Granular parakeratosis

INTRODUCTION — Granular parakeratosis (GP) is an uncommon, usually pruritic, benign dermatosis found most often in the axillae or other intertriginous areas. The majority of authors describe GP as a specific disease entity, but it has also been proposed that the term "granular parakeratosis" be used to describe the distinctive histopathologic characteristics (parakeratosis and retention of keratohyalin granules in the stratum corneum (picture 1A-B)) rather than to describe a specific dermatosis [1].

Other terms that have been used to refer to GP include "hyperkeratotic flexural erythema" and the colloquial term "zombie patch." (See 'Histopathology' below.)

That GP is a true clinical entity rather than a reactive histologic pattern is supported by its unique clinical appearance; it demonstrates erythematous to brown, hyperkeratotic papules that may coalesce into plaques (picture 2A-C). Since the initial description of GP involving the axilla in 1991 [2], it has been reported in other intertriginous areas, including inframammary, inguinal, genital, and perianal skin; beneath the abdominal pannus; and in nonintertriginous sites, particularly on the lumbosacral area.

The clinical features, diagnosis, and management of GP will be reviewed here.

EPIDEMIOLOGY — GP appears to be uncommon but is likely underreported. In a retrospective study of over 360,000 cutaneous biopsy specimens submitted to a dermatopathology institute, 0.005 percent of specimens confirmed a diagnosis of GP [3].

GP has been reported more often in women than in men [4]; a higher likelihood for women to seek treatment may be a contributing factor. Most reports describe it in persons over 40 years of age, although all age groups may be affected, including children and infants [4]. There is at least one report of congenital GP [5].

ETIOLOGY AND PATHOGENESIS — The cause of GP is unknown. It appears to be a reactive process in the skin [1], and most reports elaborate associations with skin maceration (due to occlusion [2], warm environments [6], sweating, obesity, repeated washing [7]) or skin irritation from external agents (eg, antiperspirants, deodorants, and zinc oxide). Exposure to benzalkonium chloride, a preservative and antiseptic used in many products including laundry rinses, personal hygiene wipes, medical solutions, and more, has been proposed as an inciting factor in case reports [8,9]. Development of GP following the use of a depilatory cream has also been reported [10].

The pathogenic mechanism of GP most likely involves a stimulus (either external or internal) that triggers a failure of normal keratinocyte maturation in the stratum granulosum. This results in the retention of nuclei in the upper layers of the stratum corneum (ie, parakeratosis). There is also a failure to process profilaggrin into filaggrin that may inhibit the normal disappearance of keratohyalin granules of the stratum granulosum as the keratinocytes mature and flatten to become the stratum corneum [11]. Increased epidermal turnover may lead to epidermal hypertrophy and thickening of the stratum corneum [12].

The histologic changes of GP have been demonstrated in mouse skin treated daily with aluminum chloride 20% spray, suggesting a potential pathogenic role for topical aluminum chloride [13]. Cytochrome C and cleaved-caspase 3, both apoptosis-inducing factors, were upregulated in the granular layer of affected mouse skin. The authors postulated that aluminum chloride-induced apoptosis may contribute to manifestations of GP through interruption of keratinization and the inhibition of processing of profilaggrin to filaggrin. Inhibition of caspase 3 prevented the GP-like skin changes. (See 'Histopathology' below.)

GP has also occurred without an obvious external insult and has occurred congenitally; it is proposed that these cases may be due to an acquired disorder of cornification [5,11]. In support of this theory, mice deficient in caspase 14, a protease that is important in forming a functional skin barrier, are more prone to the development of parakeratosis than wild-type mice [14].

CLINICAL FEATURES — The primary lesion of GP is the hyperkeratotic papule. Papules may be discrete but usually coalesce into well-demarcated plaques that can have satellite papules. Reticular patterns may also occur. The papules or plaques are usually erythematous, red-brown, or brown and may become violaceous and lichenified if scratched aggressively (picture 2A-C). A follicular variant has been reported [15].

GP is typically found in intertriginous areas, such as the axillae (most common), inframammary folds, inguinal creases, beneath the abdominal pannus, or on the vulva, penis, or perianal skin. In infants, it may occur in the diaper area, especially in sites of friction or pressure. Occasionally, nonintertriginous skin is involved, such as the lumbosacral area, neck [16], or face [17]. It may be unilateral or bilateral and may occur in multiple locations [4,18].

GP is usually pruritic and may be malodorous. Due to the common location in the skin folds, the plaques may become macerated, eroded, or fissured, which may cause burning or pain. Heat and moisture (eg, warm, humid environments) may be aggravating factors.

GP generally is not associated with other diseases, but clinical findings of GP have been reported in patients receiving chemotherapy for breast [19] and ovarian carcinomas [20]. It has also occurred in a patient with dermatomyositis [21]. Whether these patients experienced significant perspiration prior to the appearance of GP is not mentioned. One publication reports seven cases of infantile GP in which five infants also had atopic dermatitis [22].

HISTOPATHOLOGY — Skin biopsies of GP show hyperkeratosis and compact parakeratosis within the stratum corneum. Cells in the upper skin strata contain basophilic keratohyalin granules, a finding that is the hallmark of the disease (picture 1A-B) [4]. The epidermis is most often thickened in a psoriasiform or acanthotic pattern with or without papillomatosis. A low-grade lymphohistiocytic infiltrate also may be present [2]. Variants of GP in which the characteristic histologic findings are localized to the follicular infundibula or the eccrine ostia have been reported [15,16].

Electron microscopy shows stellate or round keratohyalin bodies in the granular layer. Fungal and bacterial stains are negative. Direct immunofluorescence is negative.

The histopathologic finding of GP may occur in other disease entities. Incidental GP has been detected in biopsy specimens of dermatomyositis, cutaneous dermatophyte infections [23], and molluscum contagiosum [24], as well as in cutaneous neoplasms, including actinic keratosis, keratoacanthomas, and squamous cell carcinomas [25].

DIAGNOSIS — An eruption with clinical features consistent with GP (well-demarcated, red or brown, hyperkeratotic papules or plaques on intertriginous skin) can strongly suggest the diagnosis. Because the primary diagnostic criteria are histopathologic, a skin biopsy demonstrating parakeratosis and retention of keratohyalin granules in the stratum corneum is usually needed for confirmation. A punch biopsy or shave biopsy is sufficient. (See "Skin biopsy techniques".)

The findings of a small case series suggest that a superficial skin scraping may be a less invasive alternative for confirming the diagnosis in young children with clinical features of GP. In a series in which six of seven infants with clinical findings suggestive of GP had scrapings of the stratum corneum performed and stained with May-Grünwald Giemsa and Papanicolaou stains, cytologic examination revealed cells with keratohyalin granules and retained nuclei in all six patients [22].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of GP is broad and includes a variety of other disorders with a predilection for intertriginous skin. In particular, cases in which hyperkeratosis is less prominent may be mistaken for common inflammatory or infectious disorders such as inverse psoriasis, intertrigo, dermatophyte infections, and erythrasma. Inverse psoriasis plaques often exhibit a shiny appearance. A potassium hydroxide preparation will quickly identify candidal intertrigo and dermatophyte infections. Coral-red fluorescence upon illumination of involved skin with a Wood's lamp identifies erythrasma. (See "Approach to the patient with an intertriginous skin disorder" and "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Inverse (intertriginous) psoriasis' and "Erythrasma" and "Intertrigo".)

Disorders in the differential diagnosis include:

●Acanthosis nigricans (particularly for lichenified GP or GP in dark skin) (picture 3)

●Folliculitis (picture 4)

●Erythrasma (picture 5)

●Seborrheic dermatitis (picture 6A-B)

●Fox-Fordyce disease (apocrine miliaria) (picture 7)

●Eccrine miliaria (particularly miliaria rubra (picture 8))

●Hidradenitis suppurativa (picture 9)

●Contact dermatitis

●Inverse psoriasis (picture 10)

●Intertrigo (picture 11)

●Axillary syringomas

●Hailey-Hailey disease (picture 12)

●Bowen's disease (picture 13)

●Verrucae

●Darier disease (picture 14)

●Extramammary Paget disease (picture 15)

●Dermatophyte infection (picture 16)

●Epidermal nevus (picture 17)

●Inverse lichen planus (picture 18)

●Pemphigus vegetans (picture 19)

●Dowling-Degos disease (picture 20)

In infants and young children, GP often involves the diaper area. The differential diagnosis for these patients should also include:

●Acrodermatitis enteropathica (picture 21)

●Langerhans cell histiocytosis (picture 22)

NATURAL HISTORY — GP follows a variable course. Spontaneous resolution has been described, but how often this happens or how long it takes have not been elucidated. Conversely, the clinical manifestations may wax and wane or resolve for a period of time followed by recurrence. Cases persisting for more than 20 years have been reported [26].

TREATMENT — Many treatments have been used for GP, with variable success [4]. Elimination of possible causative factors is the mainstay of management, but the eruption may persist after potential exposures have been removed.

Elimination of exacerbating factors — Clinical experience suggests that measures such as changing the type of deodorant or antiperspirant, avoiding other potentially irritating topical agents, and minimizing moisture in affected areas can resolve some cases of GP [9]. The efficacy of these interventions has not been evaluated in clinical studies. There is a report of inframammary GP that was successfully treated with reduction mammoplasty [27].

We typically advise patients with axillary involvement to switch from a solid deodorant or antiperspirant to a gel or spray product to minimize skin maceration as well as to limit use of deodorants and antiperspirants as much as is acceptable. We also encourage patients to avoid applying fragranced products to affected areas. Avoidance of shaving may also be beneficial. These interventions should be implemented for at least two weeks for an adequate therapeutic trial.

Medical interventions — Although GP can be self-limited, treatment may be initiated in an attempt to accelerate resolution. Treatments for GP have included topical agents, systemic agents, and procedural interventions. However, efficacy data are limited to case reports and small case series, preventing definitive conclusions about the efficacy of these interventions [4].

Topical therapies are generally used as first-line treatment. Topical agents reported to improve GP include topical corticosteroids (alone or in combination with topical antifungal agents), topical vitamin D analogues, and topical tretinoin:

●Topical corticosteroids – Responses of GP to low-potency to high-potency topical corticosteroids alone or in combination with topical antifungal agents have been reported [18,28-31]. Because of a relatively low risk for serious side effects, low-potency topical corticosteroids such as hydrocortisone 1 to 2.5% cream or lotion are generally the first line of treatment (table 1). Responses may be evident within a few days to a few weeks. In a series of three patients, twice-daily application of the high-potency topical corticosteroid betamethasone dipropionate alone or in combination with clotrimazole 1% was associated with resolution of GP within 10 days [28].

Therapy with topical corticosteroids of any potency carries risk of cutaneous atrophy and striae in the axillae and other skin fold areas. Treatment with corticosteroids should be discontinued as soon as the clinical manifestations resolve or after a maximum of 7 to 10 days for group 1 to 4 topical corticosteroids and a maximum of four weeks for group 5 to 7 topical corticosteroids (table 1). (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

The reason topical corticosteroids may be beneficial is unclear. An effect of glucocorticoids on profilaggrin expression and processing has been postulated [28].

●Topical vitamin D analogues – Treatment with topical vitamin D analogues has been associated with improvement in GP in case reports [10,32,33]. Twice-daily treatment with topical calcitriol ointment (3 mcg/g) has been associated with complete resolution of GP within 10 days in one patient [34]. A beneficial effect of vitamin D analogues may involve inhibition of keratinocyte proliferation and the promotion of terminal differentiation.

●Topical retinoids – A case report describes complete clearance of axillary GP within five days during treatment with tretinoin 0.025% cream once daily [35]. The authors proposed that benefit may have resulted from the effects of tretinoin on filaggrin expression or keratolytic effects of tretinoin.

Skin irritation is a potential side effect that may require cessation of retinoid therapy. Because of the potential for irritation, avoiding treatment in the groin or perianal areas is prudent.

Other topical anti-inflammatory agents may also be useful but have not been specifically reported in the treatment of GP. Topical calcineurin inhibitors applied twice daily may be a good alternative to topical corticosteroids as they do not induce atrophy of the skin. Topical antibiotics such as erythromycin or clindamycin may also be helpful, likely due to both anti-inflammatory and antibacterial action.

Other interventions may be useful for GP refractory to topical therapy. Several case reports document benefit of various oral antibiotics, including amoxicillin-clavulanic acid and doxycycline [36,37]. Two or three weeks of treatment with oral isotretinoin (40 mg per day) appeared to resolve GP in a patient who did not respond to mild topical corticosteroids and tazarotene [38]. Oral isotretinoin therapy was also associated with improvement in a patient who had not improved during treatment with topical fluocinolone and oral ciprofloxacin [39]. Rapid resolution of GP has also been reported in a woman treated with a combination of itraconazole (100 mg twice daily), topical desonide, and topical ketoconazole [31].

Another report describes rapid resolution of axillary GP after botulinum toxin injection [40]. Ablative treatment with an erbium:yttrium aluminum garnet and carbon dioxide laser led to clearance of GP in one patient, albeit with residual scarring [41]. Other destructive measures may also be helpful for small lesions, such as cryotherapy or electrosurgery. Short courses of oral glucocorticoids may yield relief from severe inflammation and pruritus.

SUMMARY AND RECOMMENDATIONS

●Overview – Granular parakeratosis (GP; also known as hyperkeratotic flexural erythema) is an uncommon cutaneous disorder that typically manifests as hyperkeratotic papules or plaques on intertriginous skin. GP is distinguished by its characteristic histopathologic findings of retained keratohyalin granules in the stratum corneum and parakeratosis (picture 1A-B). (See 'Introduction' above.)

●Epidemiology – GP appears to occur most frequently in adult women but may occur at any age, including infancy. (See 'Epidemiology' above.)

●Etiology and pathogenesis – The etiology of GP is unclear. Development is frequently associated with maceration or irritation of the affected skin. These might trigger defective keratinocyte maturation, resulting in the characteristic clinical and histopathologic findings. GP may also occur in the absence of such factors. (See 'Etiology and pathogenesis' above.)

●Clinical features – GP most commonly presents as pruritic, red to brown, hyperkeratotic papules that may coalesce into well-demarcated plaques on intertriginous skin (picture 2A-C). The axilla is the most common site of involvement. GP has also been reported on nonintertriginous skin. (See 'Clinical features' above.)

●Diagnosis – A diagnosis of GP may be suspected based upon the clinical findings. A skin biopsy demonstrating parakeratosis and retained keratohyalin granules in the stratum corneum confirms the diagnosis. (See 'Diagnosis' above.)

●Course – The clinical course of GP varies. It is likely that many cases spontaneously resolve. (See 'Natural history' above.)

●Treatment – Avoidance of potential exacerbating factors is the mainstay of therapy for GP. Data on the efficacy of medical therapies are limited. We suggest topical therapies rather than systemic or procedural interventions as first-line medical treatment (Grade 2C). Topical therapies that may be useful include corticosteroids, vitamin D analogues, and tretinoin. (See 'Treatment' above.)