Transient Acantholytic Dermatosis

Back

Background

Transient acantholytic dermatosis (Grover disease) is not an uncommon condition, but, surprisingly, it was not thoroughly characterized until Grover did so in 1970.[1] Transient acantholytic dermatosis is characterized by papulovesicular eruptions on the trunk and proximal extremities. Transient acantholytic dermatosis is a reactive skin condition that resolves over a period of weeks or months, but it is more likely to be persistent (chronic). While generally accepted to be a benign, self-limited disorder, it is often persistent and difficult to manage; hence, the description of transient is misleading.[2] The presentation can be subtle, or it may closely resemble 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 (Grover disease) closely resemble those of several other conditions that are clinically distinct, which may add to potential diagnostic confusion.

Pathophysiology

The etiology of transient acantholytic dermatosis (Grover disease) 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, although this association has been challenged, citing research that demonstrates that most patients with transient acantholytic dermatosis (Grover disease) present in winter, not summer.[3]  This is particularly noteworthy given the fact that xerosis is a potential cause of transient acantholytic dermatosis and is exacerbated by cold weather. 

Many patients describe preceding exposure to sunlight, although exposure to artificial ultraviolet radiation has not been shown to reproduce the process. Transient acantholytic dermatosis (Grover disease) seems to occur more frequently in patients with atopic dermatitis and asteatotic dermatitis, although many individuals with these conditions never develop it. Viral, bacterial, and other pathogens have also been proposed, but no causative role has been established. A number of transient acantholytic dermatosis (Grover disease) case reports have described an association with lymphoma, but these seem to be in the extreme minority.[4, 5] The exact pathogenesis has not been elucidated. Melanoma therapy with CTLA-4 inhibition has been associated with the disease.[6, 7]  Similarly, a number of case reports have focused on describing a direct relationship between autoimmune antibodies and transient acantholytic dermatosis, and while there is a positive correlation between autoimmune antibodies and transient acantholytic dermatosis, it is unclear whether the autoimmune antibodies cause transient acantholytic dermatosis or if they increase as a result of transient acantholytic dermatosis.[8, 9]

Epidemiology

Frequency

Exact numbers regarding the prevalence of transient acantholytic dermatosis (Grover disease) are not available. Because of the clinical similarities with other entities and variable histopathologic findings, the disease is underdiagnosed in nondermatologic settings and probably underdiagnosed overall. Since 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.

Race

Transient acantholytic dermatosis (Grover disease) most commonly affects middle-aged white men, although it may be seen in other ethnic groups, such as Hispanics and blacks.

Sex

Men are affected three times more often than women.

Age

Transient acantholytic dermatosis (Grover disease) most commonly affects middle-aged men; however, it has been in reported in children.

Prognosis

Generally, transient acantholytic dermatosis (Grover disease) is a self-limited disorder that resolves over weeks to months, but it can be persistent and may repeatedly recur for years.

Patient Education

Transient acantholytic dermatosis (Grover disease) is not curable, and the cause is unknown. 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).

History

One of the hallmarks of transient acantholytic dermatosis (Grover disease) is pruritus, and all individuals who are affected experience variable degrees of itching, sometimes severe in nature.

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. 

While lesions may resolve over weeks to months, they commonly recur. It is also possible for lesions to bleed.

No systemic symptoms are associated with transient acantholytic dermatosis (Grover disease), but oral lesions can develop that resemble aphthae and may be slightly painful.[10]

Physical Examination

The transient acantholytic dermatosis (Grover 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).[11]



View Image

A 54-year-old man with a pruritic eruption on the trunk. Notice the slight lichenification and significant erythema from rubbing that is localized to ....



View Image

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

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 do not usually tend to coalesce. Occasionally, lesions may be acneiform, vesicular, pustular, and rarely even bullous. Although the most common presentation is that of widespread scattered papules, unusual distributions, including zosteriform or unilateral, may occur.[12]

The utility of dermoscopy is limited, as no features specific for transient acantholytic dermatosis have been reported.

Complications

Lesions may resolve with postinflammatory pigmentary alteration or with no residual change. Diagnosis can be complicated by dermatitis, because it produces scattered, rounded crusted plaques that resemble those in transient acantholytic dermatosis. Scarring is usually minimal unless induced by excoriation.

Laboratory Studies

Similar symptoms (pruritic papular eruptions on the chest), immunohistochemical findings, and histology are present in herpes virus infection. Therefore, herpes simplex virus (HSV) infection must be ruled out by ensuring 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 (Grover disease) are substantially different from scabies. More uncommon parasite infections, such as bird mite or cat mite, could mimic transient acantholytic dermatosis clinically.[14] In most cases of transient acantholytic dermatosis, immunofluorescence has been consistently negative; however, some studies have shown positive immunofluorescence.[15, 16] While this may provide an area for research in the etiology of transient acantholytic dermatosis, the results have proven inconsistent and have not yet been correlated directly to the histology.

Histologic Findings

The histology of transient acantholytic dermatosis (Grover disease) contains certain characteristic features, but for a precise diagnosis to be rendered, clinicopathologic correlation is needed (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.[17, 18] Acrosyringeal acantholysis may be present,[19] and multinucleated cells may suggest herpetic infection.[20]



View Image

Histopathology of Darier-type Grover disease. A focus of acantholytic dyskeratosis is present in the epidermis with slight epithelial hyperplasia and ....



View Image

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

Several distinct histologic patterns of transient acantholytic dermatosis (Grover disease) have been described: (1) a pattern that simulates Hailey-Hailey disease; (2) a pattern that simulates Darier disease; (3) a pattern characterized mainly by spongiotic dermatitis; (4) a pattern that simulates pemphigus vulgaris; and (5) a pattern that simulates pemphigus foliaceus. Although one pattern may predominate, each pattern may be seen in different lesions from the same patient or, in some cases, within a single specimen. Other newly described patterns include (6) a pattern characterized by parakeratosis; (7) a pattern resembling a solar lentigo/Dowling-Degos disease, characterized by intraepidermal vesicles; (8) a pattern with lymphocytic infiltrate; and (9) a pattern characterized by disordered keratinocyte maturation.[21] The key discriminating features are described below:

Other Tests

Negative immunofluorescence; negative stains for VZV, HSV1, and HSV2

Approach Considerations

Success in treatment relies heavily on correct identification of the disease early in its course and treatment of any features of underlying atopy. Recurrence is the rule, not the exception; the term "transient" should be dropped as it is inaccurate and confusing and replaced with "recurrent pruritic". The role of sweat antigen or high sweat metal concentrations in patients with refractory and/or severe disease has not be evaluated but should be considered in those patients.

Medical Care

Potent topical corticosteroids may be effective in diminishing inflammation and in controlling itching associated with transient acantholytic dermatosis (Grover disease). Menthol or pramoxine-containing lotions may also be helpful for itching.

For refractory disease, retinoids, such as vitamin A 50,000 U 3 times a day for 2 weeks then daily for up to 12 weeks or isotretinoin 40 mg/d for 2-12 weeks, may be effective.[22]

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

Activity

Excess heat and sweating are frequently associated with an increase in the symptoms of transient acantholytic dermatosis (Grover disease). Activities that cause these symptoms should be avoided. 

Prevention

Patients should avoid activities that cause excessive heat, such as exercise and prolonged sun exposure. Patients should also avoid applying topical irritants.

Long-Term Monitoring

Initial care for transient acantholytic dermatosis (Grover disease) 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.

Acitretin, calcipotriol, and UVA-1 have been described as useful in patients with disease that is difficult to manage.[23] Additionally, oral retinoids, methotrexate, etanercept, and phototherapy have also been reported to help.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Fluocinonide gel 0.05% should be applied twice a day. Never apply to the face, the axillae, or the genital areas. Desoximetasone may be used in place of fluocinonide. High potency (class I) topical steroids, such as Temovate or Diprolene, are limited to 2 weeks' use. They can cause atrophy if used longer and, therefore, should be avoided.

Hydroxyzine 10-30 mg can be used every 6 hours as needed for itching. As a substitute, Benadryl 25-50 mg may be used every 6 hours as needed. Both may cause drowsiness.

Isotretinoin (Amnesteem, Claravis, Myorisan, Sotret)

Clinical Context:  Isotretinoin is a synthetic 13-cis isomer of the naturally occurring tretinoin (trans- retinoic acid). Both agents are structurally related to vitamin A.

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.

Class Summary

These agents decrease the cohesiveness of abnormal hyperproliferative keratinocytes, and they may reduce the potential for malignant degeneration. They also affect keratinocyte differentiation.

Prednisone

Clinical Context:  Prednisone is an immunosuppressant used for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Methotrexate (Trexall, Rheumatrex)

Clinical Context:  Methotrexate is an antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells. It has an unknown mechanism of action in the treatment of inflammatory reactions; it may affect immune function. Methotrexate ameliorates symptoms of inflammation (eg, pain, swelling, stiffness).

Class Summary

These agents regulate cell growth and differentiation.

Vitamin A (Aquasol A, A-Natural-25, A-25)

Clinical Context:  Vitamin A is a cofactor in many biochemical processes. For refractory disease, vitamin A may be administered at 50,000 U 3 times a day for 2 weeks then daily for up to 12 weeks.

Class Summary

Vitamins are are used to meet necessary dietary requirements and are used in metabolic pathways, as well as DNA and protein synthesis.

What is transient acantholytic dermatosis (Grover disease)?What is the pathophysiology of transient acantholytic dermatosis (Grover disease)?What is the prevalence of transient acantholytic dermatosis (Grover disease)?What is the racial predilection of transient acantholytic dermatosis (Grover disease)?What is the sexual predilection of transient acantholytic dermatosis (Grover disease)?Which age groups are at highest risk for transient acantholytic dermatosis (Grover disease)?What is the prognosis of transient acantholytic dermatosis (Grover disease)?What should be included in the patient education about transient acantholytic dermatosis (Grover disease)?What are the signs and symptoms of transient acantholytic dermatosis (Grover disease)?Which physical findings are characteristic of transient acantholytic dermatosis (Grover disease)?What are the complications of transient acantholytic dermatosis (Grover disease)?How is transient acantholytic dermatosis (Grover disease) differentiated from other skin conditions?What are the differential diagnoses for Transient Acantholytic Dermatosis?What is the role of skin scraping in the diagnosis of transient acantholytic dermatosis (Grover disease)?Which histologic findings are characteristic of transient acantholytic dermatosis (Grover disease)?What are key histologic patterns and features of transient acantholytic dermatosis (Grover disease)?How is transient acantholytic dermatosis (Grover disease) treated?What is the role of corticosteroids in the treatment of transient acantholytic dermatosis (Grover disease)?What is the role of activity modification in the treatment of transient acantholytic dermatosis (Grover disease)?How is transient acantholytic dermatosis (Grover disease) prevented?What is included in long-term monitoring of patients with transient acantholytic dermatosis (Grover disease)?What is the role of drug treatment for transient acantholytic dermatosis (Grover disease)?Which medications in the drug class Vitamins are used in the treatment of Transient Acantholytic Dermatosis?Which medications in the drug class Antineoplastics, Antimetabolite are used in the treatment of Transient Acantholytic Dermatosis?Which medications in the drug class Corticosteroids are used in the treatment of Transient Acantholytic Dermatosis?Which medications in the drug class Retinoid-like Agents are used in the treatment of Transient Acantholytic Dermatosis?

Author

Clay J Cockerell, MD, President and Owner, Cockerell Dermatopathology; Adjunct Clinical Professor, Department of Internal Medicine (Dermatology), Division of Dermatopathology, University of North Texas Health Science Center at Forth Worth

Disclosure: Nothing to disclose.

Coauthor(s)

Sidra Ibad, BA, MD Candidate, Icahn School of Medicine at Mount Sinai

Disclosure: Nothing to disclose.

Specialty Editors

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.

Steven R Feldman, MD, PhD, Professor, Departments of Dermatology, Pathology and Public Health Sciences, and Molecular Medicine and Translational Science, Wake Forest Baptist Health; Director, Center for Dermatology Research, Director of Industry Relations, Department of Dermatology, Wake Forest University School of Medicine

Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbvie for consulting; Received honoraria from Galderma for speaking and teaching; Received consulting fee from Lilly for consulting; Received ownership interest from www.DrScore.com for management position; Received ownership interest from Causa Reseasrch for management position; Received grant/research funds from Janssen for consulting; Received honoraria from Pfizer for speaking and teaching; Received consulting fee from No.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Arash Taheri, MD, Research Fellow, Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine

Disclosure: Nothing to disclose.

Edward J Zabawski, Jr, DO, Medical and Surgical Dermatology

Disclosure: Nothing to disclose.

References

  1. Grover RW. Transient acantholytic dermatosis. Arch Dermatol. 1970 Apr. 101(4):426-34. [View Abstract]
  2. Streit M, Paredes BE, Braathen LR, Brand CU. [Transitory acantholytic dermatosis (Grover disease). An analysis of the clinical spectrum based on 21 histologically assessed cases]. Hautarzt. 2000 Apr. 51(4):244-9. [View Abstract]
  3. Scheinfeld N, Mones J. Seasonal variation of transient acantholytic dyskeratosis (Grover's disease). J Am Acad Dermatol. 2006 Aug. 55(2):263-8. [View Abstract]
  4. Fujita Y, Sato-Matsumura KC, Ohnishi K. Transient acantholytic dermatosis associated with B symptoms of follicular lymphoma. Clin Exp Dermatol. 2007 Nov. 32(6):752-4. [View Abstract]
  5. Ishibashi M, Nagasaka T, Chen KR. Remission of transient acantholytic dermatosis after the treatment with rituximab for follicular lymphoma. Clin Exp Dermatol. 2008 Mar. 33(2):206-7. [View Abstract]
  6. Uemura M, Faisal F, Haymaker C, McQuail N, Sirmans E, Hudgens CW, et al. A case report of Grover's disease from immunotherapy-a skin toxicity induced by inhibition of CTLA-4 but not PD-1. J Immunother Cancer. 2016. 4:55. [View Abstract]
  7. Koelzer VH, Buser T, Willi N, Rothschild SI, Wicki A, Schiller P, et al. Grover's-like drug eruption in a patient with metastatic melanoma under ipilimumab therapy. J Immunother Cancer. 2016. 4:47. [View Abstract]
  8. Phillips C, Kalantari-Dehaghi M, Marchenko S, Chernyavsky AI, Galitovskiy V, Gindi V, et al. Is Grover's disease an autoimmune dermatosis?. Exp Dermatol. 2013 Dec. 22 (12):781-4. [View Abstract]
  9. Ellenbogen E, Geller S, Azrielant S, Zeeli T, Goldberg I, Schmidt E, et al. Grover disease and bullous pemphigoid: a clinicopathological study of six cases. Clin Exp Dermatol. 2019 Jul. 44 (5):524-527. [View Abstract]
  10. Kanzaki T, Hashimoto K. Transient acantholytic dermatosis with involvement of oral mucosa. J Cutan Pathol. 1978 Feb. 5(1):23-30. [View Abstract]
  11. Fantini F, Kovacs E, Scarabello A. Unilateral transient acantholytic dermatosis (Grover's disease) along Blaschko lines. J Am Acad Dermatol. 2002 Aug. 47(2):319-20. [View Abstract]
  12. Liss WA, Norins AL. Zosteriform transient acantholytic dermatosis. J Am Acad Dermatol. 1993 Nov. 29(5 Pt 1):797-8. [View Abstract]
  13. Gilchrist H, Jackson S, Morse L, Nicotri T, Nesbitt LT. Galli-Galli disease: A case report with review of the literature. J Am Acad Dermatol. 2008 Feb. 58(2):299-302. [View Abstract]
  14. Zabawski EJ, Costner M, Franklin G, Witheiler DD, Eichorn PJ, Cockerell CJ. A potpourri of parasitic infestations. Cutis. 1999 Feb. 63 (2):81-5. [View Abstract]
  15. Millns JL, Doyle JA, Muller SA. Positive cutaneous immunofluorescence in Grover's disease. Arch Dermatol. 1980 May. 116 (5):515. [View Abstract]
  16. Weaver J, Bergfeld WF. Grover disease (transient acantholytic dermatosis). Arch Pathol Lab Med. 2009 Sep. 133 (9):1490-4. [View Abstract]
  17. Fernández-Figueras MT, Puig L, Cannata P, Cuatrecases M, Quer A, Ferrándiz C, et al. Grover disease: a reappraisal of histopathological diagnostic criteria in 120 cases. Am J Dermatopathol. 2010 Aug. 32(6):541-9. [View Abstract]
  18. Lacarrubba F, Boscaglia S, Nasca MR, Caltabiano R, Micali G. Grover's disease: dermoscopy, reflectance confocal microscopy and histopathological correlation. Dermatol Pract Concept. 2017 Jul. 7 (3):51-54. [View Abstract]
  19. Joshi R, Taneja A. Grover's Disease with Acrosyringeal Acantholysis: A Rare Histological Presentation of an Uncommon Disease. Indian J Dermatol. 2014 Nov. 59 (6):621-3. [View Abstract]
  20. Cohen PR, Paravar T, Lee RA. Epidermal multinucleated giant cells are not always a histopathologic clue to a herpes virus infection: multinucleated epithelial giant cells in the epidermis of lesional skin biopsies from patients with acantholytic dermatoses can histologically mimic a herpes virus infection. Dermatol Pract Concept. 2014 Oct. 4 (4):21-7. [View Abstract]
  21. Fernández-Figueras MT, Puig L, Cannata P, Cuatrecases M, Quer A, Ferrándiz C, et al. Grover disease: a reappraisal of histopathological diagnostic criteria in 120 cases. Am J Dermatopathol. 2010 Aug. 32 (6):541-9. [View Abstract]
  22. Helfman RJ. Grover's disease treated with isotretinoin. Report of four cases. J Am Acad Dermatol. 1985 Jun. 12(6):981-4. [View Abstract]
  23. Miljkovic J, Marko PB. Grover's disease: successful treatment with acitretin and calcipotriol. Wien Klin Wochenschr. 2004. 116 Suppl 2:81-3. [View Abstract]

A 54-year-old man with a pruritic eruption on the trunk. Notice the slight lichenification and significant erythema from rubbing that is localized to the central part of the torso. Also note the red-brown papules in the abdominal region.

Close-up view of the abdominal area of a patient with a pruritic eruption on the trunk. Multiple, small, discrete, red-brown papules characteristic of Grover disease are present.

Histopathology of Darier-type Grover disease. A focus of acantholytic dyskeratosis is present in the epidermis with slight epithelial hyperplasia and hyperkeratosis, a sign of rubbing as a consequence of the pruritic nature of the disease (hematoxylin and eosin, original magnification X40).

Higher magnification reveals the acantholytic dyskeratosis to better advantage. Note the corps ronds and grains (hematoxylin and eosin, original magnification X400).

A 54-year-old man with a pruritic eruption on the trunk. Notice the slight lichenification and significant erythema from rubbing that is localized to the central part of the torso. Also note the red-brown papules in the abdominal region.

Close-up view of the abdominal area of a patient with a pruritic eruption on the trunk. Multiple, small, discrete, red-brown papules characteristic of Grover disease are present.

Histopathology of Darier-type Grover disease. A focus of acantholytic dyskeratosis is present in the epidermis with slight epithelial hyperplasia and hyperkeratosis, a sign of rubbing as a consequence of the pruritic nature of the disease (hematoxylin and eosin, original magnification X40).

Higher magnification reveals the acantholytic dyskeratosis to better advantage. Note the corps ronds and grains (hematoxylin and eosin, original magnification X400).