Review
Generalized eruptive keratoacanthomas of Grzybowski C. Lane Anzalone1, BS, and Philip R. Cohen2–5, MD
1 Medical School, 2Department of Dermatology, University of Texas Medical School at Houston, 3University of Texas Health Science Center, University of Texas, 4 Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX, USA, and 5Division of Dermatology, University of California San Diego, San Diego, CA, USA
Correspondence Philip R. Cohen, MD 10991 Twinleaf Court San Diego, CA 92131 USA E-mail: [email protected] Conflicts of interest: None.
Abstract Background The initial patient with generalized eruptive keratoacanthomas was described by Grzybowski in 1950. The condition presents as hundreds to thousands of small (1– 5 mm), flesh-colored to erythematous papules. Objective To review the clinical characteristics and treatments of generalized eruptive keratoacanthomas of Grzybowski. Materials and methods We retrospectively reviewed the medical literature using PubMed, searching the terms “eruptive,” “generalized,” “Grzybowski,” “keratoacanthoma,” and “multiple.” Patient reports and previous reviews of the subject were critically assessed and the salient features presented to the best of our knowledge. Results Generalized eruptive keratoacanthomas of Grzybowski typically present in the fifth to seventh decades of life and display an equal preponderance for both men and women. The keratoacanthomas are pruritic and predominately appear in sun-exposed regions, such as the face (in which they often demonstrate the sign of Zorro) and the upper trunk; the tumors also show a predilection for intertriginous areas. Topical, intralesional, and systemic treatment modalities have been used; oral retinoids are considered the preferred method of treatment. Conclusion Generalized eruptive keratoacanthomas of Grzybowski is a rare form of keratoacanthoma and is considered a serious condition because the eruptions are diffuse, persistent, and recurrent. Constant pruritus, ectropion, visceral neoplasms, and unsatisfactory response to treatment are ominous prognostic factors. Successful management of this condition has been observed in patients treated with systemic retinoids, such as acitretin.
Introduction Generalized eruptive keratoacanthomas of Grzybowski is an uncommon variant of keratoacanthoma, presenting with hundreds of small, umbilicated keratinous papules.1 Approximately 30 additional patients have been reported with this rare condition.2,3 Middle-aged adults in the fifth to seventh decades of life are typically affected with equal prevalence for both men and women.4 Commonly associated findings include severe pruritus, ectropion, and a masked facies of tumors; the latter finding is referred to as the sign of Zorro. The course of the disease is chronic and often demonstrates a poor response to therapy. Currently, the preferred method of treatment is oral retinoids; several alternative treatments exist for patients refractory to this regimen.5
generalized epithelial tumors of the skin, which were assumed to be a fairly exact replica of Ferguson-Smith multiple primary self-healing squamous epithelioma of the skin, differing only by the far greater number of tumors and the involvement of the oral mucosa.6 The cutaneous tumors, previously known as molluscum sebaceum, are now more appropriately termed keratoacanthoma.2 The keratoacanthoma is a relatively common tumor, characterized by rapid growth and viewed by many investigators to represent a low-grade squamous cell carcinoma.7 The significant difference between idiopathic keratoacanthomas and those associated with Grzybowski tumors is the very large number of small lesions in the latter condition; therefore the term generalized eruptive keratoacanthomas of Grzybowski is commonly used in reference to this variant.1–20
History Generalized eruptive keratoacanthomas were first described by Grzybowski in 1950.6 The condition was initially reported in a 57-year-old man who had peculiar ª 2013 The International Society of Dermatology
Epidemiology The onset of keratoacanthomas of Grzybowski typically occurs in patients between the fifth and seventh decades International Journal of Dermatology 2014, 53, 131–136
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of life.4 The condition displays an equal sex distribution.4 There is no pattern of inheritance.4 Approximately 30 patients have been recorded in the literature. The condition has been described in one black American and two Japanese patients; the remainder of patients with keratoacanthomas of Grzybowski are white individuals.1,2 Clinical Characteristics The condition manifests as a sudden eruption, and subsequent progressive onset, of hundreds to thousands of small (1–5 mm) skin-colored to erythematous papules, which have a central umbilication containing a horny, keratotic plug.1 Lesions often show koebnerization and predominate in sun-exposed areas, including the face (Fig. 1) and upper trunk; tumors also have a predilection for intertriginous regions.1,2,8 Keratoacanthomas may appear on any body site, including the head (such as forehead and scalp [Fig. 2] and ears), neck, chin, abdomen, arms, and legs. Extensive facial involvement may produce a sign of Zorro: a masked facies of lesions in the periorbital region (Fig. 1). Zorro is a fictional character created in 1919 by author Johnston McCulley.21 Zorro is the secret identity of Don Diego de la Vega, a nobleman of Spanish descent.21 Diegos alias Zorro plays a role as an outlaw and defender of the people; his appearance is characterized by a black mask covering the periorbital region in an effort to conceal his identity.21 Generalized eruptive keratoacanthomas of Grzybowski typically present in the aforementioned distribution as characteristic lesions of the upper and lower eyelids as well as the surrounding orbital regions. Ectropion has also been reported.8 Other sites, less often affected by the new appearance of keratoacanthom-
(a)
(b)
Figure 2 Distant view of the scalp shows the generalized eruptions of tumors covering these areas in a 68-year-old man. Histologic examination of multiple tumors all demonstrated keratoacanthomas
as, include the buccal mucosa (Fig. 3) and larynx.1 Cutaneous pruritus is also a common symptom.2 Differential Diagnosis Generalized eruptive keratoacanthomas of Grzybowski is a rare disorder for which several similar appearing conditions might be considered in the differential diagnosis. Smaller lesions exhibit less crater formation and might be mistaken for pseudoepitheliomatous hyperplasia or welldifferentiated squamous cell carcinoma.8 Multiple keratoacanthomas of the Ferguson-Smith variety closely mimic lesions of the Grzybowski type.2 Differentiating characteristics of Ferguson-Smith include autosomal dominant inheritance, onset during adolescence, and fewer lesions that typically leave depressed scars.1,2 Familial keratoacanthomas of Witten and Zak demonstrate both large and military-type lesions.9
(c)
Figure 1 Generalized eruptive keratoacanthomas of Gryzbowski in a 68-year-old man who presented with generalized eruption of pruritic lesions located on his face, scalp, ears, lip, buccal mucosa, chest, abdomen, arms, and leg. Six months earlier, he had completed treatment for metastatic colon cancer to his liver. Views of his distant (a), right (b), and left (c) periorbital view depict a characteristic masked facies of keratoacanthomas, showing hundreds of small (1–5 mm) flesh-colored to erythematous papules, which have a central umbilication containing a horny, keratotic plug. The distribution of keratoacanthomas is referred to as the sign of Zorro, as the lesions mimic the mask of the fictional character Zorro International Journal of Dermatology 2014, 53, 131–136
ª 2013 The International Society of Dermatology
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individuals had latent syphilis: a 47-year-old black woman and a 74-year-old woman.23,24 An 84-year-old female patient had hemolytic anemia.25 The association of these conditions in patients with generalized eruptive keratoacanthomas of Grzybowski appears to be coincidental.11 Pathogenesis
Figure 3 Lower extremity of a 68-year-old man with generalized eruptive keratoacanthomas of Grzybowski
Muir–Torre syndrome, a condition that can include the presence of multiple persistent keratoacanthomas, may also be considered in the differential diagnosis of keratoacanthomas of Grzybowski.2 Muir–Torre syndrome is an autosomal dominant genodermatosis of malignant potential characterized by the development of sebaceous neoplasms associated with a visceral malignancy.20 Some of the keratoacanthomas in patients with Muir–Torre syndrome have sebaceous differentiation when tumors are evaluated microscopically.20 Histopathology The pathologic changes observed in solitary and generalized eruptive keratoacanthomas are similar. Characteristics include a well-demarcated border with a central keratin-filled crater.4 There is acanthosis, and the epithelial cells are eosinophilic and hyalinated.4 Larger lesions exhibit these typical features, while smaller lesions may show less crater formation.11 The epithelium extends into underlying dermis; keratinized horn pearls and neutrophilic microabscesses may also be observed.4 In some regions, the squamous proliferation is associated with an underlying dense lichenoid infiltrate.14 Associated Conditions Several conditions have been associated with generalized eruptive keratoacanthomas of Grzybowski. Three patients have had an associated internal malignancy: a 42-year-old female patient with metastasizing carcinoma of the fallopian tube and stem cell leukemia; 53-year-old male patient with Gilbert’s syndrome; and our patient, a 68-year-old man with metastatic colon cancer.14,22 Two ª 2013 The International Society of Dermatology
The etiology of eruptive keratoacanthomas is unknown. A viral pathogenesis was proposed by Grzybowski due to the large number of tumors and their tendency to koebnerize.1 Human papillomavirus has been detected in many solitary keratoacanthomas, as well as in tumors of the Witten and Zak variant.10 Although early studies reported an association with human papillomavirus and the Grzybowski variant, further observation suggests that these keratoacanthomas are probably human papillomavirus independent.10 The preference for sun-exposed areas and reported initiation and exacerbation of tumor development following sun exposure suggest a role for ultraviolet radiation as a causative factor for keratoacanthomas of Grzybowski.8 Studies have yet to reproduce lesions with ultraviolet irradiation.1 Interleukin-2 deficiency has also been implicated as a factor in the development of the Grzybowski variant.12 The use of H2 receptor antagonist drugs (known to increase interleukin-2 production) causes a regression of lesions, further supporting this relationship.13 Chemicals such as oils, tars and turf paper, immunosuppression, and pre-existing cutaneous conditions such as eczematous dermatitis, psoriasis, seborrheic dermatitis, and trauma are also proposed as causative factors.1,11 Treatment Treatment of generalized eruptive keratoacanthomas of Grzybowski has not been uniformly satisfactory. The disease is frequently progressive and chronic, with significant morbidity. However, several treatment modalities have been attempted in the management of this condition. Surgical excision or physical destruction such as cryotherapy, curettage, or radiotherapy is impractical due to the number of lesions.1 Topical therapies have included corticosteroids, 5-fluorouracil, podophyllin, and tretinoin.11 Intralesional regimens of bleomycin, 5-fluorouracil, methotrexate, or triamcinolone have each produced variable results.11 Systemic therapy is the preferred treatment regimen for generalized eruptive keratoacanthomas of Grzybowski, although results are still substandard. These treatments include aminopterin, cyclophosphamide, c-interferon, a-interferon, methotrexate, and oral retinoids.1 Only one International Journal of Dermatology 2014, 53, 131–136
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patient, a 42-year-old woman, has demonstrated spontaneous resolution.14 Oral retinoids currently appear to be the preferred treatment option for the management of eruptive keratoacanthomas. The antikeratinizing effects of retinoids are well established, and a low toxicity profile, in comparison with other treatment methods, proves advantageous when these drugs are used as a systemic treatment modality. Oral etretinate may provide a regression of lesions; however, access to this medication may be limited. In addition, etretinate did not prove effective against smaller, generalized eruptive keratoacanthomas of Grzybowski in a 63-year-old woman; the lesions recurred after discontinuation of the drug.15 A 68-year-old man was treated with isotretinoin over the course of four months, and complete resolution of lesions was observed.5 Acitretin has also been used successfully; our 68-year-old man with generalized eruptive keratoacanthomas of Grzybowski was treated with an initial dose of 10 mg/day. After increasing the dose to 40 mg/day, nearly all of his lesions cleared after two months (Fig. 4). After acitretin was discontinued, occasional keratoacanthomas would periodically appear and spontaneously resolve. Methotrexate has displayed some success in treating generalized eruptive keratoacanthomas of Grzybowski.16,17 If both oral retinoids and methotrexate prove ineffective, cyclophosphamide provides an alternative
Figure 4 The 68-year-old man with generalized eruptive keratoacanthomas of Grzybowski was treated with acitretin (Soriatane). The initial dose was 10 mg daily; the dosage was progressively increased to 40 mg/day for the next 2 months. There was complete regression of almost all of his keratoacanthomas and diminished pruritus in lesional areas. The dosage was decreased incrementally over the next 3 months before being discontinued. The patient would periodically present with additional randomly located keratoacanthomas, which would resolve spontaneously over the following 3–6 months. He continues to have periodic follow-up visits for examination of his skin. The periorbital views show resolution of the sign of Zorro International Journal of Dermatology 2014, 53, 131–136
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means of treatment. Remission has been reported in several patients.18,19 Yet, due to the significant potential side effects of cyclophosphamide, including a dose-related risk of leukemic disorders and hemorrhagic cystitis, investigators recommend that use of this drug should be employed only when other treatment modalities have been exhausted.18 Conclusions Generalized eruptive keratoacanthomas of Grzybowski is a rare variant of keratoacanthoma, presenting with hundreds of small, umbilicated keratinous papules. The condition typically affects adults in the fifth to seventh decades of life, with equal preponderance for men and women. Severe pruritus and ectropion often occur. A masked facies of keratoacanthomas, referred to as the sign of Zorro, is also a commonly associated finding. Many investigators consider keratoacanthoma a form of squamous cell carcinoma. There are multiple treatment options available; retinoids, and particularly acitretin, are the current treatment of choice. Methotrexate and cyclophosphamide may be considered in patients who are refractory to retinoid therapy. Questions (see answers on page 136) 1 What is the significant difference between generalized eruptive keratoacanthomas of Gryzbowski and idiopathic keratoacanthomas? a Association with human papillomavirus b Autosomal dominant inheritance c Increased risk of ovarian cancer d Very large number of small lesions 2 Where are lesions of generalized eruptive keratoacanthomas of Grzybowski typically located? a Groin region b Mucosal surfaces c Plantar surfaces d Sun-exposed areas (face and upper trunk) and intertriginous regions 3 What is the average age of onset of generalized eruptive keratoacanthomas of Grzybowski? a First to third decades of life b Third to fifth decades of life c Fifth to seventh decades of life d No average age of onset 4 What is the first-line therapy for treatment of generalized eruptive keratoacanthomas of Grzybowski? a 5-fluorouracil 5% cream b Imiquimod 5% cream c Intralesional methotrexate d Oral retinoids ª 2013 The International Society of Dermatology
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5 If treatment of generalized eruptive keratoacanthomas of Grzybowski with oral retinoids is unsuccessful, what other therapies have been demonstrated to be effective in some patients? a Cyclophosphamide and methotrexate b Doxorubicin and sorafenib c Infliximab and suramin d Surgical excision and cryotherapy 6 Approximately how many cases of generalized eruptive keratoacanthomas of Grzybowski have been reported in the literature? a 3 b 30 c 300 d 3000 7 What clinical features are commonly associated with generalized eruptive keratoacanthomas of Grzybowski? a Acneiform lesions b Alopecia c Ectropion d Stomatitis 8 What is the clinical presentation of generalized eruptive keratoacanthomas of Grzybowski? a Blisters and superficial ulcers in sun-exposed areas. b Diffusely disseminated, erythematous-based pustules. c Hundreds of small (1–5 mm), flesh-colored to erythematous umbilicated papules with keratin-filled central craters. d Widely distributed, erythematous, thick plaques skin with silver-white scales. 9 What other conditions may be considered in the differential diagnosis of generalized eruptive keratoacanthomas of Grzybowski? a Ehler–Danlos syndrome b Marfan syndrome c Muir–Torre syndrome d Rothmund–Thompson syndrome 10 What is the moniker for the characteristic masked facies of keratoacanthomas that present in patients with generalized eruptive keratoacanthomas of Grzybowski? a Sign of Badger b Sign of Bandit c Sign of Lemur d Sign of Zorro References 1 Consigli JE, Gonzalez ME, Morsino R, et al. Generalized eruptive keratoacanthoma (Grzybowski variant). Br J Dermatol 2000; 142: 800–803. ª 2013 The International Society of Dermatology
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2 Schwartz RA, Blaszczyk M, Jablonska S. Generalized eruptive keratoacanthoma of Grzybowski: follow-up of the original description and 50-year retrospect. Dermatology 2002; 205: 345. 3 Lu PD, Lee A, Cassetty CT, et al. Generalized eruptive keratoacanthomas of Grzybowski. Dermatol Online J 2009; 15: 6. 4 Chu DH, Hale EK, Robins P. Generalized eruptive keratoacanthomas. Dermatol Online J 2003; 9: 36. 5 Vandergriff T, Nakamura K, High WA. Generalized eruptive keratoacanthomas of Grzybowski treated with isoretinoin. J Drugs Dermatol 2008; 7: 1069– 1071. 6 Grzybowski M. A case of peculiar generalized epithelial tumours of the skin. Br J Dermatol Syph 1950; 62: 310– 313. 7 Schwartz RA. The keratoacanthoma: a review. J Surg Oncol 1979; 12: 305–317. 8 Kavanagh GM, Marshman G, Hanna MM. A case Grzybowskis generalized eruptive keratoacanthoma. Australas J Dermatol 1995; 36: 83–85. 9 Karaa A, Khachemoune A. Keratoacanthoma: a tumor in search of a classification. Int J Dermatol 2007; 46: 671– 678. 10 Haas N, Schadendorf D, Henz BM, et al. Nine-year follow-up of a case of Grzybowski type multiple keratoacanthomas and failure to demonstrate human papillomavirus. Br J Dermatol 2002; 147: 793–796. 11 Jaber PW, Cooper PH, Greer KE. Generalized eruptive keratoacanthoma of Grzybowski. J Am Acad Dermatol 1993; 29: 299–304. 12 Blitstein-Willinger E, Haas N, Nurnberger F, et al. Immunological findings during treatment of multiple keratoacanthoma with etretinate. Br J Dermatol 1986; 114: 109–116. 13 Claudy A, Thivolet J. Multiple keratoacanthoma: association with deficient cell mediated immunity. Br J Dermatol 1975; 93: 593–595. 14 Weber G, Stetter H, Pleiss G, et al. Syntropy of eruptive keratoacanthomas, carcinoma of the fallopian tube and stem-cell leukemia. Arch Klin Exp Dermatol 1970; 238: 107–119. 15 Street ML, White JW Jr, Gibson LE. Multiple keratoacanthomas treated with oral retinoids. J Am Acad Dermatol 1990; 23: 862–866. 16 Tarnowski WM. Multiple keratoacanthomata: response of a case to systemic chemotherapy. Arch Dermatol 1966; 94: 74–80. 17 Kestel JL Jr, Blair SD. Keratoacanthoma treated with methotrexate. Arch Dermatol 1973; 108: 723–724. 18 Grine RC, Hendrix JD, Greer KE. Generalized eruptive keratoacanthoma of Grzybowski: response to cyclophosphamide. J Am Acad Dermatol 1997; 36: 786–787. 19 Oakley A, Ng S. Grzybowskis generalized eruptive keratoacanthoma: remission with cyclophosphamide. Australas J Dermatol 2005; 46: 118–123.
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20 Cohen PR, Kohn SR, Davis DA, et al. Muir-Torre syndrome. Clin Dermatol 1995; 13: 79–89. 21 Allende I. Zorro: A Novel. New York: Harper, 2005. 22 Laaff H, Mittelviefhaus H, Wokalek H, et al. Grzybowski type eruptive keratoacanthomas and ectropion. A therapeutic problem. Hautarzt 1992; 43: 143–147. 23 Rossman RR, Freedman RG, Knox J. Multiple keratoacanthomas. A case study of the eruptive type with observations on pathogenesis. Arch Dermatol 1981; 117: 788–790. 24 Sterry W, Steigleder GK, Pullmann H, et al. Eruptive keratoacanthoma. Hautarzt 1981; 32: 119–125. 25 Cabotin PP, Vignon-Pennamen MD, Miclea JM, et al. Multiple eruptive keratoacanthoma disclosing lymphoma. Ann Dermatol Venereol 1989; 116: 860–862.
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Answers to questions on page 134 1 d 2 d 3 c 4 d 5 a 6 b 7 c 8 c 9 c 10 d
ª 2013 The International Society of Dermatology
Generalized eruptive keratoacanthomas of Grzybowski C. Lane Anzalone1, BS, and Philip R. Cohen2–5, MD
1 Medical School, 2Department of Dermatology, University of Texas Medical School at Houston, 3University of Texas Health Science Center, University of Texas, 4 Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX, USA, and 5Division of Dermatology, University of California San Diego, San Diego, CA, USA
Correspondence Philip R. Cohen, MD 10991 Twinleaf Court San Diego, CA 92131 USA E-mail: [email protected] Conflicts of interest: None.
Abstract Background The initial patient with generalized eruptive keratoacanthomas was described by Grzybowski in 1950. The condition presents as hundreds to thousands of small (1– 5 mm), flesh-colored to erythematous papules. Objective To review the clinical characteristics and treatments of generalized eruptive keratoacanthomas of Grzybowski. Materials and methods We retrospectively reviewed the medical literature using PubMed, searching the terms “eruptive,” “generalized,” “Grzybowski,” “keratoacanthoma,” and “multiple.” Patient reports and previous reviews of the subject were critically assessed and the salient features presented to the best of our knowledge. Results Generalized eruptive keratoacanthomas of Grzybowski typically present in the fifth to seventh decades of life and display an equal preponderance for both men and women. The keratoacanthomas are pruritic and predominately appear in sun-exposed regions, such as the face (in which they often demonstrate the sign of Zorro) and the upper trunk; the tumors also show a predilection for intertriginous areas. Topical, intralesional, and systemic treatment modalities have been used; oral retinoids are considered the preferred method of treatment. Conclusion Generalized eruptive keratoacanthomas of Grzybowski is a rare form of keratoacanthoma and is considered a serious condition because the eruptions are diffuse, persistent, and recurrent. Constant pruritus, ectropion, visceral neoplasms, and unsatisfactory response to treatment are ominous prognostic factors. Successful management of this condition has been observed in patients treated with systemic retinoids, such as acitretin.
Introduction Generalized eruptive keratoacanthomas of Grzybowski is an uncommon variant of keratoacanthoma, presenting with hundreds of small, umbilicated keratinous papules.1 Approximately 30 additional patients have been reported with this rare condition.2,3 Middle-aged adults in the fifth to seventh decades of life are typically affected with equal prevalence for both men and women.4 Commonly associated findings include severe pruritus, ectropion, and a masked facies of tumors; the latter finding is referred to as the sign of Zorro. The course of the disease is chronic and often demonstrates a poor response to therapy. Currently, the preferred method of treatment is oral retinoids; several alternative treatments exist for patients refractory to this regimen.5
generalized epithelial tumors of the skin, which were assumed to be a fairly exact replica of Ferguson-Smith multiple primary self-healing squamous epithelioma of the skin, differing only by the far greater number of tumors and the involvement of the oral mucosa.6 The cutaneous tumors, previously known as molluscum sebaceum, are now more appropriately termed keratoacanthoma.2 The keratoacanthoma is a relatively common tumor, characterized by rapid growth and viewed by many investigators to represent a low-grade squamous cell carcinoma.7 The significant difference between idiopathic keratoacanthomas and those associated with Grzybowski tumors is the very large number of small lesions in the latter condition; therefore the term generalized eruptive keratoacanthomas of Grzybowski is commonly used in reference to this variant.1–20
History Generalized eruptive keratoacanthomas were first described by Grzybowski in 1950.6 The condition was initially reported in a 57-year-old man who had peculiar ª 2013 The International Society of Dermatology
Epidemiology The onset of keratoacanthomas of Grzybowski typically occurs in patients between the fifth and seventh decades International Journal of Dermatology 2014, 53, 131–136
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of life.4 The condition displays an equal sex distribution.4 There is no pattern of inheritance.4 Approximately 30 patients have been recorded in the literature. The condition has been described in one black American and two Japanese patients; the remainder of patients with keratoacanthomas of Grzybowski are white individuals.1,2 Clinical Characteristics The condition manifests as a sudden eruption, and subsequent progressive onset, of hundreds to thousands of small (1–5 mm) skin-colored to erythematous papules, which have a central umbilication containing a horny, keratotic plug.1 Lesions often show koebnerization and predominate in sun-exposed areas, including the face (Fig. 1) and upper trunk; tumors also have a predilection for intertriginous regions.1,2,8 Keratoacanthomas may appear on any body site, including the head (such as forehead and scalp [Fig. 2] and ears), neck, chin, abdomen, arms, and legs. Extensive facial involvement may produce a sign of Zorro: a masked facies of lesions in the periorbital region (Fig. 1). Zorro is a fictional character created in 1919 by author Johnston McCulley.21 Zorro is the secret identity of Don Diego de la Vega, a nobleman of Spanish descent.21 Diegos alias Zorro plays a role as an outlaw and defender of the people; his appearance is characterized by a black mask covering the periorbital region in an effort to conceal his identity.21 Generalized eruptive keratoacanthomas of Grzybowski typically present in the aforementioned distribution as characteristic lesions of the upper and lower eyelids as well as the surrounding orbital regions. Ectropion has also been reported.8 Other sites, less often affected by the new appearance of keratoacanthom-
(a)
(b)
Figure 2 Distant view of the scalp shows the generalized eruptions of tumors covering these areas in a 68-year-old man. Histologic examination of multiple tumors all demonstrated keratoacanthomas
as, include the buccal mucosa (Fig. 3) and larynx.1 Cutaneous pruritus is also a common symptom.2 Differential Diagnosis Generalized eruptive keratoacanthomas of Grzybowski is a rare disorder for which several similar appearing conditions might be considered in the differential diagnosis. Smaller lesions exhibit less crater formation and might be mistaken for pseudoepitheliomatous hyperplasia or welldifferentiated squamous cell carcinoma.8 Multiple keratoacanthomas of the Ferguson-Smith variety closely mimic lesions of the Grzybowski type.2 Differentiating characteristics of Ferguson-Smith include autosomal dominant inheritance, onset during adolescence, and fewer lesions that typically leave depressed scars.1,2 Familial keratoacanthomas of Witten and Zak demonstrate both large and military-type lesions.9
(c)
Figure 1 Generalized eruptive keratoacanthomas of Gryzbowski in a 68-year-old man who presented with generalized eruption of pruritic lesions located on his face, scalp, ears, lip, buccal mucosa, chest, abdomen, arms, and leg. Six months earlier, he had completed treatment for metastatic colon cancer to his liver. Views of his distant (a), right (b), and left (c) periorbital view depict a characteristic masked facies of keratoacanthomas, showing hundreds of small (1–5 mm) flesh-colored to erythematous papules, which have a central umbilication containing a horny, keratotic plug. The distribution of keratoacanthomas is referred to as the sign of Zorro, as the lesions mimic the mask of the fictional character Zorro International Journal of Dermatology 2014, 53, 131–136
ª 2013 The International Society of Dermatology
Anzalone and Cohen
Generalized eruptive keratoacanthomas of Grzybowski
Review
individuals had latent syphilis: a 47-year-old black woman and a 74-year-old woman.23,24 An 84-year-old female patient had hemolytic anemia.25 The association of these conditions in patients with generalized eruptive keratoacanthomas of Grzybowski appears to be coincidental.11 Pathogenesis
Figure 3 Lower extremity of a 68-year-old man with generalized eruptive keratoacanthomas of Grzybowski
Muir–Torre syndrome, a condition that can include the presence of multiple persistent keratoacanthomas, may also be considered in the differential diagnosis of keratoacanthomas of Grzybowski.2 Muir–Torre syndrome is an autosomal dominant genodermatosis of malignant potential characterized by the development of sebaceous neoplasms associated with a visceral malignancy.20 Some of the keratoacanthomas in patients with Muir–Torre syndrome have sebaceous differentiation when tumors are evaluated microscopically.20 Histopathology The pathologic changes observed in solitary and generalized eruptive keratoacanthomas are similar. Characteristics include a well-demarcated border with a central keratin-filled crater.4 There is acanthosis, and the epithelial cells are eosinophilic and hyalinated.4 Larger lesions exhibit these typical features, while smaller lesions may show less crater formation.11 The epithelium extends into underlying dermis; keratinized horn pearls and neutrophilic microabscesses may also be observed.4 In some regions, the squamous proliferation is associated with an underlying dense lichenoid infiltrate.14 Associated Conditions Several conditions have been associated with generalized eruptive keratoacanthomas of Grzybowski. Three patients have had an associated internal malignancy: a 42-year-old female patient with metastasizing carcinoma of the fallopian tube and stem cell leukemia; 53-year-old male patient with Gilbert’s syndrome; and our patient, a 68-year-old man with metastatic colon cancer.14,22 Two ª 2013 The International Society of Dermatology
The etiology of eruptive keratoacanthomas is unknown. A viral pathogenesis was proposed by Grzybowski due to the large number of tumors and their tendency to koebnerize.1 Human papillomavirus has been detected in many solitary keratoacanthomas, as well as in tumors of the Witten and Zak variant.10 Although early studies reported an association with human papillomavirus and the Grzybowski variant, further observation suggests that these keratoacanthomas are probably human papillomavirus independent.10 The preference for sun-exposed areas and reported initiation and exacerbation of tumor development following sun exposure suggest a role for ultraviolet radiation as a causative factor for keratoacanthomas of Grzybowski.8 Studies have yet to reproduce lesions with ultraviolet irradiation.1 Interleukin-2 deficiency has also been implicated as a factor in the development of the Grzybowski variant.12 The use of H2 receptor antagonist drugs (known to increase interleukin-2 production) causes a regression of lesions, further supporting this relationship.13 Chemicals such as oils, tars and turf paper, immunosuppression, and pre-existing cutaneous conditions such as eczematous dermatitis, psoriasis, seborrheic dermatitis, and trauma are also proposed as causative factors.1,11 Treatment Treatment of generalized eruptive keratoacanthomas of Grzybowski has not been uniformly satisfactory. The disease is frequently progressive and chronic, with significant morbidity. However, several treatment modalities have been attempted in the management of this condition. Surgical excision or physical destruction such as cryotherapy, curettage, or radiotherapy is impractical due to the number of lesions.1 Topical therapies have included corticosteroids, 5-fluorouracil, podophyllin, and tretinoin.11 Intralesional regimens of bleomycin, 5-fluorouracil, methotrexate, or triamcinolone have each produced variable results.11 Systemic therapy is the preferred treatment regimen for generalized eruptive keratoacanthomas of Grzybowski, although results are still substandard. These treatments include aminopterin, cyclophosphamide, c-interferon, a-interferon, methotrexate, and oral retinoids.1 Only one International Journal of Dermatology 2014, 53, 131–136
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patient, a 42-year-old woman, has demonstrated spontaneous resolution.14 Oral retinoids currently appear to be the preferred treatment option for the management of eruptive keratoacanthomas. The antikeratinizing effects of retinoids are well established, and a low toxicity profile, in comparison with other treatment methods, proves advantageous when these drugs are used as a systemic treatment modality. Oral etretinate may provide a regression of lesions; however, access to this medication may be limited. In addition, etretinate did not prove effective against smaller, generalized eruptive keratoacanthomas of Grzybowski in a 63-year-old woman; the lesions recurred after discontinuation of the drug.15 A 68-year-old man was treated with isotretinoin over the course of four months, and complete resolution of lesions was observed.5 Acitretin has also been used successfully; our 68-year-old man with generalized eruptive keratoacanthomas of Grzybowski was treated with an initial dose of 10 mg/day. After increasing the dose to 40 mg/day, nearly all of his lesions cleared after two months (Fig. 4). After acitretin was discontinued, occasional keratoacanthomas would periodically appear and spontaneously resolve. Methotrexate has displayed some success in treating generalized eruptive keratoacanthomas of Grzybowski.16,17 If both oral retinoids and methotrexate prove ineffective, cyclophosphamide provides an alternative
Figure 4 The 68-year-old man with generalized eruptive keratoacanthomas of Grzybowski was treated with acitretin (Soriatane). The initial dose was 10 mg daily; the dosage was progressively increased to 40 mg/day for the next 2 months. There was complete regression of almost all of his keratoacanthomas and diminished pruritus in lesional areas. The dosage was decreased incrementally over the next 3 months before being discontinued. The patient would periodically present with additional randomly located keratoacanthomas, which would resolve spontaneously over the following 3–6 months. He continues to have periodic follow-up visits for examination of his skin. The periorbital views show resolution of the sign of Zorro International Journal of Dermatology 2014, 53, 131–136
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means of treatment. Remission has been reported in several patients.18,19 Yet, due to the significant potential side effects of cyclophosphamide, including a dose-related risk of leukemic disorders and hemorrhagic cystitis, investigators recommend that use of this drug should be employed only when other treatment modalities have been exhausted.18 Conclusions Generalized eruptive keratoacanthomas of Grzybowski is a rare variant of keratoacanthoma, presenting with hundreds of small, umbilicated keratinous papules. The condition typically affects adults in the fifth to seventh decades of life, with equal preponderance for men and women. Severe pruritus and ectropion often occur. A masked facies of keratoacanthomas, referred to as the sign of Zorro, is also a commonly associated finding. Many investigators consider keratoacanthoma a form of squamous cell carcinoma. There are multiple treatment options available; retinoids, and particularly acitretin, are the current treatment of choice. Methotrexate and cyclophosphamide may be considered in patients who are refractory to retinoid therapy. Questions (see answers on page 136) 1 What is the significant difference between generalized eruptive keratoacanthomas of Gryzbowski and idiopathic keratoacanthomas? a Association with human papillomavirus b Autosomal dominant inheritance c Increased risk of ovarian cancer d Very large number of small lesions 2 Where are lesions of generalized eruptive keratoacanthomas of Grzybowski typically located? a Groin region b Mucosal surfaces c Plantar surfaces d Sun-exposed areas (face and upper trunk) and intertriginous regions 3 What is the average age of onset of generalized eruptive keratoacanthomas of Grzybowski? a First to third decades of life b Third to fifth decades of life c Fifth to seventh decades of life d No average age of onset 4 What is the first-line therapy for treatment of generalized eruptive keratoacanthomas of Grzybowski? a 5-fluorouracil 5% cream b Imiquimod 5% cream c Intralesional methotrexate d Oral retinoids ª 2013 The International Society of Dermatology
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5 If treatment of generalized eruptive keratoacanthomas of Grzybowski with oral retinoids is unsuccessful, what other therapies have been demonstrated to be effective in some patients? a Cyclophosphamide and methotrexate b Doxorubicin and sorafenib c Infliximab and suramin d Surgical excision and cryotherapy 6 Approximately how many cases of generalized eruptive keratoacanthomas of Grzybowski have been reported in the literature? a 3 b 30 c 300 d 3000 7 What clinical features are commonly associated with generalized eruptive keratoacanthomas of Grzybowski? a Acneiform lesions b Alopecia c Ectropion d Stomatitis 8 What is the clinical presentation of generalized eruptive keratoacanthomas of Grzybowski? a Blisters and superficial ulcers in sun-exposed areas. b Diffusely disseminated, erythematous-based pustules. c Hundreds of small (1–5 mm), flesh-colored to erythematous umbilicated papules with keratin-filled central craters. d Widely distributed, erythematous, thick plaques skin with silver-white scales. 9 What other conditions may be considered in the differential diagnosis of generalized eruptive keratoacanthomas of Grzybowski? a Ehler–Danlos syndrome b Marfan syndrome c Muir–Torre syndrome d Rothmund–Thompson syndrome 10 What is the moniker for the characteristic masked facies of keratoacanthomas that present in patients with generalized eruptive keratoacanthomas of Grzybowski? a Sign of Badger b Sign of Bandit c Sign of Lemur d Sign of Zorro References 1 Consigli JE, Gonzalez ME, Morsino R, et al. Generalized eruptive keratoacanthoma (Grzybowski variant). Br J Dermatol 2000; 142: 800–803. ª 2013 The International Society of Dermatology
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2 Schwartz RA, Blaszczyk M, Jablonska S. Generalized eruptive keratoacanthoma of Grzybowski: follow-up of the original description and 50-year retrospect. Dermatology 2002; 205: 345. 3 Lu PD, Lee A, Cassetty CT, et al. Generalized eruptive keratoacanthomas of Grzybowski. Dermatol Online J 2009; 15: 6. 4 Chu DH, Hale EK, Robins P. Generalized eruptive keratoacanthomas. Dermatol Online J 2003; 9: 36. 5 Vandergriff T, Nakamura K, High WA. Generalized eruptive keratoacanthomas of Grzybowski treated with isoretinoin. J Drugs Dermatol 2008; 7: 1069– 1071. 6 Grzybowski M. A case of peculiar generalized epithelial tumours of the skin. Br J Dermatol Syph 1950; 62: 310– 313. 7 Schwartz RA. The keratoacanthoma: a review. J Surg Oncol 1979; 12: 305–317. 8 Kavanagh GM, Marshman G, Hanna MM. A case Grzybowskis generalized eruptive keratoacanthoma. Australas J Dermatol 1995; 36: 83–85. 9 Karaa A, Khachemoune A. Keratoacanthoma: a tumor in search of a classification. Int J Dermatol 2007; 46: 671– 678. 10 Haas N, Schadendorf D, Henz BM, et al. Nine-year follow-up of a case of Grzybowski type multiple keratoacanthomas and failure to demonstrate human papillomavirus. Br J Dermatol 2002; 147: 793–796. 11 Jaber PW, Cooper PH, Greer KE. Generalized eruptive keratoacanthoma of Grzybowski. J Am Acad Dermatol 1993; 29: 299–304. 12 Blitstein-Willinger E, Haas N, Nurnberger F, et al. Immunological findings during treatment of multiple keratoacanthoma with etretinate. Br J Dermatol 1986; 114: 109–116. 13 Claudy A, Thivolet J. Multiple keratoacanthoma: association with deficient cell mediated immunity. Br J Dermatol 1975; 93: 593–595. 14 Weber G, Stetter H, Pleiss G, et al. Syntropy of eruptive keratoacanthomas, carcinoma of the fallopian tube and stem-cell leukemia. Arch Klin Exp Dermatol 1970; 238: 107–119. 15 Street ML, White JW Jr, Gibson LE. Multiple keratoacanthomas treated with oral retinoids. J Am Acad Dermatol 1990; 23: 862–866. 16 Tarnowski WM. Multiple keratoacanthomata: response of a case to systemic chemotherapy. Arch Dermatol 1966; 94: 74–80. 17 Kestel JL Jr, Blair SD. Keratoacanthoma treated with methotrexate. Arch Dermatol 1973; 108: 723–724. 18 Grine RC, Hendrix JD, Greer KE. Generalized eruptive keratoacanthoma of Grzybowski: response to cyclophosphamide. J Am Acad Dermatol 1997; 36: 786–787. 19 Oakley A, Ng S. Grzybowskis generalized eruptive keratoacanthoma: remission with cyclophosphamide. Australas J Dermatol 2005; 46: 118–123.
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20 Cohen PR, Kohn SR, Davis DA, et al. Muir-Torre syndrome. Clin Dermatol 1995; 13: 79–89. 21 Allende I. Zorro: A Novel. New York: Harper, 2005. 22 Laaff H, Mittelviefhaus H, Wokalek H, et al. Grzybowski type eruptive keratoacanthomas and ectropion. A therapeutic problem. Hautarzt 1992; 43: 143–147. 23 Rossman RR, Freedman RG, Knox J. Multiple keratoacanthomas. A case study of the eruptive type with observations on pathogenesis. Arch Dermatol 1981; 117: 788–790. 24 Sterry W, Steigleder GK, Pullmann H, et al. Eruptive keratoacanthoma. Hautarzt 1981; 32: 119–125. 25 Cabotin PP, Vignon-Pennamen MD, Miclea JM, et al. Multiple eruptive keratoacanthoma disclosing lymphoma. Ann Dermatol Venereol 1989; 116: 860–862.
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Answers to questions on page 134 1 d 2 d 3 c 4 d 5 a 6 b 7 c 8 c 9 c 10 d
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