Confluent and Reticulated Papillomatosis
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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. [6]
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. [7] 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. [8]
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 [9, 10, 11, 12] and the possibility of confluent and reticulated papillomatosis representing a variant of amyloidosis. [13]
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. [14]
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. [15]
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. [16]
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. [8]
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. [17] 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.
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. [8]
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. [8]
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.
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Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine
William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology
Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.
Ponciano D Cruz, Jr, MD Professor and Vice-Chair, Paul R Bergstresser Chair, Department of Dermatology, University of Texas Southwestern Medical Center
Ponciano D Cruz, Jr, MD is a member of the following medical societies: Texas Medical Association
Disclosure: Received consulting fee from RCTS for independent contractor; Received honoraria from Mary Kay Cosmetics for consulting; Received grant/research funds from Galderma for principal investigator.
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Kenneth A. Becker, MD, to the development and writing of this article.
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