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Generalized eruptive keratoacanthoma of Grzybowski
Journal of the American Academy of Dermatology Volume 29. Number 2, Part 2
7. Castanet J, Lacour PP, Ortonne JP. Formes cliniques atypiquesdes pemphigoides bulleuses.Ann Dermatol VenereoI1990;117:73-82. 8. AmatoDA,Si.lversteinJ, ZitelliJ.The prodrome of bullous pemphigoid. lnt J Dermatol 1988;27:560-3. 9. Asbrink E, Hovmark A. Clinical variations in bullous pemphigoid with respect to early symptoms. Acta Derm Venereol (Stockh) 1981;61 :417-21. 10. Person JP, Rogers RS, Perry HO . Localized pemphigoid. Br J Dermatol 1976;95:531-4. I I. Winkelmann RK, Su WPD. Pemphigoid vegetans. Arch Dermatol 1979;115:446-8. 12. Yung CW, Soltan i K, Lorincz AL. Pemphigoid nodularis. J AM ACAD DERMATOL 1981;5:54-60. 13. Honeyman JF, Honeyman AR, DelaParra MA, et al. Polymorphic pemphigoid. Arch Dermatol 1979;115:423-7. 14. Tappeiner G, Konrad K, Holubar K. Erythrodermic bullous pemphigoid. J AM A CAD DERMATOL 1982;6:489-92. 15. Pehamberger H, Gschnait F, Konrad K, et al. Bullous pemphigoid, herpes gestationis and linear dermatitis her-
Strohal et al.
petiformis: circulating anti-basement membrane zone antibodies; in vitro studies. J InvestDermatoI1980;74:105-8. 16. Rappersberger K, Tschachler E, Tani M , et al. Bullous disease in systemic lupus erythematosus. J AM ACAD DERMATOL 1989;21 :745-52. 17. Rappersberger K, Konrad K, Schenk P, et al. Epidermolysis bullosa acquisita. Eine klinisch-pathologische Studie, Hautarzt 1988;39:355-62. 18. Stanley JR , Koulu L, Th ivolet C. Distinction between epidermal antigens binding pemphigus vulgaris and pemphigus foliaceusautoantibodies. J Clin Invest 1984;74:313-20. 19. Katz M, Holubar K. Pemphigus herpetiformis. Hautarzt 1984;35:478-80. 20. Chorzelski TP, Jablonska S, BeutnerEH. Bullous pemphigoid:relationship ofimmunopathology to clinicalfindings. In: Beutner EH, Chorzelski TP, Kumar V, eds. Immunopathology of the skin. New York: John Wiley & Sons, 1987:337-55. 21. Thomsen K,Schmidt H. PUVA-induced bullous pemphigoid. Br J Dermatol 1976;95:568-9.
Generalized eruptive keratoacanthoma of Grzybowski W. J aber, MD,a Philip H. Cooper, MD,a, b and Kenneth E. Greer, MDa Charlottesville, Virginia
Peter
A patient with generalized e~uptive keratoacanthoma of Grzybowski is described. Our findings, along with those of the 21 reported cases from the world literature, are summarized.This rare variant of kerato acanthoma most commonly affects patients in the fifth to seventh decades oflife and appears as a generalized eruption of hundreds to thousands of follicular papules. These small papules often have a keratotic center and demonstrate the microscopic features of keratoac anthoma. Marked facial involvement is characteristic and can lead to masked facies with ectropion. Severe prur itus, mucosal lesions, and koebneri zation are features of th e disease. The course is chronic and the response to therapy is poor, although a few patients have improved with the use of systemic retinoids. (J AM ACAD DERMATOL 1993;29:299-304.) In 1950 Grzybowski' described eruptive keratoacanthoma. Since t hen 20 additional cases have been reported. 2- 18 We des cribe a patient with eruptive keratoacanthoma a nd review t he literature. CASE REPORT
A 35-year-old woman had a 5-month history of a progressive, pruritic eruption on most of her body. It began
From the Departments of Dermatology" and Pathology," University of Virginia School of Medicine. Reprints not available. Copyrigh l
(<)
1993 by the Amer ican Academy of Dermatology, Inc.
0\ 90-9622/93 $1.00 + .10
16/4/44996
on her head and quickly extended onto her neck and trunk . The lesions tended to appear in crops. The patient also had severe pruritus and painful int raoral lesions. She had morbid obesity and non-insulin-dependent diabetes mellitus . There was no family history of similar skin lesions and the patient had no known exposure to tars or other carcinogens. She had a history of moderate sun exposure but no documented precancerous or cancerous skin conditions. Clinic al examination revealed an obese, middle-aged woman with an extensive, generalized papular eruption. The eruption was most marked on her face and neck, where the lesions tended to coalesce and resulted in a masked facies with mild ectropion (Figs. I and 2). The papules extended throughout the scalp and were conflu-
299
Journal of the Amer ican Academy of Dermatology August 1993
300 Jaber et al.
Fig. 1. exposed Fig. 2. Fig. 3. Fig. 4.
Multiple keratoacanthomas on face and neck demonstrate accentuation in sunareas. Individual and coalescing lesions on lateral face and neck. Accentuation of papules in and about cars. Multiple papillomas on tongue.
ent about the ears, imparting the appearance of large wartlike growths (Fig. 3). She also had multiple intraoral, white papillomatous tumors that were especially prominent on her tongue and buccal mucosa (Fig. 4). The lesions were plentiful on the anterior neck and upper trunk, where they clearly showed a tendency to localize in sunexposed areas. All extremities were involved, and the lesions tended to be larger and fewer in number on the extremities. Individual lesions were predominantly small , firm, I to 3 mm papules. Some of the largest lesions measured 7 to 10 mm . Many appeared to be follicular and a few showed central umbilication with a horny plug. Findings of biopsy specimens from the left retroauricular area and left arm showed sharply marginated segments of epidermal hyperplasia. The epidermal surfaces showed shallow depressions that were filled with or-
thokeratin . The proliferating cells either closely resembled normal epidermis or, in some foci, were increa sed in size and contained glassy eosinophilic cytoplasm and enlarged vesicular nuclei with prom inent central nucleoli. A specimen from the chest showed similar features but the tumor was larger and demonstrated a better defined, flask-shaped configuration . All three lesions had small fociof fibroblastic proliferation at their interface with the dermis that were associated with patchy infiltrates of lymphocytes accompanied by scattered neutrophils and isolated eosinophile. None of the specimens showed convincing evidence that the proliferations had originated in follicular infundibula. Sections of a nodule from the right arm demonstrated findings of a small keratoacanthoma (Fig. 5). Sections of n lesion from the tongue showed a well-marginated,
Journal of the American Academy of Dermatology Volume 29, Numhcr 2, Part 2
Jaber et al. 301
Fig. 5. Lesion from right arm. (Hematoxylin-eosin stain; X60.) plaque!ike zone of epithelial hyperplasia in the form of elongated, variably branched, and focally interconnecting epithelial cords. These were composed of orderly, cytologically uniform, benign-appearing squamous cells. Some squamous cords showed centrally located clusters of heavily keratinized cells with compressed nuclei but there was no semblance of lumen formation or a flasklike configuration. Two specimenswere analyzed for the presenceof multiple human papillomaviruses (HPV) by the polymerase chain reaction as previouslydescribed.*19 HPV DNA sequences were not found. Laboratory evaluation showed only moderately elevated glucose and triglyceride levels. Evaluation of peripheral lymphocytes showed normal subpopulations of B, T-hclper, and T-suppressor cells. Results of serum protein electrophoresisand quantitative immunoglobulin studies were normal. Findings of intradermal antigen skin testing revealed a positiveresponse to tetanus toxoid and negative reactions to tuberculin, Trichophyton, and Candida. A diagnosis of eruptive keratoacanthoma of Grzybowski was made. The patient was treated with isotretinoin, 40 mg/day, which was gradually increased to 120 rug/day. She also received antihistamines and topical emollient therapy. Within 4 weeks she reported a slight reduction in formation of new lesionsbut her triglyceride level had risen to 1314 mg/dl, Isotretinoin was stopped and the triglyceride level returned to baseline. The patient's condition worsened and etretinate, 50 rug/day, ·Neal S, Penneys, MD performed this study.
was begun. This was increased to 75 rug/day, but there was no clinical improvement. The patient developed severe intertriginous inflammation and etretinate was discon tinued. The patient continued to develop new lesions, including some on the palms, soles, and perineum. Koebnerization was noted in several areas. Her ectropion worsened, which resulted in xerophthalmia, recurrent conjunctivitis, and early keratopathy. Painful external auditory lesions developed, some of which became secondarily infected. The number and size of her intraoral lesions continued to increase, especially on the tongue. The pruritus was marked, most notably where smaller lesions were prevalent. Therapy with oral methotrexate, 15 mg/week, was initiated. After 4 weeksthe patient noted a slight decrease in development of new lesions, but subsequent improvement has been minimal a nd methotrexate was discontinued after 6 months of therapy. The patient has also developed moderate hoarseness ca used by extensive oropharyngeal and laryngeal involvement by keratoacanthomas. Sun avoidance and the use of sunscreens have been emphasized. DISCUSSION The Grzybowski type of keratoacanthoma is extremely rare, with only 22 reported cases (including the present case), the first of which was reported by Grzybowski in 1950. I Thirteen patients were women and nine were men. There was one black patient and two Japanese patients; and the remaining 19 patients were white. The age of onset ranged from 32
302 Jaber et al. to 84 years (median age, 57 years). All cases were sporadic. Clinically most patients have hundreds to thousands of small follicular papules. Typically the lesions are 1 to 5 mm and some show a central umbilication that contains a horny, keratotic plug. The lesions are usually flesh-colored to erythematous. The distribution shows a preference for sun-exposed regions. The face and head are usually the first sites to become involved, followed by the v of the neck and the upper trunk. Lastly, the upper extremities and the rest of the body can become affected. Lesions of the palms and soles, although not common, appeared in our patient and in several other patients. The lesions have a tendency to coalesce, especially on the face, upper trunk, and intertriginous areas. Facial involvement can be severe, leading to masked facies with ectropion. Xerophthalmia and conjunctivitis can result and progress to corneal ulceration and scarring. A corrective blepharoplasty was recommended in our patient and one other patient to prevent further keratopathy.J'' Perioral grouping of lesions and narrowing of the oral aperture can also be present. Most patients have severe pruritus and larger keratoacanthomas can be painful, especially if they occur at sites that are easily traumatized. Lesions often show koebnerization. Some patients reported that sunlight either triggered the onset of new lesions or stimulated the growth of existing ones. A prominent feature is mucous membrane involvement. These lesions are characteristically intraoral, often multiple, and favor the buccal mucosa, palate, and tongue. They can also involve the oropharynx and larynx, causing pain, dysphagia, and hoarseness. The histologic features in the single and multiple varieties of keratoacanthoma are generally similar. Larger, well-developed lesions of eruptive keratoacanthoma often show the characteristic features of keratoacanthoma. The smaller cutaneous and mucosal lesions may show less crater formation than their solitary counterpart and can be misinterpreted as nonspecific pseudoepitheliomatous hyperplasia or well-differentiated squamous cell carcinoma. Malignant transformation has not been reported in patients with eruptive keratoacanthoma, but sq uamous cell carcinoma has been reported to occur in association with other varieties of keratoacanthoma. 20, 21 No specific laboratory findings have been identified in patients with eruptive keratoacanthoma. Three of the 22 patients had an associated internal malignancy.s 9,14 two had latent syphilis.v l"
Journal of the American Academy of Dermatology August 1993
and one had hemolytic anemia with circulating immune cornplexes.!" However, these associations appear to be coincidental. There are no systemic manifestations of this disease, aside from those caused by upper airway involvement. The cause and pathogenesis of eruptive keratoacanthoma are unknown. The characteristic rapid growth and expulsion of the keratin plug followed by spontaneous resolution of a typical keratoacanthoma has been compared with the hair growth cycle. 22 Early keratoacanthomas are often found adjacent to or involving hair follicles, and most authors agree that cutaneous keratoacanthomas develop from a portion of the hair follicle. Electron microscopy of human lesions and experimental induction of tumors in animals support this hypothesis. 22-24 However, this cannot explain tumors on the mucous membranes, palms, and soles. Some authors have speculated that intraoral lesions may develop from ectopic sebaceous glands or surface epithelium. 25, 26 Lesions of the palms and soles may develop from other epidermal appendages, including eccrine structures. 27 Chemicals, viruses, sunlight, trauma, and altered immunity have been implicated as causative agents. Exposure to tars, oils, or other carcinogens has long been believed to be an inducer of keratoacanthomas. Keratoacanthomas can be induced in rodents by topical application of tar derivatives." and they can be induced in patients treated with tar. 29, 30 Workers in the coal and petroleum industries apparently have an increased incidence of keratoacanthoma. 21,24,31 Repeated applications of a carcinogen to rabbit ears can induce keratoacanthomas that demonstrate a mutation in the rasH oncogene.I- 33 This mutation, which has also been demonstrated in human keratoacanthomas.U: 34 activates the rasH gene. Whereas chemical exposure may be important in some cases of keratoacanthoma, it has not been implicated in eruptive keratoacanthoma. A viral pathogenesis was postulated by Grzybowski, who noted the large number of wartlike growths and their tendency to group and koebnerize, but attempts to grow the tumor or virus in animals or humans have met with consistent failure/' Most recently, highly sensitive and specific DNA probes for HPV have been used. In one study of solitary keratoacanthoma, 12 of 15 specimens were found to be positive for HPV. 35 However, another study found no HPV DNA in 31 keratoacanthomas.l'' DNA hybridization probes are extraordinarily sen-
Journal of the American Academy of Dermatology Volume 29, Number 2, Part 2
sitive, and these findings could represent false positives (caused by accidental contamination) or chance associations of HPV antigens and keratoacanthomas. Two patients with eruptive keratoacanthomas were tested in this manner and no evidence of HPV was detected. Exposure to sunlight appears to be important in eruptive keratoacanthoma of Grzybowski. Excessive sun exposure has been associated with both the initiation and exacerbations of this disease. The immunosuppressive actions of ultraviolet light may playa role but this would not explain extensive lesions in the scalp, behind the ears, and in the oropharynx. Trauma has been suggested as an inciting agent, and koebnerization has been reported frequently. The clinical and histopathologic findings during spontaneous involution of keratoacanthoma support the hypothesis that an immune-mediated process is involved. Increased numbers of Langerhans cells, along with an inflammatory infiltrate and expression of HLA-DR, are observed in resolving keratoacanthomas. Detailed studies have not been undertaken in patients with eruptive keratoacanthoma, but these patients have a normal white blood cell count and normal subpopulations of T and B cells. Serum immunoglobulin levels have also been normal. The patients do not appear to be more predisposed to infections. However, multiple keratoacanthomas are known to occur with higher incidence in immunosuppressed patients who have undergone transplantation 37 , 38 and in patients with leukemia-? and leprosy,40 and they have also been reported after PUV A therapy." thermal burns,42 and megavoltage radiation therapy.v' It seems plausible that a yet-to-bedefined immunologic defect in genetically predisposed persons, potentiated by sunlight exposure and perhaps in conjunction with a viral effect, might explain the pathogenesis of this rare disease. The treatment of eruptive keratoacanthomas has not been satisfactory. The disease has significant morbidity and is frequently progressive and chronic despite therapy. Only one patient has demonstrated spontaneous resolution.? In this patient sudden and complete remission of all keratoacanthomas occurred just days before death caused by metastatic adenocarcinoma of the fallopian tube. Therapies used for solitary keratoacanthoma have been applied to eruptive keratoacanthoma with variable results. Surgical excision or physical destruction is impractical because of the number of le-
Jaber et al. 303 sions. Topical regimens have included vitamin A ointment, tretinoin, 5-f1uorouracil,podophyllin, corticosteroids, and various emollients, all with little benefit. Roentgen therapy in one patient had little effect.5 Intralesional therapy with 5-f1uorouracil, bleomycin, triamcinolone, or methotrexate, while having some efficacyin solitary keratoacanthoma, is impractical in the eruptive form. Because of the generalized nature of this condition, systemic therapy offers the best hope. Oral methotrexate was slightly beneficial in our patient and one other patient. Aminopterin therapy in two patients had minimal results. 'Y Interferon was used in one patient without any demonstrable effect. Isotretinoin and etretinate have shown the best efficacy. When effective they have arrested the growth of active lesions, prevented the occurrence of new ones, and prompted the resolution of existing ones. Systemic retinoids were tried in 13 patients and resulted in full control and remission of the disease in three patients. The therapy was moderately helpful in four patients, somewhat beneficial in four others, and not effective in the remaining two patients. Whereas retinoid therapy can induce regression of the larger, more typical keratoacanthomas, the small follicular keratoacanthomas often remain unaffected. Induction doses ranged from 1 to 2 vag] kg/day, and when benefits were seen a lower dose maintenance therapy was apparently effective in preventing recurrences. REFERENCES
I. Grzybowski M. A case of peculiar generalized epithelial tumours of the skin. Br J Dermatol19 50;62:310-3. . 2. Witten VH, Zak FG. Multiple, primary, self-healing prickle-cell epithelioma of the skin. Cancer 1952;5:539-50. 3. Rossman RE, Freeman RG, Knox JM. Multiple keratoacanthomas: a case study of the eruptive type with observations on pathogenesis. Arch Dermatol 1964;89:374-81. 4. Jolly HW, Carpenter CL. Multiple keratoacanthomata. Arch Dermatol 1966;93:348-53. 5. Winklemann RK, Brown 1. Generalized eruptive keratoacanthoma. Arch Dermatol 1968;97:615-23. 6. Weber G, Stetter H, Pliess G, et al. Assoziiertes Vorkornmen von eruptiven Keratoacanthomen, Tubencarcinom und Paramyeloblasten leukamie. Arch Klin Exp Derm /970;238: 107-19. 7. Tachi T, Kawashima Y, Eguchi K, et al, Eruptive keratoacanthoma. Hifu Rinsyo 1978;20:381-7. 8. Balus L, Fazio M, Carducci M, et al. Une variete de kerato-acanthome multiple: Le kerato-acanthome eruptif. Ann Derrnutol VenereoI1981;108:995-LOOO. 9. Snider BL, Benjamin DR. Eruptive keratoacanthoma with an internal malignant neoplasm. Arch Dermatol 1981; 117:788-90. 10. Sterry W, Steigleder GK, Pullmann H, et al. Eruptive keratoakanthome. Hauturzt 1981;32:119-25.
304 Jaber et al. II . Yoshikawa K, H irano S, Kato T, et aI. A cast: of eruptive keratoacanthoma treated by oral etretinate. Br J Dermatol 1985;112:579-83. 12. Blitstein-Willinger E, Haas N, Nurnberger F, et al. Immunological findings during treatment of multiple keratoacanthoma with etretinate. Br J DermatoI1986 jll4:10916. 13. Young SK, Larsen PE, Markowitz NR. Generalized eruptive keratoacanthoma. Oral Surg Oral Med Oral Pathol 1986;62:422-6. 14. Cabotin PP, Vignon-Pennarnen MD, Miclea JM, et al. Kerato-acanthomes multiples eruptifs revelateurs d'un lymphome. Ann Dermatol Venereol 1989 ;116:860-2. I5. Lloyd KM, Madsen DK, Lin PY. Grzybowski's eruptive keratoacanthoma. JAM A CAD DERMATOL 1989;16: 1023·4. 16. Street ML, White JW, Gibson LE. Multiple keratoacanthomas treated with oral retinoids. JAM ACADDERMATOL 1990;23:862-6. 17. Yell JA. Grzybowski's generalized eruptive keratoacanthoma. J R Soc Med 1991 ;84: 170- L 18. Laaf H, Mittelviefhaus H, Wokalek H, et al. Eruptive keratoakanthome Typ Grzybowski und Ektropium. Hautarzt 1992;43:143-7. I9. Manos MM, Ting Y, WrightDK,etal. Use of polymerase chain reaction amplification for the detection of genital human papillomavirus. In: Furth M, Greaves M, eds. Molecular diagnostics of human cancer. New York: Cold Spring Harbor, I989:209-l4. 20. Chapman RS, Finn OA. Carcinoma of the larynx in two patients with keratoacanthoma. Br J Dermatol 1974; 90:685-8. 21. Rook A, Whimster 1. Keratoacanthoma-A thirty year retrospect. Br J DermatoI1979;100:4l-7. 22. GhadiaUy FN. The role of the hair follicle in the origin and evolution of some cutaneous neoplasms in experimental animals. Cancer 1961;14:801-16 . 23. Carrington SG, Wilburn WH o A tridimensional view of keratoacanthomas. Scanning Electr Microsc 1980;3:495504. 24. Ghadially FN, Barton BW, Kenidge DF. The etiology of keratoacanthoma. Cancer 1963; 16:603-1 L 25. Surisky JA, Freedman PD, Lumerman H . Solitary intraoral keratoacanthoma. OralSurg Oral Med Oral Pathol 1977;43:116-22. 26. Eversole LR, Leider AS, Alexander G. Intraoral and labial keratoacanthoma. Oral Surg Oral Med Oral Pathol 1982; 54:663-7.
Journal of the American Academy of Dermatology August 1993
27. Olmos L, Laugier P, Hunziker N. Etude au microscope electronique de kerato-acanthome: Participation des glandes sudorales. Ann Dermatol Syph (Paris) 1972;99:518-22. 28. Ghadially FN. The experimental production of keratoacanthoma in the hamster and the mouse. J Pathol Bact 1959;77:277-82. 29. Vickers CFH, Ghadially FN. Keratoacanthoma associated with psoriasis . Br J Dermatol 1961;73:120-4. 30. DeMoragas JM. Multiple keratoacanthomas. Arch Derm atoI1966;93 :679-83. 31. Colomb D, Descos L, Gauthier D. Kerato-acanthomes multiples et maladie du brai de houille . Rev Lyon Med 1966;15:449-62. 32. Corominas M, Leon J, Kamino H, et al. Oncogene involvement in tumor regression-H-ras activation in the rabbit keratoacanthoma model. Oncogene I991;4:645-51. 33. Leon J, Kamino H, Steinberg JJ, et al. H-ras activation in benign and self-regressing skin tumors (keratoacanthomas) in both humans and an animal model system. Mol Cell Bioi 1988;8:786-93. 34. Corominas M, Sloan SR, Leon J, et al. H-ras activation in human tumors and animal model systems. Environ Health Perspect 1991;93 :19-25. 35. Gassenmaier A, Pfister H, Hornstein OP. Human papillomavirus 25-related DNA in solitary keratoacanthoma. Arch Dermatol Res 1986;279:73-6. 36. Hopf! RM, Schir MM, Fritsch PO. Keratoacanthomas: human papillomavirus associated? Arch Dermatol 1992; 128:563-4. 37. Guillot B, Fesneau H , Mourad G, et a1. Keratoacanthomes multiples sous ciclosporine. Presse Mcd 1990; 19:1286. 38. Walder BK, Robertson MR, Jeremy D . Skin cancer and immunosuppression. Lancet 1971;2: I 282-3. 39. Degos R, Bernard J, Delort J, et al. Keratoacanthomes centrifuges dissernines. Bull Soc Fr Dermatol Syph 1967; 74:417-9. 40. Job CK . Keratoacanthoma associated with leprosy. Indian J Pa thol Bacteriol 1963;6:I60-2. 41. S ina B, Adrian RM. Multiple keratoacanthomas possibly induced by psoralens and ultraviolet A photochemotherapy. JAM ACAD DERMATOL 1983;9:686-8. 42. Hendricks WM. Sudden appearance of multiple keratoac anthomas three weeks after thermal burns. Cutis 1991; 17:110-2. 43. Shaw JC, Storrs FJ, Everts E. Multiple keratoacanthomas after megavoltage radiation therapy. J AM ACAD D ERMATOL 1990;23:1009-11.
7. Castanet J, Lacour PP, Ortonne JP. Formes cliniques atypiquesdes pemphigoides bulleuses.Ann Dermatol VenereoI1990;117:73-82. 8. AmatoDA,Si.lversteinJ, ZitelliJ.The prodrome of bullous pemphigoid. lnt J Dermatol 1988;27:560-3. 9. Asbrink E, Hovmark A. Clinical variations in bullous pemphigoid with respect to early symptoms. Acta Derm Venereol (Stockh) 1981;61 :417-21. 10. Person JP, Rogers RS, Perry HO . Localized pemphigoid. Br J Dermatol 1976;95:531-4. I I. Winkelmann RK, Su WPD. Pemphigoid vegetans. Arch Dermatol 1979;115:446-8. 12. Yung CW, Soltan i K, Lorincz AL. Pemphigoid nodularis. J AM ACAD DERMATOL 1981;5:54-60. 13. Honeyman JF, Honeyman AR, DelaParra MA, et al. Polymorphic pemphigoid. Arch Dermatol 1979;115:423-7. 14. Tappeiner G, Konrad K, Holubar K. Erythrodermic bullous pemphigoid. J AM A CAD DERMATOL 1982;6:489-92. 15. Pehamberger H, Gschnait F, Konrad K, et al. Bullous pemphigoid, herpes gestationis and linear dermatitis her-
Strohal et al.
petiformis: circulating anti-basement membrane zone antibodies; in vitro studies. J InvestDermatoI1980;74:105-8. 16. Rappersberger K, Tschachler E, Tani M , et al. Bullous disease in systemic lupus erythematosus. J AM ACAD DERMATOL 1989;21 :745-52. 17. Rappersberger K, Konrad K, Schenk P, et al. Epidermolysis bullosa acquisita. Eine klinisch-pathologische Studie, Hautarzt 1988;39:355-62. 18. Stanley JR , Koulu L, Th ivolet C. Distinction between epidermal antigens binding pemphigus vulgaris and pemphigus foliaceusautoantibodies. J Clin Invest 1984;74:313-20. 19. Katz M, Holubar K. Pemphigus herpetiformis. Hautarzt 1984;35:478-80. 20. Chorzelski TP, Jablonska S, BeutnerEH. Bullous pemphigoid:relationship ofimmunopathology to clinicalfindings. In: Beutner EH, Chorzelski TP, Kumar V, eds. Immunopathology of the skin. New York: John Wiley & Sons, 1987:337-55. 21. Thomsen K,Schmidt H. PUVA-induced bullous pemphigoid. Br J Dermatol 1976;95:568-9.
Generalized eruptive keratoacanthoma of Grzybowski W. J aber, MD,a Philip H. Cooper, MD,a, b and Kenneth E. Greer, MDa Charlottesville, Virginia
Peter
A patient with generalized e~uptive keratoacanthoma of Grzybowski is described. Our findings, along with those of the 21 reported cases from the world literature, are summarized.This rare variant of kerato acanthoma most commonly affects patients in the fifth to seventh decades oflife and appears as a generalized eruption of hundreds to thousands of follicular papules. These small papules often have a keratotic center and demonstrate the microscopic features of keratoac anthoma. Marked facial involvement is characteristic and can lead to masked facies with ectropion. Severe prur itus, mucosal lesions, and koebneri zation are features of th e disease. The course is chronic and the response to therapy is poor, although a few patients have improved with the use of systemic retinoids. (J AM ACAD DERMATOL 1993;29:299-304.) In 1950 Grzybowski' described eruptive keratoacanthoma. Since t hen 20 additional cases have been reported. 2- 18 We des cribe a patient with eruptive keratoacanthoma a nd review t he literature. CASE REPORT
A 35-year-old woman had a 5-month history of a progressive, pruritic eruption on most of her body. It began
From the Departments of Dermatology" and Pathology," University of Virginia School of Medicine. Reprints not available. Copyrigh l
(<)
1993 by the Amer ican Academy of Dermatology, Inc.
0\ 90-9622/93 $1.00 + .10
16/4/44996
on her head and quickly extended onto her neck and trunk . The lesions tended to appear in crops. The patient also had severe pruritus and painful int raoral lesions. She had morbid obesity and non-insulin-dependent diabetes mellitus . There was no family history of similar skin lesions and the patient had no known exposure to tars or other carcinogens. She had a history of moderate sun exposure but no documented precancerous or cancerous skin conditions. Clinic al examination revealed an obese, middle-aged woman with an extensive, generalized papular eruption. The eruption was most marked on her face and neck, where the lesions tended to coalesce and resulted in a masked facies with mild ectropion (Figs. I and 2). The papules extended throughout the scalp and were conflu-
299
Journal of the Amer ican Academy of Dermatology August 1993
300 Jaber et al.
Fig. 1. exposed Fig. 2. Fig. 3. Fig. 4.
Multiple keratoacanthomas on face and neck demonstrate accentuation in sunareas. Individual and coalescing lesions on lateral face and neck. Accentuation of papules in and about cars. Multiple papillomas on tongue.
ent about the ears, imparting the appearance of large wartlike growths (Fig. 3). She also had multiple intraoral, white papillomatous tumors that were especially prominent on her tongue and buccal mucosa (Fig. 4). The lesions were plentiful on the anterior neck and upper trunk, where they clearly showed a tendency to localize in sunexposed areas. All extremities were involved, and the lesions tended to be larger and fewer in number on the extremities. Individual lesions were predominantly small , firm, I to 3 mm papules. Some of the largest lesions measured 7 to 10 mm . Many appeared to be follicular and a few showed central umbilication with a horny plug. Findings of biopsy specimens from the left retroauricular area and left arm showed sharply marginated segments of epidermal hyperplasia. The epidermal surfaces showed shallow depressions that were filled with or-
thokeratin . The proliferating cells either closely resembled normal epidermis or, in some foci, were increa sed in size and contained glassy eosinophilic cytoplasm and enlarged vesicular nuclei with prom inent central nucleoli. A specimen from the chest showed similar features but the tumor was larger and demonstrated a better defined, flask-shaped configuration . All three lesions had small fociof fibroblastic proliferation at their interface with the dermis that were associated with patchy infiltrates of lymphocytes accompanied by scattered neutrophils and isolated eosinophile. None of the specimens showed convincing evidence that the proliferations had originated in follicular infundibula. Sections of a nodule from the right arm demonstrated findings of a small keratoacanthoma (Fig. 5). Sections of n lesion from the tongue showed a well-marginated,
Journal of the American Academy of Dermatology Volume 29, Numhcr 2, Part 2
Jaber et al. 301
Fig. 5. Lesion from right arm. (Hematoxylin-eosin stain; X60.) plaque!ike zone of epithelial hyperplasia in the form of elongated, variably branched, and focally interconnecting epithelial cords. These were composed of orderly, cytologically uniform, benign-appearing squamous cells. Some squamous cords showed centrally located clusters of heavily keratinized cells with compressed nuclei but there was no semblance of lumen formation or a flasklike configuration. Two specimenswere analyzed for the presenceof multiple human papillomaviruses (HPV) by the polymerase chain reaction as previouslydescribed.*19 HPV DNA sequences were not found. Laboratory evaluation showed only moderately elevated glucose and triglyceride levels. Evaluation of peripheral lymphocytes showed normal subpopulations of B, T-hclper, and T-suppressor cells. Results of serum protein electrophoresisand quantitative immunoglobulin studies were normal. Findings of intradermal antigen skin testing revealed a positiveresponse to tetanus toxoid and negative reactions to tuberculin, Trichophyton, and Candida. A diagnosis of eruptive keratoacanthoma of Grzybowski was made. The patient was treated with isotretinoin, 40 mg/day, which was gradually increased to 120 rug/day. She also received antihistamines and topical emollient therapy. Within 4 weeks she reported a slight reduction in formation of new lesionsbut her triglyceride level had risen to 1314 mg/dl, Isotretinoin was stopped and the triglyceride level returned to baseline. The patient's condition worsened and etretinate, 50 rug/day, ·Neal S, Penneys, MD performed this study.
was begun. This was increased to 75 rug/day, but there was no clinical improvement. The patient developed severe intertriginous inflammation and etretinate was discon tinued. The patient continued to develop new lesions, including some on the palms, soles, and perineum. Koebnerization was noted in several areas. Her ectropion worsened, which resulted in xerophthalmia, recurrent conjunctivitis, and early keratopathy. Painful external auditory lesions developed, some of which became secondarily infected. The number and size of her intraoral lesions continued to increase, especially on the tongue. The pruritus was marked, most notably where smaller lesions were prevalent. Therapy with oral methotrexate, 15 mg/week, was initiated. After 4 weeksthe patient noted a slight decrease in development of new lesions, but subsequent improvement has been minimal a nd methotrexate was discontinued after 6 months of therapy. The patient has also developed moderate hoarseness ca used by extensive oropharyngeal and laryngeal involvement by keratoacanthomas. Sun avoidance and the use of sunscreens have been emphasized. DISCUSSION The Grzybowski type of keratoacanthoma is extremely rare, with only 22 reported cases (including the present case), the first of which was reported by Grzybowski in 1950. I Thirteen patients were women and nine were men. There was one black patient and two Japanese patients; and the remaining 19 patients were white. The age of onset ranged from 32
302 Jaber et al. to 84 years (median age, 57 years). All cases were sporadic. Clinically most patients have hundreds to thousands of small follicular papules. Typically the lesions are 1 to 5 mm and some show a central umbilication that contains a horny, keratotic plug. The lesions are usually flesh-colored to erythematous. The distribution shows a preference for sun-exposed regions. The face and head are usually the first sites to become involved, followed by the v of the neck and the upper trunk. Lastly, the upper extremities and the rest of the body can become affected. Lesions of the palms and soles, although not common, appeared in our patient and in several other patients. The lesions have a tendency to coalesce, especially on the face, upper trunk, and intertriginous areas. Facial involvement can be severe, leading to masked facies with ectropion. Xerophthalmia and conjunctivitis can result and progress to corneal ulceration and scarring. A corrective blepharoplasty was recommended in our patient and one other patient to prevent further keratopathy.J'' Perioral grouping of lesions and narrowing of the oral aperture can also be present. Most patients have severe pruritus and larger keratoacanthomas can be painful, especially if they occur at sites that are easily traumatized. Lesions often show koebnerization. Some patients reported that sunlight either triggered the onset of new lesions or stimulated the growth of existing ones. A prominent feature is mucous membrane involvement. These lesions are characteristically intraoral, often multiple, and favor the buccal mucosa, palate, and tongue. They can also involve the oropharynx and larynx, causing pain, dysphagia, and hoarseness. The histologic features in the single and multiple varieties of keratoacanthoma are generally similar. Larger, well-developed lesions of eruptive keratoacanthoma often show the characteristic features of keratoacanthoma. The smaller cutaneous and mucosal lesions may show less crater formation than their solitary counterpart and can be misinterpreted as nonspecific pseudoepitheliomatous hyperplasia or well-differentiated squamous cell carcinoma. Malignant transformation has not been reported in patients with eruptive keratoacanthoma, but sq uamous cell carcinoma has been reported to occur in association with other varieties of keratoacanthoma. 20, 21 No specific laboratory findings have been identified in patients with eruptive keratoacanthoma. Three of the 22 patients had an associated internal malignancy.s 9,14 two had latent syphilis.v l"
Journal of the American Academy of Dermatology August 1993
and one had hemolytic anemia with circulating immune cornplexes.!" However, these associations appear to be coincidental. There are no systemic manifestations of this disease, aside from those caused by upper airway involvement. The cause and pathogenesis of eruptive keratoacanthoma are unknown. The characteristic rapid growth and expulsion of the keratin plug followed by spontaneous resolution of a typical keratoacanthoma has been compared with the hair growth cycle. 22 Early keratoacanthomas are often found adjacent to or involving hair follicles, and most authors agree that cutaneous keratoacanthomas develop from a portion of the hair follicle. Electron microscopy of human lesions and experimental induction of tumors in animals support this hypothesis. 22-24 However, this cannot explain tumors on the mucous membranes, palms, and soles. Some authors have speculated that intraoral lesions may develop from ectopic sebaceous glands or surface epithelium. 25, 26 Lesions of the palms and soles may develop from other epidermal appendages, including eccrine structures. 27 Chemicals, viruses, sunlight, trauma, and altered immunity have been implicated as causative agents. Exposure to tars, oils, or other carcinogens has long been believed to be an inducer of keratoacanthomas. Keratoacanthomas can be induced in rodents by topical application of tar derivatives." and they can be induced in patients treated with tar. 29, 30 Workers in the coal and petroleum industries apparently have an increased incidence of keratoacanthoma. 21,24,31 Repeated applications of a carcinogen to rabbit ears can induce keratoacanthomas that demonstrate a mutation in the rasH oncogene.I- 33 This mutation, which has also been demonstrated in human keratoacanthomas.U: 34 activates the rasH gene. Whereas chemical exposure may be important in some cases of keratoacanthoma, it has not been implicated in eruptive keratoacanthoma. A viral pathogenesis was postulated by Grzybowski, who noted the large number of wartlike growths and their tendency to group and koebnerize, but attempts to grow the tumor or virus in animals or humans have met with consistent failure/' Most recently, highly sensitive and specific DNA probes for HPV have been used. In one study of solitary keratoacanthoma, 12 of 15 specimens were found to be positive for HPV. 35 However, another study found no HPV DNA in 31 keratoacanthomas.l'' DNA hybridization probes are extraordinarily sen-
Journal of the American Academy of Dermatology Volume 29, Number 2, Part 2
sitive, and these findings could represent false positives (caused by accidental contamination) or chance associations of HPV antigens and keratoacanthomas. Two patients with eruptive keratoacanthomas were tested in this manner and no evidence of HPV was detected. Exposure to sunlight appears to be important in eruptive keratoacanthoma of Grzybowski. Excessive sun exposure has been associated with both the initiation and exacerbations of this disease. The immunosuppressive actions of ultraviolet light may playa role but this would not explain extensive lesions in the scalp, behind the ears, and in the oropharynx. Trauma has been suggested as an inciting agent, and koebnerization has been reported frequently. The clinical and histopathologic findings during spontaneous involution of keratoacanthoma support the hypothesis that an immune-mediated process is involved. Increased numbers of Langerhans cells, along with an inflammatory infiltrate and expression of HLA-DR, are observed in resolving keratoacanthomas. Detailed studies have not been undertaken in patients with eruptive keratoacanthoma, but these patients have a normal white blood cell count and normal subpopulations of T and B cells. Serum immunoglobulin levels have also been normal. The patients do not appear to be more predisposed to infections. However, multiple keratoacanthomas are known to occur with higher incidence in immunosuppressed patients who have undergone transplantation 37 , 38 and in patients with leukemia-? and leprosy,40 and they have also been reported after PUV A therapy." thermal burns,42 and megavoltage radiation therapy.v' It seems plausible that a yet-to-bedefined immunologic defect in genetically predisposed persons, potentiated by sunlight exposure and perhaps in conjunction with a viral effect, might explain the pathogenesis of this rare disease. The treatment of eruptive keratoacanthomas has not been satisfactory. The disease has significant morbidity and is frequently progressive and chronic despite therapy. Only one patient has demonstrated spontaneous resolution.? In this patient sudden and complete remission of all keratoacanthomas occurred just days before death caused by metastatic adenocarcinoma of the fallopian tube. Therapies used for solitary keratoacanthoma have been applied to eruptive keratoacanthoma with variable results. Surgical excision or physical destruction is impractical because of the number of le-
Jaber et al. 303 sions. Topical regimens have included vitamin A ointment, tretinoin, 5-f1uorouracil,podophyllin, corticosteroids, and various emollients, all with little benefit. Roentgen therapy in one patient had little effect.5 Intralesional therapy with 5-f1uorouracil, bleomycin, triamcinolone, or methotrexate, while having some efficacyin solitary keratoacanthoma, is impractical in the eruptive form. Because of the generalized nature of this condition, systemic therapy offers the best hope. Oral methotrexate was slightly beneficial in our patient and one other patient. Aminopterin therapy in two patients had minimal results. 'Y Interferon was used in one patient without any demonstrable effect. Isotretinoin and etretinate have shown the best efficacy. When effective they have arrested the growth of active lesions, prevented the occurrence of new ones, and prompted the resolution of existing ones. Systemic retinoids were tried in 13 patients and resulted in full control and remission of the disease in three patients. The therapy was moderately helpful in four patients, somewhat beneficial in four others, and not effective in the remaining two patients. Whereas retinoid therapy can induce regression of the larger, more typical keratoacanthomas, the small follicular keratoacanthomas often remain unaffected. Induction doses ranged from 1 to 2 vag] kg/day, and when benefits were seen a lower dose maintenance therapy was apparently effective in preventing recurrences. REFERENCES
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27. Olmos L, Laugier P, Hunziker N. Etude au microscope electronique de kerato-acanthome: Participation des glandes sudorales. Ann Dermatol Syph (Paris) 1972;99:518-22. 28. Ghadially FN. The experimental production of keratoacanthoma in the hamster and the mouse. J Pathol Bact 1959;77:277-82. 29. Vickers CFH, Ghadially FN. Keratoacanthoma associated with psoriasis . Br J Dermatol 1961;73:120-4. 30. DeMoragas JM. Multiple keratoacanthomas. Arch Derm atoI1966;93 :679-83. 31. Colomb D, Descos L, Gauthier D. Kerato-acanthomes multiples et maladie du brai de houille . Rev Lyon Med 1966;15:449-62. 32. Corominas M, Leon J, Kamino H, et al. Oncogene involvement in tumor regression-H-ras activation in the rabbit keratoacanthoma model. Oncogene I991;4:645-51. 33. Leon J, Kamino H, Steinberg JJ, et al. H-ras activation in benign and self-regressing skin tumors (keratoacanthomas) in both humans and an animal model system. Mol Cell Bioi 1988;8:786-93. 34. Corominas M, Sloan SR, Leon J, et al. H-ras activation in human tumors and animal model systems. Environ Health Perspect 1991;93 :19-25. 35. Gassenmaier A, Pfister H, Hornstein OP. Human papillomavirus 25-related DNA in solitary keratoacanthoma. Arch Dermatol Res 1986;279:73-6. 36. Hopf! RM, Schir MM, Fritsch PO. Keratoacanthomas: human papillomavirus associated? Arch Dermatol 1992; 128:563-4. 37. Guillot B, Fesneau H , Mourad G, et a1. Keratoacanthomes multiples sous ciclosporine. Presse Mcd 1990; 19:1286. 38. Walder BK, Robertson MR, Jeremy D . Skin cancer and immunosuppression. Lancet 1971;2: I 282-3. 39. Degos R, Bernard J, Delort J, et al. Keratoacanthomes centrifuges dissernines. Bull Soc Fr Dermatol Syph 1967; 74:417-9. 40. Job CK . Keratoacanthoma associated with leprosy. Indian J Pa thol Bacteriol 1963;6:I60-2. 41. S ina B, Adrian RM. Multiple keratoacanthomas possibly induced by psoralens and ultraviolet A photochemotherapy. JAM ACAD DERMATOL 1983;9:686-8. 42. Hendricks WM. Sudden appearance of multiple keratoac anthomas three weeks after thermal burns. Cutis 1991; 17:110-2. 43. Shaw JC, Storrs FJ, Everts E. Multiple keratoacanthomas after megavoltage radiation therapy. J AM ACAD D ERMATOL 1990;23:1009-11.