Gougerot and Carteud originally described confluent and reticulated papillomatosis (CRP) in 1927 under the name papillomatose pigmentée innominée and later renamed it papillomatose pigmentée confluente et réticulée.[1, 2, 3] Confluent and reticulated papillomatosis was subsequently categorized as a new form of cutaneous papillomatosis and diagnostic criteria were established. Wise described the first case in the United States in 1937 and called it confluent and reticular papillomatosis.[4, 5] The existence of confluent and reticulated papillomatosis as a distinct entity was argued for many years because of the clinical and histologic similarities between confluent and reticulated papillomatosis and the different forms of acanthosis nigricans, but the disease is now generally accepted as a distinct entity.
Confluent and reticulated papillomatosis is a rare disease typically affecting young persons. Confluent and reticulated papillomatosis is characterized by grayish blue hyperkeratotic papules, usually located on the trunk. The lesions coalesce to form confluent plaques centrally and a reticular pattern peripherally. Confluent and reticulated papillomatosis may represent an endocrine disturbance, a disorder of keratinization, an abnormal host reaction to fungi or bacteria, a hereditary disorder, or a variant of amyloidosis. The eruption is chronic with exacerbations and remissions. Confluent and reticulated papillomatosis is responsive to treatment but frequently recurs after discontinuation of therapy.
Both electron microscopy studies and immunohistochemical analysis of lesions of confluent and reticulated papillomatosis support the concept of abnormal keratinocyte differentiation and maturation. These findings include an increased transition cell layer and increased lamellar granules in the stratum granulosum, along with increased involucrin, keratin 16, and Ki-67 expression. Increased melanosomes in the stratum corneum probably account for the observed pigmentary changes.
Yeastlike spores were evident in 6 of 10 Lebanese cases, supporting a role for Malassezia furfur in the pathogenesis of confluent and reticulated papillomatosis.
The frequency of confluent and reticulated papillomatosis in the United States is unknown.
The frequency of confluent and reticulated papillomatosis internationally is unknown. It is considered to be rare.
Older reviews report confluent and reticulated papillomatosis being more common among blacks than other races, with a ratio of 2:1, but more recent surveys, including one survey of 90 cases, show a predominance in whites.
The proportion of women to men affected by confluent and reticulated papillomatosis has been reported to be as high as 2.8:1, but the ratio is probably closer to 1.4:1. The opposite is true in Japan, where confluent and reticulated papillomatosis is more common in men than in women. In one study of 10 Lebanese cases, half were of each sex.
The onset of confluent and reticulated papillomatosis usually occurs shortly after puberty. The mean patient age at onset varies from 18.5-21 years, with a range of 5-63 years. Similarly, the average patient age at onset is 17.1 years in Japan, with a range of 3-30 years. In one study of 10 Lebanese cases, the mean age at diagnosis was 19 years.
Patients with confluent and reticulated papillomatosis are often asymptomatic, but they may experience mild pruritus. In a study of cases in Japan, 57.1% were asymptomatic, while the rest experienced pruritus. Eight of ten were without symptoms in a Lebanese survey Patients observe reticulated and pigmented macules, patches, and plaques most commonly on the chest.
Physical findings of confluent and reticulated papillomatosis are limited to the skin, as shown in the images below.
Grayish brown hyperkeratotic papules and plaques in a confluent pattern on the intermammary region with a reticular pattern peripherally.
Close-up view of the interscapular area, again demonstrating a confluent pattern centrally and a more reticular pattern peripherally.
Lesions begin as slightly hyperkeratotic to warty papules that are 1-2 mm in diameter. They enlarge to 4-5 mm in diameter and coalesce to form a reticular pattern peripherally and confluent plaques centrally.
Skin markings are preserved and sometimes exaggerated, especially in the neck and the axillae, where the skin may be thickened.
Atrophic macules rarely may be seen.
Scraping of lesions produces a fine powdery scale or mealy deposit.
This autosomal dominant trait is characterized by many asymptomatic oval macules symmetrically distributed on axillae, groin, face, neck, arms, and trunk; scattered comedolike papules (dark dot follicles); and pitted acneiform scars.
Confluent and reticulated papillomatosis usually begins on the skin of the intermammary or epigastric region, spreading over a period of weeks or months to the breasts, the lower abdomen, the flanks, and the pubic area.
In one case, lesions were entirely confined to the cheeks ; in another case, lesions were entirely confined to the pubic area.
The eruption may be found in the interscapular region, from which it spreads to the shoulders, the nape of the neck, and the gluteal cleft.
Involvement of the face and the proximal extremities may be seen. It may also occur on the forehead.
The mucous membranes are spared.
Early lesions are erythematous and later become grayish brown.
Theories as to the etiology of confluent and reticulated papillomatosis include an endocrine disturbance, a disorder of keratinization, and an abnormal host reaction to Pityrosporum organisms or bacteria. Reports also exist of familial cases of confluent and reticulated papillomatosis[14, 15, 16, 17] and the possibility of confluent and reticulated papillomatosis representing a variant of amyloidosis.
Gougerot himself suggested the possibility of an endocrine disturbance having a role in confluent and reticulated papillomatosis. Others have also advanced this theory in light of the common observation of endocrine disturbances in patients with confluent and reticulated papillomatosis (eg, Cushing disease, menstrual irregularities, obesity, abnormal glucose tolerance or diabetes mellitus, thyroid disease, pituitary dysfunction, hirsutism or hypertrichosis). It has been described in at least one patient with hyperthyroidism.
In Japan, 76.5% of cases of confluent and reticulated papillomatosis are associated with obesity or rapid weight gain.
In addition, lesions of confluent and reticulated papillomatosis have been noted to remit during pregnancy or with weight loss.
No single endocrine abnormality is seen; however, in many of the cases, no abnormality exists at all.
Miescher first proposed that confluent and reticulated papillomatosis is due to a defect in keratinization. This idea is supported by electron microscopic studies, which demonstrate increased lamellar granules in the stratum granulosum, a finding seen in conditions of increased cell turnover and desquamation (eg, psoriasis), and an increased transition cell layer, which represents the zone where granular cells are converted into cornified cells.
The above findings are consistent with immunohistochemical studies of lesions of confluent and reticulated papillomatosis, which demonstrate increased expression of involucrin, keratin 16, and Ki-67—protein markers for keratinocyte differentiation and maturation.
Further evidence for the role of a defect of keratinization is the response of confluent and reticulated papillomatosis to topical and oral retinoids, which are useful in treating such defects. Most recently, confluent and reticulated papillomatosis has been shown to respond to topical analogues of vitamin D, agents that also regulate cell differentiation and inhibit keratinocyte proliferation.
Ultraviolet light exposure and avitaminosis have been associated with the development of confluent and reticulated papillomatosis, and they may trigger or exacerbate the underlying abnormality.
Another interesting association is that of 2 patients with both confluent and reticulated papillomatosis and atopy, a condition where other disorders of keratinization are found.
Another theory holds that confluent and reticulated papillomatosis represents an abnormal host reaction to Pityrosporum orbiculare, either in the yeast or the hyphal form. This theory is based on the observation that confluent and reticulated papillomatosis is sometimes colonized with Pityrosporum organisms, and clearance occurs with antifungals and the associated eradication of Pityrosporum organisms.
Many cases of confluent and reticulated papillomatosis do not have any evidence of Pityrosporum infection, and fail to respond to antifungal therapy.
In one study, 20 of 31 cases of confluent and reticulated papillomatosis had negative potassium hydroxide examinations, and 14 of 19 patients treated with topical imidazoles failed to respond, with no correlation between potassium hydroxide (KOH) examinations and response to therapy.
In another study, P obiculare was isolated in only 15 of 54 cases, and only 8 of 26 cases improved with antimycotic therapy. Similarly, in Japan, fungus could be detected in only 6 of 44 cases. However, yeastlike spores were evident in 6 of 10 Lebanese cases, supporting a role for Malassezia furfur in the pathogenesis of confluent and reticulated papillomatosis.
A genetic or diet-induced abnormal keratinizing response is suggested to be triggered by P orbiculare.
The use of antibiotics in the treatment of confluent and reticulated papillomatosis was introduced after the fortuitous discovery of improvement in a patient who was taking furacycline for arthritis. Since then, an increase has occurred in the number of reports of successful treatment of confluent and reticulated papillomatosis with antibiotics of the tetracycline, macrolide, cephalosporin and (most recently) steroid classes. This finding has lead to the concept that bacteria, perhaps within the hair follicle, are the etiologic agents.
An exciting development in our understanding of the cause of confluent and reticulated papillomatosis is the report of a newly described dietzia strain of Actinomyces, isolated from a patient with confluent and reticulated papillomatosis. Antibiotic minimal inhibitory concentrations suggested sensitivity to tetracycline and erythromycin, and the patient responded to treatment with these medications. The authors of this study propose that confluent and reticulated papillomatosis is probably a reaction pattern to bacterial infection in susceptible individuals, resulting in epidermal proliferation, and have named this A dietzia strain X.
Another explanation for the effectiveness of antibiotics may be the anti-inflammatory and antiproliferative actions of these agents; however, some authors argue that confluent and reticulated papillomatosis is not an inflammatory disorder.
Heredity in confluent and reticulated papillomatosis: Six familial reports of confluent and reticulated papillomatosis have raised the possibility of it being a heritable disorder. These cases include 2 sisters and a brother; 2 sisters and 1 of their daughters; a mother, a daughter, and a son; and 3 sets of brothers, including 1 observed by the authors of this article. This small number of reports does not suggest any particular pattern or mode of inheritance.
The report of amyloid in skin lesions of only 3 patients makes this theory unlikely.
In confluent and reticulated papillomatosis, the epidermis shows compact hyperkeratosis, often associated with the presence of Pityrosporum yeast. Other features are less consistent and include a decreased or absent granular cell layer, papillomatosis, and a stratum spinosum that varies from acanthotic to atrophic. Because papillomatosis is an inconsistent feature, one paper has proposed changing the name of confluent and reticulated papillomatosis to confluent and reticulated papulosquamous eruption. This name is also less than perfect because most patients have little-to-no scale associated with the lesions. The dermis may contain a perivascular lymphocytic infiltrate.
On electron microscopy, some lesions demonstrate an alteration in the arrangement and the structure of cornified cells, an increased transitional cell layer, an increase in the number of lamellar bodies in the stratum granulosum, and an increased number of melanosomes in the stratum corneum.
Immunohistochemical analysis shows suprabasal keratin 16 expression with intense focal staining in the stratum granulosum and an increased number of epidermal cells with Ki-67 binding in the basal layer and stratum malpighii. See the image below.
A biopsy specimen showing hyperkeratosis, papillomatosis, and a mild superficial perivascular inflammation (hematoxylin and eosin, original magnificat....
Confluent and reticulated papillomatosis is strictly a disorder of the skin that results in cosmetic disfigurement, with no adverse systemic effects; therefore, no treatment is necessary other than for eradication of the rash (see Medication).
Many different modalities have been used in the treatment of confluent and reticulated papillomatosis, with variable results. The most consistent results may be seen with minocycline.[27, 28, 29, 30, 31, 32] Other modalities include keratolytics; intramuscular, oral, and topical forms of vitamin A; sodium thiosulphate; ammoniated mercury; oral contraceptives; oral and topical retinoids[21, 33, 34, 35, 36] ; thyroid extract; ultraviolet light; propylene glycol; antibiotics[31, 37, 38, 39, 40, 41, 42, 43, 44] ; antimycotics; and calcipotriene.[45, 46, 47, 48]
The most consistently effective treatment for confluent and reticulated papillomatosis, and the only one evaluated by retrospective and prospective studies, has been oral antibiotics. Successful treatment of confluent and reticulated papillomatosis has been reported with topical mupirocin. Another therapeutic option in confluent and reticulated papillomatosis may be tazarotene gel. The treatment was well tolerated and may be an alternative to systemic retinoid therapy.
A good part of the hyperpigmentation can be removed using 70% alcohol swabbing.
Surgical treatment of confluent and reticulated papillomatosis has been unsuccessful.
The lesions of confluent and reticulated papillomatosis may regress with weight reduction.
The goals of pharmacotherapy in confluent and reticulated papillomatosis are to reduce morbidity and to prevent complications. Numerous agents are used. The effects of the often-used antibiotics include their various anti-inflammatory or immunomodulating properties. Successful treatment with oral minocycline has been described.[25, 52] Erythromycin-resistant confluent and reticulated papillomatosis may respond to minocycline. Low-dose isotretinoin may be beneficial in some patients with confluent and reticulated papillomatosis. Oral 13-cis-retinoic acid cleared one patient after a 20-week course. Topical tacrolimus is another option.
Clinical Context: Broad-spectrum antifungal agent that inhibits yeast growth by altering cell membrane permeability, causing death of fungal cells. Reevaluate diagnosis if no clinical improvement after 4 wk. Use 1% solution
Clinical Context: Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out and resulting in fungal cell death. Lotion is preferred in intertriginous areas. If cream is used, apply sparingly to avoid maceration effects. Use 2% cream.
Clinical Context: Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak and resulting in fungal cell death.
These agents are directed against Pityrosporum infection. Selenium also has keratolytic properties.
Clinical Context: Inhibits microcomedo formation and eliminates existing lesions. Makes keratinocytes in sebaceous follicles less adherent and easier to remove. Available as 0.025%, 0.05%, and 0.1% creams. Also available as 0.01% and 0.025% gels.
Clinical Context: Oral agent that treats serious dermatologic conditions. Isotretinoin is the synthetic 13-cis isomer of the naturally occurring tretinoin (trans- retinoic acid). Both agents are structurally related to vitamin A. Decreases sebaceous gland size and sebum production. May inhibit sebaceous gland differentiation and abnormal keratinization.
A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.
Clinical Context: Retinoid prodrug whose active metabolite modulates differentiation and proliferation of epithelial tissue; may also have anti-inflammatory and immunomodulatory properties.
These agents correct disorders of keratinization.
Clinical Context: Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Clinical Context: Treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible Chlamydia, Rickettsia, and Mycoplasma organisms.
Clinical Context: Used to treat uncomplicated skin and skin structure infections. Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Clinical Context: Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Clinical Context: Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition.
Clinical Context: Third-generation cephalosporin indicated for uncomplicated skin infections.
These agents are antibacterials, and they may have anti-inflammatory or antiproliferative effects.
Clinical Context: Synthetic vitamin D-3 analog that regulates skin cell production and development. Use 0.005% cream, ointment, or solution.
Clinical Context: Selenium has keratolytic properties . Blocks enzymes involved in growth of epithelial tissue.
Agents that inhibit enzymes involved in growth of epithelial tissue may be used. These agents correct disorders of keratinization.[57, 58, 59]
Confluent and reticulated papillomatosis is a chronic disease characterized by exacerbations and remissions. Discontinuation of successful therapy usually results in recurrence of the confluent and reticulated papillomatosis.