Report

Squamous Cell Carcinoma Developing in Epidermolysis Bullosa Dystrophica K. Yoshioka, M.D., T. Kono, M.D., Ph.D., J. Kitajima, M.D., K. Nakagawa, M.D., N. Yashiro, M.D., S. Taniguchi, M.D., M. Furukawa, M.D., and T. Hamada, M.D., Ph.D.

Abstract: Two patients with epidermolysis bullosa dystrophica recessiva who had squamous cell carcinoma are presented. Case 1 is a 40-year-old woman who had ulcers on her left lower leg. Case 2 is a 42-year-old man who had a tumor on his left first toe. Wide surgical excision with skin coverage by autograft was performed in case 1. Amputation of the toe in case 2 was performed. A review of the cases of epidermolysis bullosa dystrophica associated with cancer reported in Japan is also presented.

biopsy specimen taken from the ulcer border revealed a relatively well differentiated SCC (Fig. 2). The lesion was widely excised down to the deep fascia. The resultitig defect was autografted with split skin taken from her thigh. Nine months after the operation, a shallow ulcer developed in the lateral aspect of the left lower leg. As

Neoplasms, in particular squamous cell carcinoma (SCC), are the most serious complications of epidermolysis bullosa (EB), and develop most commonly in patients with the dystrophic recessive type (EBDR).' In the Western world from 1913 to 1988, there have been 43 patients reported with neoplasms complicating EBDR.^"'" A poor prognosis has been associated with this complication. In Japan, there have been nine cases reported in the literature.''-22 We report two additional patients and present a short review of the cases reported in Japan. Case Reports Case 1 • A 40-year-old woman exhibited persistent generalized blistering with subsequent scarring since birth. Her hands exhibited partial syndactylism and loss of nails. She had scarring ofthe scalp with alopecia since 15 years of age, and multiple dental caries. She reported difficulty with swallowing. The patient was seen in December 1988 with a large oval ulcer in the medial aspect of her left lower leg and malleolus (Fig. 1). Histopathologic examination ofthe

From the Department of Dermatology, Osaka City University Medical School, Osaka, Japan. Address correspondence to: T. Kono, M.D., Ph.D., Department of Dermatology, Osaka City University Medical School, 1-5-7, Asahimachi, Abeno-ku, Osaka 545, Japan. 718

Figure 1. Ulcerated lesion on the medial aspect of the left lower leg and malleolus of case 1. Ulceration (5.5 X 9.5 cm) with undermined edges, violaceous border, and a red glanulating floor. The lesion was freely movable in relation to the bone. October 1991, Vol. 30, No. 10

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Squamous Cell Carcinoma in EBD • Yoshioka et al.

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Figure 2, Light microscopic features of the biopsy specimen taken from the ulcer border in case 1, showing relatively well-differentiated squamous cell carcinoma with only slight atypicality and several horn pearls. Mild inflammatory infiltrate and fibrosis are observed in dermis (H&E, X650),

freshly blistered skin showed cleavage beneath the basal lamina as well as coUagenolysis (not shown). These findings confirmed the diagnosis of EBDR. Hematologic and urinary studies were normal except for hypochromic anemia.

histologic examination revealed SCC, the lesion was widely resected and autografted. There is no evidence of local recurrence or metastases 6 months after resection. Her family history was negative and her parents were not known to be related. An electron micrograph of

Table 1. Cases of Carcinoma Associated with Epidermoiysis Bullosa Dystrophica Reported in Japan

Author

Year

Age at Onset of Cancer (yr)

Kawase & Sugawara" Nishiyama & Fujita"* Yanagawa et al," Noguchi et

1966

56

F

1979

43

1980

Takijiri et al," Takijiri et al," Murayama et

Multiple (M)/ Solitary (S)

Type

Metastases

Both hands

M

SCC

+

+

?

M

Right hand

S

SCC

?

?

?

56

F

Tongue

S

SCC

-

1984

8

M

Right knee

Osteosarcoma

+

Radiation, & chemotherapy Chemotherapy

1984

27

F

Left hand

s s

+ Accidental +

SCC

-1-

+

1984

32

M

s

SCC

-

-

1985

65

F

Right forearm Genitals

Paget disease

—

Mizuta et al,^' Kumei et al,"

1987

61

F

Left lower

s s

Chemotherapy & amputation Chemotherapy & amputation Excision

SCC

—

—

Excision

s

SCC

-

-

Chemotherapy & excision

Case 1

1990

M

SCC

-

-

Excision

S

SCC

—

—

Amputation

Sex

Site

Death

Treatment

leg

1988

46

F

Left foot

(Cases reported here) F Left lower 40 leg

Case 2

1990

42

SCC: squamous cell carcinoma.

M

Left 1-toe

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International Journal of Dermatology • October 1991

Vol. 30

Table 2. Epidemiologic Factors in C i ases of Cancer in Epidermolysis Bullosa Dystrophica Reported in the Western World and Japan Clinical Parameter No. of reported cases Age at onset of cancer in yr (mean ± SD)

Western World 43

16-65 (38.2 ± 12.0)

Japan 11 8-65 (43.3 ±15.9)

Spy

Male Female Sex ratio (male:female) No. of primary cancers Single Multiple Site of the cancer Mouth Throat Upper limbs Lower limbs Trunk Genitals Multiple Intestine Histologic condition SCG

Bowen SCG SCC + BCE SCC -1- keratoacanthoma SCC -1- hemagiomata Paget disease Sarcoma of osteogenetic Prognosis Death from cancer Accidental death Living Unknown Metastasis + Unknown

28 15

1.9:1

4 7 1:1.75

25 18

9 2

5 I 18 20 4 1 2 2

1 0 4 5 0 1 0 0

37 1 2 1 1 0

9 0

1(?)

0 0

0 1 1

24 2 13 4

3 1 4 3

22 12 9

3 6 2

SCC: squamous cell carcinoma; BCE: basal cell epithelioma; SD: standard deviation.

Case 2 • A 42-year-old man has had epidermolysis bullosa dystrophica since birth. The blistering and scarring has occurred on his trunk and extremities. His family history was negative. He presented in J uly 1981 with a 4-month history of a large tumor on the dorsal aspect ofthe first toe on the left foot. Histopathologic examination ofthe biopsy specimen showed a well differentiated SCC. His left first toe was amputated. Urinary and hematologic evaluations were normal. There has been no evidence of recurrence and metastases 8 years after the amputation.

Discussion Development of carcinoma in patients with EB, especially in EBDR, has been reported. Didlkar et al.^ and Reed et al.^"^ reviewed the previously reported cases

since 1913. Subsequently, several other authors confirmed this complication,''"'^ and there have been 43 cases of carcinoma associated with EBDR reported in the West (the case of Miranda,"* not reviewed by Didlkar et al.^ or Reed et al.,^~^ was added). In Japan, nine cases with this complication in EBDR have been reported,"~^^ and we would like to add two additional patients (Table 1). Epidemiologic factors in those cases in the West and Japan are summarized in Table 2. In the West, this association is characterized by a predominance of men over women (1.9:1), skewing of the incidence to a younger age group (mean: 38.2 years), occurrence on the extremities (especially on the left lower limb), and multiple primary carcinomas. Almost all cases were SCC, including two cases of SCC and basal cell epithelioma (BCE),2'^'5 one case each of Bowen SCC and SCC

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Squamous Cell Carcinoma in EBD • Yoshioka et al.

with hemangiomata^'^'^ or keratoacanthoma.^ A case with sarcoma of suspected osteogenetic origin was also reported.''* In Japan, almost all cases are SCC, and lesions are located primarily on the extremities, as in the cases presented here; hence, these cases are similar to those reported in the West. In addition, one case each of osteosarcoma'^ and Paget disease^" have been reported in Japan. However, the age at onset of the cancer is slightly older than in the West, and there are only two cases of multiple primary carcinomas (case 1 presented here and Kawase's case'^). Interestingly, the sex ratio in the Japanese cases (men:women = 1:1.75) is the reverse of that of the Western group. There is no significant difference in the incidence of EBDR between men and women in Japan.^^ Extrapolating from the current 11 cases, the prognosis for cases in Japan is slightly better than that for the Western cases. This may be due to the smaller incidence of multiple tumors seen in Japan. In the West, skin cancer has been reported complicating both the acquired and dominant form of £g 5,24,25 jhere h^ve been no such reports in Japan involving these types of EB, except for a rare case of concurrent simplex-type EB and monocytic leukemia.^* The reason for these differences between Japanese and Western cases remains unclear. Racial differences or other complex social factors may be related. The mechanism of carcinogenesis in EB has been intensively discussed. Chronic skin inflammation in EB may contribute. Recently, abnormalities ofthe dermal collagen and fibroblasts have been reported in EB.''^~^ These new findings warrant further investigation. References 1, Goldberg Gl, Eisen AZ, Bauer EA, Tissue stress and tumor promotion: Possible relevance to epidermolysis bullosa. Arch Dermatol, 1988;124:737-741, 2, Didlkar MS, Gerner RE, Moore GE, Epidermolysis bullosa dystrophica and epithelioma ofthe skin: Review of published cases and report of an additional patient. Cancer, 1974;33:198-202, 3, Reed WB, College J Jr, Francis MJO, et a), Epidermolysis bullosa dystrophica with epidermal neoplasms. Arch Dermatol, 1974; 110:894-902, 4, Reed WB, Torres-Rodriguez V, Francis MJO, et al, Dystrophic epidermolysis bullosa with epidermal neoplasms with emphasis on a dermal collagen defect. Birth Defects Orig Article Ser, 1975;11:153-166, 5, Reed WB, Roenigk H Jr, Dorner W Jr, et al. Epidermal neoplasms with epidermolysis bullosa dystrophica with first report of carcinoma with the acquired type. Arch Dermatol Res, 1975;253:1-14, 6, Gipson M, Squamous cell carcinoma in epidermolysis bullosa dystrophica. Hand, 1975;7:179-182,

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7, Carapeto FJ, Pastor JA, Martin J, et al. Recessive dystrophic epidermolysis bullosa and multiple squamous carcinoma, Dermatologica, 1982;165:39-46, 8, Tidman MJ, Atherton DJ, Eady RAJ, Squamous cell carcinoma as a complication of dystrophic epidermolysis bullosa, J R Soc Med, 1984;77(Suppl):37-39, 9, Monk BE, Pembroke AC, Epidermolysis bullosa with squamous cell carcinoma. Clin Exp Dermatol, 1987;12:373-374, 10, Cordoso J, Azevedo J, e Costa HL, Squamous cell carcinoma in recessive epidermolysis bullosa dystrophica: a case report. Skin Cancer, 1986; 1:61-64, 11, Callen JP, Hudson CP, Bilateral ulcers in a patient with a hereditary bullous dermatosis. Arch Dermatol, 1987;123:811-816, 12, Keefe M, Wakeel RA, Dick DC, Death from metastatic, cutaneous, squamous cell carcinoma in autosomal recessive dystrophic epidermolysis bullosa despite inpatient care, Dermatologica, 1988;177:180-184, 13, Jain SS, De Lisa JA, Successful prostheticfittingof a patient with epidermolysis bullosa dystrophica. Am J Phys Med Rehabil, 1988;67:104-107, 14, Miranda R, Epidermolisi boUosa distrofica-displastica ulcero-vegetante e sarcoma secondario della cute, Rassegna di Dermatologia e di Sifilografia, 1969;22; 143-154, 15, Kawase K, Sugawara H, A case of epidermolysis bullosa associated with squamous cell carcinoma, Jpn J Dermatol. 1966;76:309 (in Japanese), 16, Nishiyama K, Fujita E, Epidermolysis bullosa dystrophica recessiva associated with squamous cell carcinoma, Jpn J Dermatol, 1979;41:794 (in Japanese), 17, Yanagawa T, Sato M, Yoshida H, et al, A case of carcinoma of the tongue which occurred in the patient of epidermolysis bullosa hereditaria, Jpn J Oral Surgery, 1980;26:1552-1556 (in Japanese), 18, Noguchi N, Manabe M, Takamori K, et al. Two autopsy cases of recessive dystrophic epidermolysis bullosa, Rinsho Hihuka (Jpn J Clin Dermatol), 1984;38:549-554 (in Japanese), 19, Takijiri C, Masada Y, Sano S, et al. Two cases of recessive dystrophic epidermolysis bullosa with squamous cell carcinoma. Jpn J Dermatol, 1984;94:!591-1597 (in Japanese), 20, Murayama M, Yamamoto O, Suenaga Y, et al. Epidermolysis bullosa hereditaria associated with Paget's disease, Jpn J Dermatol, 1985;47:752 (in Japanese), 21, Mizuta E, Numahara T, Takaiwa T, et al, Epidermolysis bullosa associated with squamous cell carcinoma, Jpn J Dermatol, 1987;49:359 (in Japanese), 22, Kumei A, Nogi N, Tsurumachi K, et al, Epidermolysis bullosa dystrophica recessiva (EBDR) with squamous cell carcinoma (SCC), Rinsho Hihuka (Jpn J Clin Dermatol), 1989;43:13211325 (in Japanese), 23, Sasai Y, Kitamura K, Epidemiology of Epidermolysis Bullosa and the Consultation on its Heredity, Dermatology MOOK No, 3, Tokyo: Kanehara, 1985:29-36 (in Japanese), 24, Schwartz RA, Birnkrant AP, Rubenstein DJ, et al, Squamous cell carcinoma in dominant type epidermolysis bullosa dystrophica. Cancer, 198I;47:615-620, 25, Song IC, Dicksheet S, Management of squamous cell carcinoma in a patient with dominant-type epidermolysis bullosa dystrophica: A surgical challenge, Plast Reconstr Surg, 1984;75:732736, 26, Ando 1, Yu H, Ogawa K, et al, A case of epidermolysis bullosa hereditaria with annular eruption, Rinsho Hihuka (Jpn J Clin Dermatol), 1982;36:573-578 (in Japanese),