epidermal cells. As indicated above, transmission is primarily by skin-to-skin contact, but a lesser role for fomites may also be possible. The incubation period after inoculation of the virus averages about 4-8 weeks, but much longer intervals have been reported. Virus latency in epidermal cells does not seem to occur. MCV cannot be cultured using artificial media.
Resolution of the infection is associated with the development of both a humoral and a CMI response. Antibodies to MCV are found in most patients with molluscum contagiosum. However, the timing of antibody appearance and the titer levels do not closely parallel the severity or duration of the infection. One’s CMI response is much more important than antibodies in resolving the infection. The onset of the CMI is sometimes clinically apparent by the development of inflammation with accompanying redness in and around individual lesions. Once such inflamed lesions are present, total resolution of all lesions usually follows within about a month.
Management
In immunocompetent patients, untreated individual lesions of molluscum contagiosum resolve spontaneously over a matter of several months. But, “seeding” of virus into surrounding skin or at distant sites frequently occurs such that new lesions develop while old ones are resolving. The total duration of the entire infection averages about 2 years; however, considerably shorter and longer time frames (such as 12-36 months) have been reported. On the other hand, in immunocompromised persons, the number of lesions is larger, the variability in size is greater and spontaneous resolution takes much longer or may not occur at all. Secondary bacterial infection is possible, but it is often “overcalled” because of the CMI-related reddening before spontaneous resolution or because of induced inflammation following treatment.
All of the treatments currently available are controversial or problematic in one way or another. Specifically, there is no evidence-based consensus as to what constitutes the best treatment.10,11 For this reason, most clinicians advise “watchful waiting” rather than active therapy, especially for pediatric patients. For adults and for patients who insist on treatment, both medical and procedural approaches are possible.
Office Medical Management
Cantharidin 0.9% solution is applied very carefully to individual papules in order to prevent contact with the normal surrounding skin. Special care must be taken if cantharidin is used in intertriginous areas so as to prevent unwanted secondary bacterial infection or spread of the applied solution. For lesions in the anogenital area, it is useful to apply a loose bandage (such as a Band-Aid) over treated lesions to prevent spread of the cantharidin due to friction and retained sweat. Many clinicians advise that the cantharidin be washed off 6-8 hours after application, but I (PJL) have not found it necessary to do so. In any event, a blister develops within 24 hours at the cantharidin application site and the lesion is eventually sloughed off about a week later when the blister roof peels away. Because new lesions will likely continue to appear, several office visits for repeated applications are usually necessary. Cantharidin is painlessness when initially applied, and for this reason, it is most often the treatment of choice for children. Mild pain and irritation may occur later. The clearance rate for individually treated lesions approaches 100%, and patient (or parent) satisfaction is quite high.
Trichloroacetic acid 85% solution can be applied, but even more carefully, so that the solution does not run off of the papule onto normal skin, causing necrosis and possible scaring. This approach is quite effective, but it is somewhat painful within moments of application. All treated lesions are likely to be destroyed with a single application, but several treatments will be required for new lesions as they appear.
Home Medical Management
Five percent imiquimod cream may be used at home, and the method in which it is used is identical to that described in the section above on genital warts. Home application
decreases patient embarrassment for MC occurring in the anogenital area and also reduces the number and expense of multiple office visits. However, this therapeutic approach is accompanied by considerable discomfort due to inflammation at the application site. Moreover, the duration of treatment required is long enough to hamper patient compliance. Finally, there is even some controversy as to whether or not imiquimod therapy actually out-performs its vehicle and thus may be just a placebo.
decreases patient embarrassment for MC occurring in the anogenital area and also reduces the number and expense of multiple office visits. However, this therapeutic approach is accompanied by considerable discomfort due to inflammation at the application site. Moreover, the duration of treatment required is long enough to hamper patient compliance. Finally, there is even some controversy as to whether or not imiquimod therapy actually out-performs its vehicle and thus may be just a placebo.
Potassium hydroxide (KOH), usually in a concentration of 10%, can also be applied to individual MC papules at home. The recommended frequency of application varies from once every other day to twice a day. In any event, it is applied until inflammation occurs. It appears that 10% KOH solution and imiquimod are about equally effective and are about equally irritating. Perhaps, the effectiveness of both depends on the inflammation they cause, which might in turn initiate the cell-mediated immunity that results in clearing the infection.
Many other medical approaches are possible, but limited experience with them and a lack of studies regarding their effectiveness restrict our recommendation for their use. Some of these, which will not be further discussed, include podophyllotoxin, glycolic acid, lactic acid, salicylic acid, retinoids, benzoyl peroxide, tea tree oil, injected interferon alpha, and oral cimetidine.
Procedural Management
The most commonly used procedural approaches are cryotherapy and curettage. Liquid nitrogen cryotherapy is used in the same manner as is used for warts (q.v. “Genital Warts” in this chapter). It can be applied using a spray technique or with a probe and is available in most gynecology and almost all dermatology offices. A total freeze time of about 10-15 seconds is recommended, and this can be obtained either in a single freeze or in a freezethaw-freeze cycle. It is moderately painful and moderately effective, but as for all therapy, several visits are necessary to treat new MC as they develop.
Curettage, in which the lesion is scraped away with the edge of a skin curette, is also moderately painful, but the fact that all visible lesions are completely removed after the first treatment session leads to high patient satisfaction. Because of discomfort, both cryotherapy and curettage are best used for adults, especially when the number of lesions is small. In the hands of a skilled operator, the likeliness of adverse effects such as scaring is quite small.
Several other procedural approaches are available. Electrosurgery is very effective, but use of this approach is limited because MC are very superficial and, unfortunately, destruction depth with electrosurgery is somewhat difficult to control. Thus, this procedure is associated with some potential for secondary infection and scaring. Laser therapy is likewise quite effective, but its use is also restricted due to high cost and limited availability.
MOLLUSCUM CONTAGIOSUM Management
Consider observation without specific therapy in children.
Office application of cantharidin is painless and effective.
Liquid nitrogen cryotherapy if lesion number is large.
Curettage for removal if lesion number is small.
Imiquimod cream or potassium hydroxide can be considered for home therapy.
Skin Tag (Acrochordon, Fibroepithelial Polyp)
Skin tags are common benign skin growths that affect at least half of the adult population. They begin to develop in midlife or earlier in those who are overweight. They then slowly increase in number until about age 70.12 Small lesions are usually referred to as skin tags, whereas large lesions may be termed fibroepithelial polyps (Figs. 7-17 and 7-18). People with obesity, lipid disorders, acanthosis nigricans, darker skin pigmentation, and diabetes mellitus appear to be predisposed to develop skin tags.13
Skin tags (acrochordons) are soft, asymptomatic, skincolored to tan papules. They are most commonly stalklike lesions averaging 2 mm in diameter and 3-8 mm in length; they have a predilection to occur in the axillae, around the neck, and on the trunk. Small skin tags are usually numerous and somewhat clustered. Longer, larger skin tags (fibroepithelial polyps) are pedunculated with a thin (1-3 mm) base and larger (5-15 mm) body. These larger, often solitary fibroepithelial polyps are more likely to be found on the upper inner thighs, inguinal creases,
and the buttocks. Skin tags are only rarely encountered on the penis and vulvar vestibule. Note, however, that skin tags (especially larger and edematous ones) are found more often than would be expected in patients with inflammatory bowel disease, especially those with Crohn disease.14
and the buttocks. Skin tags are only rarely encountered on the penis and vulvar vestibule. Note, however, that skin tags (especially larger and edematous ones) are found more often than would be expected in patients with inflammatory bowel disease, especially those with Crohn disease.14
 Fig. 7-17. Skin tags are small, fleshy, pedunculated papules that occur primarily in skin folds and are especially common in patients who are overweight. |
 Fig. 7-18. A fibroepithelial polyp is a large, usually solitary skin tag. |
The diagnosis of skin tags is made on a clinical basis. Rarely, they may be confused with genital warts, intradermal nevi, and isolated neurofibromas. Skin tags are always benign, and no treatment is necessary unless they become inflamed because of skin friction, spontaneous torsion, or having been caught in clothing. In this situation, the lesions can be snipped with fine scissors. The slight bleeding that occurs can be stopped by the application of Monsel (ferric subsulfate) solution, aluminum chloride, or light electrosurgery. Silver nitrate is not a good choice for hemostasis because of the potential for skin staining. Very small skin tags can be obliterated by liquid nitrogen cryotherapy, cautery, or light electrodessication. There is an effective, but seldom recommended, home remedy in which a thread is tied tightly around the base of a lesion. A week or so later, the skin tag undergoes necrosis and both it and the ligature fall off.
Intradermal Nevi (Dermal Nevi)
Intradermal nevi are benign neoplasms. They differ from junctional and compound nevi clinically by their lighter color and histologically by the location of the nevus cells (melanocytes) only within the dermal connective tissue. They present as soft, usually hemispherical, papules 5-15 mm in diameter (Fig. 7-19). Color is variable, and they can be skin-colored, pink, or light tan. Intradermal nevi rarely occur on the penis, scrotum, or within the vulva but are encountered fairly commonly on the thighs, buttocks, and in the pubic area. These lesions need to be differentiated from basal cell carcinomas (BCCs), genital warts, molluscum contagiosum, and isolated neurofibromas. In some instances, they are pedunculated enough to be confused with skin tags. They are always benign and are never precursors of melanoma. No treatment is necessary unless they are inflamed as a result of trauma. If removal is necessary, they can be shaved tangentially or excised.
 Fig. 7-19. Intradermal nevi are benign tumors of melanocytes, but these generally are skin colored, well demarcated, and soft to the touch. |
Pearly Penile Papules
Pearly penile papules are so common as to be considered a normal variant rather than as a disease (see also Chapter 1).15 They are estimated to be present in about 25% of men, but their prevalence is higher in both uncircumcised and African American men. These papules may appear as early as at puberty, and their prevalence generally increases until the third decade of life. Although they are asymptomatic and completely benign, their presence may cause anxiety because of concern on the part of the patient, or the sexual partner, that they represent a STD. PPP are small, skin-colored, whitish, or pink papules that can be either elongated (filiform) or dome shaped (Figs. 7-8 and 7-20, 7-21, 7-22). The smallest lesions are only about 1 mm in diameter and height, while larger filiform lesions can be 2 mm wide and up to 4-5 mm in length. They are most commonly located on the dorsal corona of the penis, but they often entirely encircle the glans. A single row of lesions may be present, but it is not uncommon to encounter double or triple rows. Less often, they occur in the coronal sulcus or even on the distal shaft of the penis.
The diagnosis is made on the basis of the characteristic morphology and location. Dermoscopy shows a whitish pink cobblestoned or grapelike appearance with
central dotted or commalike vessels in each papule.16 They should be differentiated from enlarged sebaceous glands that occur on both the inner prepuce (Tyson glands) and on the distal shaft of the penis (Fordyce spots). Occasionally biopsy, demonstrating angiofibromatous histology, is needed to differentiate PPP from filiform genital warts. Treatment is unnecessary, but if the patient or the sexual partner is troubled by their presence, they can be destroyed with electrosurgery, cryotherapy, or laser ablation.15
central dotted or commalike vessels in each papule.16 They should be differentiated from enlarged sebaceous glands that occur on both the inner prepuce (Tyson glands) and on the distal shaft of the penis (Fordyce spots). Occasionally biopsy, demonstrating angiofibromatous histology, is needed to differentiate PPP from filiform genital warts. Treatment is unnecessary, but if the patient or the sexual partner is troubled by their presence, they can be destroyed with electrosurgery, cryotherapy, or laser ablation.15
 Fig. 7-20. The patient with pearly penile papules has papules clustered around the frenulum as well as around the corona. |
 Fig. 7-21. These skin-colored, small pearly penile papules are found in a significant minority of uncircumcised men but are often subtle and overlooked. |
 Fig. 7-22. Both dome-shaped papules and filiform lesions are evident in this man with pearly penile papules. |
Vulvar Vestibular Papillomatosis
Vulvar vestibular papillomatosis (VVP) is a normal anatomic variant and can be considered as the analogue of PPP in the male.17 Early publications described a prevalence of only 1%, but later reports, and our own clinical experience, indicate that VVP occurs in about one-third of premenopausal women (see also Chapter 1). The papillae are asymptomatic, soft, hemispherical, or slightly elongated papules with a diameter and height of about 1-2 mm. However, some filiform lesions may be as tall as 5 mm. The papules are pink or red and, as such, similar to the color of the vestibular tissue from which they arise. Sometimes only a few papules are present, but it is not uncommon to see 50-100 clustered such that the entire vestibule is carpeted with them (Figs. 7-7, 7-23 and 7-24).
The papules may be arranged in a cobblestone pattern, but often, on close inspection, they can be observed as occurring in linear rows (Fig. 7-25).
The papules may be arranged in a cobblestone pattern, but often, on close inspection, they can be observed as occurring in linear rows (Fig. 7-25).
 Fig. 7-23. These vestibular papillae have the typical dome-shaped tips and lesions that are discrete to the base. |
 Fig. 7-24. Although these papillae are called vulvar vestibular papillae, they occur on other areas of the modified mucous membranes as well; these cover the medial labia minora. |
The papules in vestibular papillomatosis must not be confused with vestibular genital warts, as indeed they were until about 30 years ago. Clinical differentiation from genital warts is based on the following characteristics of VVP: (1) the overall appearance is very homogenous with each papule being very similar in morphology to its neighbors; (2) the papules remain separate and discrete down to their base; (3) the papules are soft to touch; and (4) a linear pattern of arrangement can often be discerned. Early on, the confusion with genital warts was engendered by reports that HPV DNA was sometimes present within the papules. Today, however, there is consensus, based on special histological staining and molecular studies, that HPV DNA is present no more often than it is found in vestibules of women with no VVP.
 Fig. 7-25. Vulvar papillomatosis sometimes consists of smaller, dome-shaped, nearly confluent papules that confer a cobblestoned appearance to the skin. |
The diagnosis is made clinically and is assisted, if necessary, by magnification via dermoscopy, colposcopy, or reflectance confocal microscopy. Dermoscopy shows profuse and irregular vascular channels in multiple cylindrical filiform projections.17 But if biopsy is performed, the clinician (and the pathologist) should be aware that large cells, somewhat resembling the koilocytes found in genital warts, are present in normal mucosal epithelium. This sometimes results in an incorrect diagnosis of HPV infection. The papules of VVP should also be differentiated from ectopic sebaceous glands (Fordyce spots), which are fewer in number, less elevated, and more yellow in color. Because the lesions are asymptomatic, no treatment needs to be undertaken.
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