Angel Fernandez-Flores

Jose A. Manjon

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16Acta Dermatovenerol Croat                  2009;17(1):16-19                                CASE REPORTMorphological Evidence of Periodical Exacerbation  of Hyperkeratosis Lenticularis PerstansAngel Fernandez-Flores1,3, Jose A. Manjon2  1Department of Anatomic Pathology, 2Department of Dermatology, Hospital El Bierzo; 3Department of Cellular Pathology, Clinica Ponferrada, Ponferrada, SpainCorresponding author:Angel Fernandez-Flores, MD, PhDS. Patología CelularClinica PonferradaAvenida Galicia 124400 PonferradaSpain gpyauflowerlion@terra.esReceived: April 2, 2008Accepted: Januray 20, 2009Summary We present a case of hyperkeratosis lenticularis perstans (Flegel’s disease) in a 71-year-old-woman. Apart from all the typical morphological features of the disease, we evidenced mounds of parakeratosis that contained neutrophils, alternating with other strata of the horny layers in which no infiltrate was seen. Such a pattern has been described in association with diseases that show a periodic clinical pattern of presentation with periods of exacerbations and remissions. Our case also showed a lichenoid inflammatory chronic infiltrate with vacuolation of the basal layer and mild spongiosis. Both findings strongly support the hypothesis that the inflammatory infiltrate might play a primary role, and that the hyperkeratosis might be a secondary event.Key wordS: Flegel disease; hyperkeratosis lenticularis perstans; kyrle’s diseaseIntroduCtIon Flegel’s disease (FD) (aka hyperkeratosis lenticularis perstans) is a cutaneous disorder of unknown etiology and pathogenesis (1). Hyper-keratosis is a diagnostic feature of this condition, while dermal inflammatory infiltrate is not a con-stant and its presence varies in different reports on the disease (2). Some claim that this infiltrate is secondary (2), whereas others claim the opposite (3,4). These discrepancies can be explained if we admit that the disease has a fluctuating course. Some clinical evidence of this fluctuating behavior of FD has already been presented (4,6). Never-theless, morphological findings supporting such a periodicity have been little emphasized, and when reported, they have mainly been based on the fact that inflammatory infiltrate is absent in old lesions of FD (7). We, therefore, considered interesting to communicate a morphological clue that supports a pattern of exacerbations and remissions of the disease.CaSe report Our patient, a 71-year-old woman, presented for consultancy, complaining of lesions that had appeared on the posterior side of the forearms, on the shoulders, knees and dorsal aspect of the feet 17ACTA DERMATOVENEROLOGICA CROATICAfor 2 years before. During this period the lesions were asymptomatic. When questioned, the patient reported a protracted course of the lesions. She was taking enalapril due to hypertension and Noctamil to help her sleep. She was allergic to acetylsalicylic acid.Vacuolization of the basal layer was evidenced (Fig. 4), although no cytoid bodies were seen. The superjacent epidermis showed mild spongiosis. The epidermis was mildly atrophic, with intense hyperkeratosis, mainly orthokeratosis (Fig. 3).  In the horny hyperkeratotic layer, signs of pe-riodicity exacerbation were easily seen (Fig. 5): they were mainly mounds of parakeratosis that contained neutrophils. They were arranged in dif-ferent strata, i.e. in a periodic fashion. dISCuSSIon Flegel’s disease is a condition of unknown etiol-ogy and pathogenesis (1). The ultrastructural find-ing of either absence or decrease of membrane coated granules has been claimed as the primary cause and mechanism of the disease (8,9). How-ever, such findings have not been supported by all studies (10,11). Figure 1. Clinical picture of the lesions on the pa-tient’s knees and legs. (HE x4)Figure 2. Lichenoid inflammatory infiltrate with orthokeratotic hyperkeratosis of the superjacent epidermis. A superficial perivascular inflammatory pattern is also seen. (HE x10) The lesions were oval, with an erythematous halo in many of them (Fig. 1). The biggest lesion measured 0.5 cm. Biopsy was obtained from one of the old lesions of the leg. Morphological study demonstrated a chronic inflammatory infiltrate distributed in a lichenoid pattern as well as in a superficial perivascular pattern (Figs. 2 and 3). Figure 3. In this view, hyperkeratosis is more prominent, although the inflammatory infiltrate is not so prominent. (HE x4)Figure 4. Vacuolation of the basal layer of the epi-dermis, along with mild spongiosis. (HE x10)Fernandez-Flores and Manjon      Acta Dermatovenerol CroatHyperkeratosis lenticularis perstans       2009;17(1):16-1918 ACTA DERMATOVENEROLOGICA CROATICA Another morphological feature of the disease is dermal inflammatory infiltrate. The latter damages the basal layer of the epidermis, with evidence of vacuolar change and some apoptotic bodies (3,4,12). Nevertheless, this latter finding is not constant (2), in a way favoring the hypothesis of damage periodicity. This is additionally supported by some recent studies demonstrating differences among FD lesions depending on the time when the biopsy has been taken (7). In the present case, an important morphological clue was evidenced, i.e. mounds of parakeratosis with neutrophils alternating with either subjacent or superjacent strata of horny layer. This feature has traditionally been associated with diseases in which periods of exacerbation alternate with peri-ods of remission (13).  Although many reports on FD mention focal distribution of parakeratosis in the lesions (3,11), other studies found no parakeratotic mound. For instance, Gutiérrez et al. report on a case of FD only showing compact hyperkeratosis with no parakeratosis (2). Interestingly, their case showed no dermal inflammatory infiltrate either. The ab-sence of inflammation in FD has also been report-ed in other cases (14), which some consider as a proof that inflammatory infiltrate is a secondary phenomenon (2). Nevertheless, there is no con-sensus on the latter claim (3,4).  On the contrary, the majority of cases reported in the literature show dermal inflammatory infiltrate (5,6,9,15-21), and it has been demonstrated that old lesions of the disease are mainly those that have no inflammatory infiltrate (7). Some of these discrepancies could be conciliated if the hypothe-sis of periodic fluctuation of the inflammatory infil-trate is admitted, with periods of exacerbation and periods of remission. The morphological details of the present case would favor such a hypothesis. Moreover, the vacuolar change in the basal layer as well as the lymphocytic epidermotropism could perhaps be the initial signs of aggression to the epidermis, later followed by epidermal hyperkera-totic change. Nevertheless, an important limitation of our re-port is the fact that it was a single case.   It is important to remember how clinical fluc-tuations of Flegel´s disease have previously been reported (4-6). Sometimes a relation between the periods of exacerbation and warm weather (sum-mertime) has been suggested (4) and ultraviolet light has been considered as a potential provoking factor (5). However, some other cases presented paradoxical spontaneous remission in summer (6). In conclusion, we present morphological evi-dence supporting periodical exacerbation of FD, with obvious limitations of a single-case study.references1.   McKee PH, Calonje E, Granter SR. Disorders of keratinization. In: McKee PH, Calonje E, Granter SR, eds. Pathology of the Skin. Phila-delphia, PA: Elsevier; 2005:37-80.2.   Gutiérrez MC, Hasson A, Arias MD, Martín L, Barat A, Requena L, et al. Localized hyperke-ratosis lenticularis perstans (Flegel’s disease). Cutis 1991;48:201-4.3.   Price ML, Jones EW, MacDonald DM. A clini-copathological study of Flegel’s disease (hy-perkeratosis lenticularis perstans). Br J Der-matol 1987;116:681-91.4.   Jang KA, Choi JH, Sung KJ, Moon KC, Koh JK. Hyperkeratosis lenticularis perstans (Flegel’s disease): histologic, immunohistochemical, and ultrastructural features in a case. Am J Dermatopathol 1999;21:395-8.5.   Rosdahl I, Rosen K. Hyperkeratosis lenticula-ris perstans: report on two cases. Acta Derm Venereol (Stockh) 1985;65:562-4.6.   Fathy S, Azadeh B. Hyperkeratosis lenticularis perstans. Int J Dermatol 1988;27:120-1.7.   Ando K, Hattori H, Yamauchi Y. Histopatho-logical differences between early and old le-sions of hyperkeratosis lenticularis perstans (Flegel’s disease). Am J Dermatopathol 2006;28:122-6.Figure 5. Mounds of parakeratosis that contain neutrophils in the horny layer, arranged in a peri-odic fashion. (HE x10)Fernandez-Flores and Manjon      Acta Dermatovenerol CroatHyperkeratosis lenticularis perstans       2009;17(1):16-1919ACTA DERMATOVENEROLOGICA CROATICA8.   Tezuka T. Dyskeratotic process of hyperkera-tosis lenticularis perstans (Flegel). The abnor-mal formation of cystine-rich protein. Derma-tologica 1982;164:379-85.9.   Langer K, Zonzits E, Konrad K. Hyperkerato-sis lenticularis perstans (Flegel’s disease). Ul-trastructural study of lesional and perilesional skin and therapeutic trial of topical tretinoin versus 5-fluorouracil. J Am Acad Dermatol 1992;27:812-6.10. Tidman MJ, Price ML, MacDonald DM. La-mellar bodies in hyperkeratosis lenticularis perstans. J Cutan Pathol 1987;14:207-11.11. Miljković J. An unusual generalized form of hyperkeratosis lenticularis perstans (Flegel’s disease). Wien Klin Wochenschr 2004;116:78-80.12. Pearson LH, Smith JG, Chalker DK. 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J Dermatol 1984;11:407-9.19. Kanitakis J, Hermier C, Hokayem D, Schmitt D. Hyperkeratosis lenticularis perstans (Flegel’s disease): a light and electronic microscopic study of involved and uninvolved epidermis. Dermatologica 1987;174:96-101.20. Buchner SA. Hyperkeratosis lenticularis perstans (Flegel’s disease): in situ characteri-zation of T cell subsets and Langerhans’ cells. Acta Derm Venereol (Stockh) 1988;68:341-5.21. Li TH, Hsu CK, Chiu HC, Chang CH. Mul-tiple asymptomatic hyperkeratotic papules on the lower part of the legs. Arch Dermatol 1997;133:910-4. Fernandez-Flores and Manjon      Acta Dermatovenerol CroatHyperkeratosis lenticularis perstans       2009;17(1):16-19Orizol cream - for removing sunspots; year 1929.(From the collection of Mr. Zlatko Puntijar)

Morphological Evidence of Periodical Exacerbation of Hyperkeratosis Lenticularis Perstans

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