Transient Acantholytic Dermatosis (Grover Disease)

Practice Essentials

Transient acantholytic dermatosis (also referred to as Grover disease) is a disorder characterized by papulovesicular eruptions on the trunk and proximal extremities. It is not uncommon, but surprisingly, it was not thoroughly characterized until Grover did so in 1970.^[1] Transient acantholytic dermatosis is a reactive skin condition that may resolve over a period of weeks or months, but it is commonly persistent (chronic). Although this disorder is generally accepted as being benign and self-limited disorder, it can be difficult to manage; thus, the inclusion of the term transient in its name is misleading.^[2]   

Transient acantholytic dermatosis can be either idiopathic or acquired. The disease may erupt occur secondary to medications, malignancies, and external factors (eg, friction). A systematic review found that cancer therapeutics were the most common causative agents.^[3]

The presentation can be subtle, or it may closely resemble those of other pruritic dermatoses. A high index of suspicion for this disease is necessary if the diagnosis is to be made correctly. Furthermore, the histologic features of transient acantholytic dermatosis closely resemble those of several other conditions that are clinically distinct, which may add to potential diagnostic confusion.

Transient acantholytic dermatosis is not curable. Although the symptoms can frequently be controlled, some cases are refractory to treatment and difficult to manage. Current methods of treating symptoms include topical steroids, retinoids, methotrexate, and 5-aminolevulinic acid photodynamic therapy (ALA-PDT).

Patients should avoid activities that cause excessive heat and sweating (eg, exercise and prolonged sun exposure). Patients should also avoid applying topical irritants.

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Pathophysiology and Etiology

The etiology of transient acantholytic dermatosis is unknown. However, a number of factors have been suggested as being potentially causal or exacerbating. The most frequent association is with heat or sweating, and the obstruction of sweat ducts has been postulated to be responsible; however, this association has been challenged on the basis of research demonstrating that most patients with transient acantholytic dermatosis present in winter, not in summer.^[4] This is particularly noteworthy, given that xerosis is a potential cause of transient acantholytic dermatosis and is exacerbated by cold weather.

Many patients describe preceding exposure to sunlight; however, exposure to artificial ultraviolet (UV) radiation has not been shown to reproduce the process. Transient acantholytic dermatosis seems to occur more frequently in patients with atopic dermatitis and asteatotic dermatitis, though many individuals with these conditions never develop it. A case of transient acantholytic dermatosis triggered by honeybee stings suggesting a hypersensitivity reaction.^[5]

Viral, bacterial, and other pathogens have also been proposed as etiologic factors, but no causative role has been established. A number of case reports have described an association of transient acantholytic dermatosis with lymphoma, but these seem to be in the extreme minority.^{[6, 7]} The exact pathogenesis has not been elucidated.

A systematic review found that cancer therapeutics were the most common agents reported in drug-induced transient acantholytic dermatosis.^[3] For example, there have been reports of cases related to pembrolizumab and nivolumab (PD-1 inhibitors),^[8] ipilimumab (CTLA-4 inhibitor)​,^{[9, 10]} and letrozole (aromatase inhibitor).^[11]

Similarly, a number of case reports have focused on describing a direct relation between autoimmune antibodies and transient acantholytic dermatosis. Although there is a positive correlation between the two, it is unclear whether the autoimmune antibodies cause transient acantholytic dermatosis or if they increase as a result of transient acantholytic dermatosis.^{[12, 13]}  Research has indicated hyperphorphorylated extracellular signal–regulated kinase (ERK) resulting from excessive activity in the mitogen-activated protein kinase kinase (MEK) pathway.^[14]  

Seli et al conducted a retrospective study of sequencing data of 15 individuals with transient acantholytic dermatosis, in which damaging single-nucleotide variants in ATP2A2 were identified in 12 individuals (80%).^[15] ATP2A2 defects are associated with Darier disease (keratosis follicularis). Because all variants identified were C>T or G>A substitutions, the researchers hypothesized that UV light–induced mutagenesis may contribute to the development of lesions. The importance of this is uncertain, given that Grover disease almost never manifests in sun-exposed areas.

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Epidemiology

United States and international statistics

Exact numbers regarding the prevalence of transient acantholytic dermatosis are not available. Because of the clinical similarities to other entities and variability of the histopathologic findings, the disease is underdiagnosed in nondermatologic settings and is probably underdiagnosed overall. Given that transient acantholytic dermatosis has been linked to immobilization occlusion, it is likely that a growing number of cases have gone undetected in the hospital setting.

Age-, sex-, and race-related demographics

Transient acantholytic dermatosis most commonly affects adults older than 50 years. In rare instances, however, it has been reported in children. Men are affected three times more often than women. Whites are most commonly affected, though the condition may also be seen in other ethnic groups (eg, Hispanics and Blacks).

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Prognosis

Generally, transient acantholytic dermatosis is a self-limited disorder that resolves over weeks to months, but it can be persistent and may repeatedly recur for years. Lesions may resolve with postinflammatory pigmentary alteration or with no residual change. Diagnosis can be complicated by the presence of dermatitis, which produces scattered, rounded crusted plaques that resemble those in transient acantholytic dermatosis. Scarring is usually minimal unless induced by excoriation.

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History

One of the hallmarks of transient acantholytic dermatosis (also referred to as Grover disease) is pruritus, and all individuals who are affected experience variable degrees of itching, which can sometimes be severe.

The clinical appearance does not always correlate to the degree of pruritus; for example, some patients with limited cutaneous disease complain of severe itching, whereas others with many lesions have few or no symptoms. 

Although the lesions may resolve over weeks to months, they frequently recur. It is also possible for lesions to bleed.

No systemic symptoms are associated with transient acantholytic dermatosis, but oral lesions can develop that resemble aphthae and may be slightly painful.^[16]

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Physical Examination

The transient acantholytic dermatosis disease process usually begins as an eruption of the skin on the anterior part of the chest, the upper part of the back, and the lower part of the rib cage (see the images below).^[17]

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54-year-old man with pruritic eruption on trunk. Note slight lichenification and significant erythema from rubbing that is localized to central part o....

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Close-up view of abdominal area of patient with pruritic eruption on trunk. Multiple small, discrete, red-brown papules characteristic of Grover disea....

Patients who are severely affected may have disseminated disease affecting the neck, the shoulders, the arms, and the legs. The scalp is usually not affected, and the palms and the soles are almost always spared.

Individual lesions are erythematous to red-brown keratotic papules that remain discrete and usually tend not to coalesce. Occasionally, lesions may be acneiform, vesicular, pustular, and even (rarely) bullous. Although the most common presentation is that of widespread scattered papules, unusual distributions, including zosteriform or unilateral, may occur.^[18]

Dermoscopy has been described as having some utility, albeit limited. In early stages, central glomerular, linear, and hairpin vessels at the margin of the lesions are visible; in later stages, a brown starlike lesion with a white radiating halo may be seen.^[19]

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Laboratory Studies

The symptoms (pruritic papular eruptions on the chest), immunohistochemical findings, and histology of transient acantholytic dermatosis (Grover disease) resemble those of herpes virus infection. Therefore, herpes simplex virus (HSV) infection must be ruled out by confirming that HSV-1 and HSV-2 stains come back negative.

A skin scraping with oil preparation to search for mites, ova, and scybala of scabies is commonly warranted in any patient with pruritus and a rash. However, the clinical features of transient acantholytic dermatosis are substantially different from those of scabies. More uncommon parasitic infestations (eg, bird mite or cat mite) could mimic transient acantholytic dermatosis clinically.^[21]

In most cases of transient acantholytic dermatosis, immunofluorescence has consistently yielded negative results; however, some studies have shown positive results.^{[22, 23]} Although this may provide an area for research into the etiology of transient acantholytic dermatosis, the results of immunofluorescence remain inconsistent and have not been shown to be directly correlated with the histology.

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Other Tests

Other tests of value in the workup include the following:

• Negative immunofluorescence
• Negative stains for varicella-zoster virus (VZV), HSV-1, and HSV-2

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Histologic Findings

The histology of transient acantholytic dermatosis contains certain characteristic features, but a precise diagnosis requires clinicopathologic correlation (see the images below). Typically, focal acantholysis and dyskeratosis are seen. Spongiosis is also commonly observed, and the presence of spongiosis, acantholysis, and vesicle formation in the same specimen should raise the possibility of transient acantholytic dermatosis.^{[24, 25]} Acrosyringeal acantholysis may be present,^[26] and multinucleated cells may suggest herpetic infection.^[27]

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Histopathology of Darier-type Grover disease. Focus of acantholytic dyskeratosis is present in epidermis with slight epithelial hyperplasia and hyperk....

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Higher magnification reveals acantholytic dyskeratosis to better advantage. Note corps ronds and grains (hematoxylin and eosin, original magnification....

Several distinct histologic patterns of transient acantholytic dermatosis have been described, including the following:

• A pattern that simulates Hailey-Hailey disease
• A pattern that simulates Darier disease
• A pattern characterized mainly by spongiotic dermatitis
• A pattern that simulates pemphigus vulgaris
• A pattern that simulates pemphigus foliaceus

Although a single pattern may predominate, multiple patterns may be seen in different lesions from the same patient or, in some cases, even within a single specimen.

Other patterns that have been described include the following^[28] :

• A pattern characterized by parakeratosis
• A pattern resembling solar lentigo/Dowling-Degos disease, characterized by intraepidermal vesicles
• A pattern with lymphocytic infiltrate
• A pattern characterized by disordered keratinocyte maturation

The key discriminating features are as follows:

• Darier disease - Virtually identical; greater tendency to involve follicles; clinical correlation essential
• Linear acantholytic epidermal nevus - Virtually identical; clinical correlation essential
• Hailey-Hailey disease - Epidermis usually more hyperplastic; more diffuse involvement
• Pemphigus vulgaris - Broad zones of suprabasilar acantholysis; mucosal involvement; involvement of adnexal structures; often abundant eosinophils
• Primary spongiotic dermatitis (allergic contact dermatitis, nummular dermatitis) - Involvement of entire epidermis; psoriasiform hyperplasia
• Acantholytic solar keratosis - Atypical keratinocytic proliferation in lower portion of epidermis with cytologic atypia and mitoses; alternating orthokeratosis and parakeratosis; solar elastosis
• Solitary acantholytic keratosis - Epidermal hyperplasia; slight papillomatosis or digitation of epidermis; clinical correlation required
• Pemphigus foliaceus/erythematosus - Broad zone of subcorneal and subgranular acantholysis; involvement of adnexal structures; often eosinophils
• Warty dyskeratoma - Cup-shaped exoendophytic cystlike lesion; acantholytic and dyskeratotic cells lining cyst wall; pseudopapillae with acantholytic dyskeratosis lined by a single layer of basal cells
• Familial dyskeratotic comedones - Small cylindrical invagination with epithelial lining demonstrating acantholytic dyskeratosis
• Porokeratotic - Parakeratosis over parts of epidermis lacking a granular layer; upper epidermal layers have occasional dyskeratosis
• Lentiginous - Rete ridge elongation; basal hyperpigmentation
• Vesicular - Intraepidermal vesicles with little acantholysis and spongiosis surrounding it
• Lichenoid - Occasional dyskeratosis; damage of the vacuoles; dermoepidermal junction has lymphocytic infiltrate
• Dysmaturation - Little hyperchromasia; nuclear pleomorphism; disordered maturation of keratinocytes

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Approach Considerations

Transient acantholytic dermatosis (also referred to as Grover disease) is not curable.  Although the symptoms can frequently be controlled, some cases are refractory to treatment and difficult to manage. Success in treatment relies heavily on correct identification of the disease early in its course and on treatment of any features of underlying atopy. Drug-induced lesions usually clear and symptoms resolve with discontinuance of the causative agent.^[3]

Because recurrence is the rule, not the exception, the descriptor "transient" is inaccurate and confusing and should therefore be discontinued. Either "recurrent pruritic" or "paroxysmal pruritic" would be preferable. However, clinicians are familiar with the current terminology.

Excess heat and sweating are frequently associated with an increase in the symptoms of transient acantholytic dermatosis. Activities that cause these symptoms should be avoided. The role of sweat antigen or high sweat metal concentrations in patients with refractory or severe disease has not been evaluated but should be considered in those patients.

Current methods of treating symptoms include the following:

• Topical steroids
• Retinoids
• Methotrexate
• 5-aminolevulinic acid photodynamic therapy (ALA-PDT)

Initial care may be limited to midpotency topical corticosteroids and oral antihistamines. Atopic skin care measures should be recommended. Regular use of moisturizers containing camphor and menthol should be advised. Several reports have described improvement with topical calcipotriol (calcipotriene). Cases resolving after treatment with dupilumab suggest a safer alternative to traditional treatments for severe disease. Improvement with immunomodulation via interleukin (IL)-4 and IL-13 aligns with the observation that many patients with Grover disease meet criteria for atopic dermatitis (personal communication with Ralph Grover, MD, 1999).

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Medical Care

Potent topical corticosteroids may be effective in diminishing inflammation and in controlling itching associated with transient acantholytic dermatosis. Topical steroid use must be limited in time and duration; long-term use can result in atropy, tachyphylaxis, and systemic absorption. Menthol or pramoxine-containing lotions may also be helpful for itching.

For refractory disease, retinoids such as vitamin A or isotretinoin may be effective.^[29]

Oral corticosteroids, ultraviolet (UV)-B light exposure, psoralen plus UV-A light (PUVA), Grenz radiation (Bucky rays), and methotrexate have all been reported to be effective in severely resistant cases. However, some cases are refractory to virtually all forms of therapy.

Acitretin,^[30] calcipotriol,^{[30, 31, 32]} and UV-A1 have been described as useful in patients with disease that is difficult to manage. Topical calcipotriol should be limited to no more than 100 g/wk; even at recommended dosages, it can cause changes in parathyroid hormone levels and serum calcium concentrations. 

The monoclonal antibody dupilumab has been successfully used to treat refractory transient acantholytic dermatosis.^{[33, 34]}

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Prednisone (Deltasone, Prednisone Intensol, Rayos)

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Isotretinoin (Absorica, Absorica LD, Amnesteem)

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Acitretin (Soriatane (DSC))

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Methotrexate (Jylamvo, Otrexup, Rasuvo)

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Calcipotriene (Calcitrene Ointment, Dovonex, Sorilux)

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Vitamin A (Aquasol A, Retinol, Retinyl acetate)

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Dupilumab (Dupixent)

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