Arch. Derm. Res. 253, 1--14 (1975) © by Springer-Verlag 1975
Epidermal Neoplasms with Epidermolysis Bullosa Dystrophica with the First Report of Carcinoma with the Acquired Type W i l l i a m B. Reed Clinical Professor of Medicine (Dermatology) University of California, Irvene H e n r y Roenigk, Jr. Head, Department of Dermatology Cleveland Clinic, Cleveland, Ohio W i l l i a m Dorner, Jr. Akron, Ohio (U.S.A.) Oliverio Welsh Head, Department of Dermatology Universided Antonoma de Nuevo Leon Monterey, N. L. (Mexico) F r a n c i s J. 0 . M a r t i n Nuffield Hospital Oxford (England) Received November 25, 1974
Summary. Carcinoma, usually always squamous cell carcinoma, is one of the most serious complications in epidcrmolysis bullosa dystrophiea. It can occur on the skin, mucous membranes, the esophagus and possibly the upper part of the bronchial tree. We are reporting on four new patients; one, the youngest to be so reported, one with a definite autosomal dominant inheritance and one with a chronic acquired dystrophiea epidermolysis bullosa. Most cases have an autosomal recessive inheritance, but the disorder is probably more hetereogeneous in its inheritance than has been reported. Studies of the collagen indicate a disturbance, but present studies indicate the defect to be more a cellular defect in the fibroblast yet undetermined. The carcinomas, usually multiple, appear to arise on scarred tissue and to metastasize rapidly with death. Zusammen/aasung. Zu den schwersten Komplikationen der Epidermolysis bullosa dystrophica z~hlt das staehelcellulgre Careinom. Es kann an der Haut, Schleimhaut, Oesophagus und m6glieherweise aueh im oberen Bereieh des Bronchialsystems auftreten. Wit berichten fiber vier neu beobachtete Patienten: den bislang jfingsten Patienten, einen Patienten mit autosomal dominantem Vererbungsmodus und einen Patienten mit Epidermolysis bullosa dystrophica acquisita. Die meisten Patienten zeigten autosomal recessive Vererbung, wahrscheinlieh jedoch ist die Erkrankung in ihrem Vererbungsmodus unterschiedlicher als bisher angenommen. Collagenanalysen weisen auf eine StSrung hin, dig naeh den hier vorliegenden Untersuehungen jcdoeh eher auf einen eellulgren Defekt der Fibroblasten beruht. Die vi~lfach multiplen Careinome entstehen vornehmlich auf Narbengewebe und metastasieren rasch mit tSdlichem Ausgang. Carcinoma, usually s q u a m o u s cell carcinoma, is one of the most serious complications of dystrophic epidermolysis bullosa. There have been 31 p a t i e n t s [ 4 , 6 , 8 - - 1 0 , 1 2 , 1 4 , 1 5 , 1 7 , 2 0 , 2 3 - - 2 6 , 2 8 - - 3 1 ] reported with this complication, i n c l u d i n g 10 of our own p a t i e n t s (Table 1). W e would like to a d d four new patients, 1 Arch.nerm. :ges., Vol.253
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Epidermal Neoplasms with Epidermolysis Bullosa Dystrophica
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i n c l u d i n g one w i t h t h e a c q u i r e d t y p e a n d one w i t h a d e f i n i t e a u t o s o m a l d o m i n a n t i n h e r i t a n c e . W e h a v e s t a r t e d e x t e n s i v e s t u d i e s o f t h e c o l l a g e n in t h e s e p a t i e n t s since t h e d i s o r d e r s are d e r m o l y t i c , w i t h t h e e p i d e r m i s s e p a r a t e d f r o m t h e d e r m i s b y t e a r s in t h e d e r m i s . P r e l i m i n a r y s t u d i e s b y one o f us (Francis) s u g g e s t a d e f e c t in c o l l a g e n m e t a b o l i s m . Case Studies
Case 1. (Supplied by Dr. Welsh) This Mexican girl, age 17, had had epidermolysis bullosa dystrophica since birth. She developing blistering and subsequent scarring on her arms and legs, with difficulty in walking. Her hands had partial syndactylism. She had scarring of the scalp with loss of hair. Her teeth were carious. She had difficulty in swallowing. Her family history was negative and the parents were not known to be related. She was seen in 1970 with a large tumor on her right hand. The biopsy diagnosis was squamous cell carcinoma. The parents refused amputation and 2 months later the girl developed axillary metastases and died 4 months later of generalized metastases. There was no autopsy. She is the youngest patient in the series.
Case 2. (Supplied by Dr. Roeniglc) This 30-year-old woman with severe epidermolysis bullosa dystrophica was seen at the Cleveland Clinic in 1947 with all the stigmata of this disorder: generalized multiple skin areas of scarring, denudation and tense bullae, involvement of the mouth with blistering, dysarthria, missing teeth because of early caries, and missing fingernails (present at birth). She denied difficulty in swallowing although mouth involvement was severe. She had generalized ichthyosis of the skin and partial alopecia of the scalp. She was poorly nourished and poorly developed. Her hands were badly deformed with shortening of her digits. Bulla formation could be found at the sites of mild pressure. A large, fairly well demarcated ulcer involved all of the left elbow, extending onto the back of the left arm (Fig. 1). Results of ~hree biopsies indicated atypical squamous epithelial cells with multiple areas of keratiniztaion, and frequent mitoses. A biopsy of one bulla showed "subepidermal cleavage". Elastic fibers were reduced in the dermis. Her left arm was amputated, but she died in less than 3 years after a steady downhill course.
Case 3. (Supplied by Dr. Dorner) A 60-year-old woman noted ulcerations on her right leg and underwent vein ligation and vein stripping in 1964. In 1969 she had a skin graft applied to the right ankle. In October 1970, she developed a duodenal ulcer and 3 months later underwent vagotomy and pyloroplasty with repair of a ventral hernia. In January 1971 she developed pigmentary and atrophic changes in both lower legs. The results of arteriography were normal. From October to January 1972, there were 5 debridements of tile ulcer. Finally in January 1972 a diagnosis of a squamous cell carcinoma was made, and in the ensuing months there were four more surgical attempts to remove the tumor of the leg. In February 1973, she started to develop bullae on the legs, buttocks and upper arms, and the finger and toe nails were noted to be missing. On dermatological examination, there was marked dystrophy or absence of all the nails except one. There was a generalized eruption of the soles, toes, ankles, distal legs, knee, proximal right thigh at the donor sites and buttocks. There were bullae, denuded areas crusting and scaling. During all these admissions, she remained in fairly good physical health, although she developed an iron deficiency anemia. Results of the following tests were negative : antinuclear antibody, latex fixation, cryoglobulin, SIA test, porphyrius, serum creatinine. The serum electrophoresis was normal, showing no abnormal gamma globulins. Her immunoglobulins showed IgG 1760 (N 600--2000), IgA 10 (40--360) and IgM 190 (45--145). She was treated with antibiotics, a silver preparation and corticosteroids with some improvement. With reduction of the eortieosteroids, new ulcerations of the left leg and foot developed (Fig. 2). A biopsy revealed a subepidermal bullae (Fig. 3). In June she developed a granulomatous area of the lateral posterior ankle. This granulomatous area was removed in August 1974 and diagnosed as a squamous
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W . B . Reed et al.
Fig. 1. Large fungating squamous cell carcinoma of left arm in patient II
Fig. 2. Large squamous cell carcinomas on ankle of patient h i . The black discoloration is due to a silver preparation
cell carcinoma (Figs.4 and 5). Many of the diagnoses of previous specimens were keratoacanthomas. Serum immunofluorescence was negative for IgG, IgA, IgM, C3 and Fibrinogen. The tumor resembled pseudoepitheliomatous hyperplasia, but the last surgical specimen is definitely a low grade squamous cell carcinoma with a near absence of mitotic activity.
Epidermal Neoplasms with Epidermolysis Bullosa Dystrophica
7
Fig.3. A subepidermal bulla with little inflammation compatible with the diagnosis of epidermolysis bullosa. × 25
Fig.4. Multiple epidermal nests of squamous cell carcinoma, well differentiated in this area (medium × 210 magnification)
However, several areas show anaplastic epidermal cells invading the dermis. Whe did not appear to have lymphoma or amyloidosis and except for the leg is in fairly good general health considering her age. The carcinoma, most likely, arose from the chronic scar tissue on the leg after a 10--15 year progressive history of acquired epidermolysis bullosa. Her generalized subepidermal bullae developed later.
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Fig. 5. Invasion of squamous cell carcinoma cells into the dermis leading to a desmoplastic collagen appearance. × 350
Case 4. (Supplied by Dr. Roenigk) This 69-year-old female was seen at the Cleveland Clinic in January, 1972 with a leg ulcer of the lower leg which was first considered a stasis ulcer. On physical examination she was found to have epidermolysis bullosa dystrophica with scarring on the elbows, neck and fingers with loss of some of the nails. She had no trouble with swallowing. The patient has seven siblings, and one brother and three sisters have had epidermolysis bullosa. Her mother had also the disorder. The biopsy of the fungating verrucous ulcer showed a well differentiated squamous cell carcinoma. She had two incisional removals, but soon after there was recurrence on the pre-tibial area. There was also a new tumor mass on the dorsum of the left foot and ankle. An amputation at the knee was performed. Examination of all biopsies and the pathological specimen revealed well differentiated squamous cell carcinoma. There were no known metastases and she was lost to follow-up. This patient is the first proved autosomal dominant epidermolysis bullosa dystrophica to develop carcinoma and also the oldest patient to do so. The severity of her lifelong disease was less than seen in the autosomal recessive patients.
Discussion T h e clinical a s p e c t s o f t h e a u t o s o m a l r e c e s s i v e d y s t r o p h i c e p i d e r m o l y s i s b u l l o s a are w e l l k n o w n a n d i n c l u d e i n v o l v e m e n t o f t h e o r a l c a v i t y , s h o r t e n i n g a n d stenosis o f t h e e s o p h a g u s , a n d s e v e r e s k i n c h a n g e s o f t h e h a n d s a n d feet. M o s t o f t h o s e m a n i f e s t a t i o n s r e p o r t e d in t h e l i t e r a t u r e a p p e a r t o be t h e d e r m o l y t i c t y p e d e s c r i b e d b y P e a r s o n [22], a l t h o u g h s y n d a c t y l i s m is n o t p r e s e n t in all p a t i e n t s . A g a i n , m u t a t i o n m u s t be c o n s i d e r e d , for n o t all p h e n o t y p i c a l p a t i e n t s
Epidermal Neoplasms with Epidermolysis Bullosa Dystrophica
9
will present the same degree of severity and obviously patients with cancer have survived longer than those without this complication. Gedde-Dahl in his extensive work [13] on this disorder in Norway and Sweden believes t h a t there are three autosomal recessive groups, each with its own clinical pattern. Different enzymes must be involved. There are severe and mild variants in each group with different mutations. The first group is epidermolysis bullosa dystrophica (dermolytie recessive group of Pearson) [22]. The second group is the junctional epidermolysis bullosa described by Pearson which m a y include the inverse type confirmed by GeddeDahl. The last new group is the epidermolysis bullosa progressiva which appears at age 1--14 and is slowly progressive, and is closely linked to the hypacusis gene [13]. Gedde-Dahl originally called this epidermolysis bullosa neurotrophiea before finding cases without deafness. However, we presented earlier a Puerto-t~ican male with squamous cell carcinomas of both his legs leading to bilateral amputation (Fig. 6). His disease started at age 5 with blistering with tramna to all parts of the body but no mucosal denudations or notable nail changes. He had lost all his teeth early through caries (Fig. 7). A sister with the disorder had died. His parents were normal and he had ten other siblings. Two unaffected brothers have had no affected children. Clinically he had the Pasini type of epidermolysis bullosa dystrophica which is usually autosomal dominant. However, there are reports of autosomal recessive inheritance [13]. Two patients in England appear also to have a different type of epidermolysis bullosa dystrophiea. The patients of Calnan [4] and l~yan [24] both developed squamous cell carcinomas on their legs with amputations. Although both had dental caries, neither had trouble with swallowing nor syndaetylism. The patient of Calnan resulted from a first cousin marriage and the squamous cell carcinoma of the leg developed at age 46. He died without metastases. The patient of lgyan developed his carcinoma of the leg at 65. He came from an inbred community near Oxford. Gedde-Daht, on reviewing these cases, believes that they are similar to his inverse type in Norway but with distinct differences. Although the recessive disorders are severe, the degree of severity does vary, and some patients survive post age 20, only to die of carcinoma and secondary amyloidosis. All the patients reported in the literature and our two new patients were over age 15. The inheritance is strongly autosomal recessive (Table 1), which is supported by consanginuous marriages and siblings with disorder. No parents had this disorder. However, only our patient No. 4 has a definite autosomal dominant inheritance. The first reported ease of carcinoma associated with epidermolysis bullosa dystrophiea was in the German medical literature in 1913 and involved the mouth. Two patients have been reported with squamous cell carcinoma of the eardia of the stomach and esophagus. Most of the other early cases were squamous cell carcinomas on the legs, but others have been seen on the hands, trunk, arms and legs and the back. Over half the patients have had multiple squamous cell carcinomas of the skin.
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Fig. 6. A Pasini type of epidermolysis bullosa dystrophica with a large squamous cell carcinoma of one leg, the other already amputated. (Courtesy of Professor Victor Torres, Puerto-Rico)
:Fig. 7. Intact fingernails. Note the cobblestone appearance of the skin and miliae on the hands
IIistopathology A n insufficient b i o p s y specimen m a y l e a d to a n incorrect diagnosis of low g r a d e m a l i g n a n c y a n d some h a v e been originally t h o u g h t to show only pseudoepitheli o l o m a t o u s h y p e r p l a s i a . Mobs [24] found i n d i v i d u a l m a l i g n a n t cells d e e p l y i n v a d i n g t h e dermis ~nd Wechsler f o u n d i n d i v i d u a l c~ncer cells deep in t h e dermis of his
Epidermal Neoplasms with Epidermolysis Bullosa Dystrophica
11
four patients [30]. Calnan [4] reported that only after thorough examination of an area with an initial diagnosis of pseudoepitheliomatous hyperplasia did he find an area of highly anaplastie cells. Thus, an ample biopsy of any vegetative lesion in a patient with epidermolysis bullosa dystrophica with a thorough histopathologie examination is mandatory to rule out carcinoma. Theories of Development When one considers why patients with epidermolysis bullosa dystrophica develop squamous cell carcinomas, one must consider the age of the patient, the status of the dermis and epidermis, and the immunological defense of the patient to cancer. It is undoubtedly important that all the patients who developed carcinomas were over age 15 and most were over age 35. All the autosomal recessive dystrophic epidermolysis bullosa disorders are probably diseases of the collagen tissue of the skin and perhaps of the mucosal membranes. Pearson found that in patients with these disorders, bulla develop in the dermis, and he considers it a disorder of the collagen in the dermis. Briggaman [2,3] used his technique of epidermal growth over dermis to demonstrate micro fibrils from the dermis to the epidermis. Dermis of patients with the recessive disease, however, did not form mierofibrils to normal epidermis. This could he easily explained by the increased collagen degradation that Francis found. The role of collagenase in this disorder is still unsolved, but it is probably a secondary phenomenon since it is increased six to eight times in the denuded area hut only slightly increased in normal collagen. Idowever, Bauer and co-authors [I] now definitely believe that collagenase is important in the blister formation. Tissue extracts from 33 patients with recessive and dominant dystrophic disease were examined. Immunoreactive collagenase by a specific radioimmunoassay technique revealed sometimes greatly elevated levels in completely unaffected skin. Nevertheless they can not claim that increased collagenase is the basic defect in epidermolysis bullosa dystrophica. However squamous cell carcinomas may produce co]lagenase [16] and, with the poor collagen formation, this would be a definite factor in the easy invasion into the dermis and metastases that characterize these benign appearing epidermal carcinomas. If collagenase is further stimulated by the inflammation [19] from the denuded areas with carcinomas, then a further explanation can be considered. H u m a n skin collagenase will degrade collagen fibrils under physiological conditions of temperature and p H [18]. The eollagenase is produced primarily in the papillary dermis and is inhibited by a component of normal human serum. Lazarus [18] found antibodies to denatured collagen in his patients similar to patients with rheumatoid arthritis [21]. The development of carcinoma in a chronic area of pseudoepitheliomatous hyperplasia must be also considered, but probably this is only partially valid since these patients have many chronically infected denuded areas with poor healing. This diagnosis was not made in nearly all our patients until further pathological examinations were performed.
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W.B. Reed et al.
Squamous cell carcinomas and more rarely, basal cell carcinomas will develop over scar tissue (thermal burus, lupus erythematosus and lupus vulgaris, and radiation). These squamous cell carcinomas readily metastasize, in contrast to the rare metastases of squamous cell carcinoma in normal individuals without these complications. Squamous carcinomas develop also in various genodematoses, in which the dermis is also likely to be defective (xeroderma pigmentosum, Rothmund-Thomson disease, Fanconi syndrome, Fanconi-like syndrome of Abels and Reed, and others). The scarring in epidermolysis bullosa dystrophica is best described as grossful defective with a papyraceous-like epidermis covering it. Keloidal scarring is not a feature. The mouth lesions mimic those of submucous fibrosis in which blisters and scarring occur in the mouth from the hot peppers eaten and tobacco chewed by Asiatic Indians [24]. Leukoplakia and later carcinoma develop an identical situation in part as seen in epidermolysis bullosa dystrophica. Immunological studies on these patients are difficult to do since venesection is even a complication. Goltz and Good in two of our patients (male siblings) reported benign hyperglobulinemic purposa. Coagulation defects have been reported in these patients. Leinbrock [20] found that his female patient had hypergammaglobulinemia, for most part glycoprotein elevations plus disturbed blood coagulation and cold agglutinins. Others have also found high values for gammaglobulin and an abnormal configuration at immunoelectrophoresis. Crikelair and co-authors found that one of their patients rejected more rapidly homographs from his mother [7]. In an extensive review of acquired epidermolysis bnllosa, Roenigk and his associates reviewed all known published cases and reported three new ones [27]. These patients develop blisters as the site appears with mucous membrane involvement and nail dystrophy. From their survey one would surmise that two diseases were etiologically important: multiple myeloma and amyloidosis (both disorders in which immunology plays an important part), although chronic ulcerative colitis and rheumatic carditis must also be considered.
Studies on Collagen
Total soluble and polymeric skin collagen amounts have been studied by the methods of Francis and Macmillian [ll] in five patients, four with carcinoma. Total collagen and extractable polymeric collagen was decreased in all patients; soluble collagen was within normal limits in three-fourths of the skin samples in which this estimate could be done. In addition, data has been obtained on the stability of the extracted polymeric collagen fraction to cold alkali and to pronase followed by thermal denaturation and to pronase followed by thermal denaturation treatments (Table 2). In all cases stability to pronase was decreased compared to age-matched controls; this decrease was generally more pronounced than that to cold alkali treatment. However, in only one case (No. 1) was the decreased stability extreme. These results suggest that there is no increased collagen biosynthesis in the skin of these patients and that the decreased amounts and stabilities of skin polymeric collagen could result from an increase in collagen turnover with the net
Epidermal Neoplasms with Epidermolysis Bullosa Dystrophica
13
Table 2. Stability of extracted polymeric collagen Patient
1~ 2 3a 4a 5a
Age
23 37 41 43 66
Sex
M F M M M
Pronase and heat treatment
Cold alkali
Patient
Age-matched controls b
Patient
15.5 61 73.5 67.5 58
80 -84.5-~ 84.5 :t: 84.5 :t: 86 :t:
13 8 8 8 8
9.5 72.5 79 70 73
Age-matched controls 80 ± 11 87 ~- 8 87 ~: 8 87 ± 8 87 4= 9
a Expressed as per cent of initial polymeric collagen sample that remains insoluble after treatment. b Means ± 2 SD. e Carcinoma(s). Cases from Ref. 24--25.
r a t e of collagen m e t a b o l i s m shifted towards degradation. T h e y are entirely c o m p a t i b l e with the findings of increased skin eollagenase a c t i v i t y f o u n d i n this conditions b y Lazarus. Y e t the p a t t e r n of collagen a b n o r m a l i t i e s is n o t extreme in four out of the five p a t i e n t s s t u d i e d a n d such collagen a b n o r m a l i t i e s as have been f o u n d m a y therefore all be secondary to a still undiscovered p r i m a r y cellular defect. I n t e r e s t i n g l y , Cockayne [5] listed the dystrophic epidermolysis bullosa as a disorder of eormective tissue, citing the absence of elastic fibers. Elastic fibers arc p r e s e n t in y o u n g patients, b u t are destroyed b y the c o n s t a n t insult to the skin. However, Cockayne was p r o b a b l y right for the connective tissue is i m p o r t a n t i n the pathogenesis of epidermolysis bnllosa dystrophica. Appreciation for their valuable help is extended to the following: Joseph College, Jr., of Eseondido, California--Tobias Gedde-Dahl of Oslo, Norway--Hugh Zachariae of Aarhus, Denmark--Mary Ann Sher of Johannesburg, South Africa--Terence Ryan of Oxford, England - - I a n Sneddon of Sheffield, England--Victor Torres-Rodriguez of San Juna, Puerto Rico-Frederick Mobs of Madison, Wisconsin--Richard Horowitz, Leo Weiss and Lillian Rowan of St. Joseph's Hospital, Burbank, California.
References 1. Bauer, E. A., Gedde-Dahl, T., Eisen, A. Z. : Role of human skin collagenase in dystrophic epidermolysis bullosa. Presented at Federation of Clinical Research, April 1974 2. Briggaman, R. A. : Epidermolysis bullosa. Acad. of Dermatology, Chicago, December 1973. 3. Briggaman, R. A., Dolldorf, F. G., Wheeler, C. E., Jr. : Formation and origin of basal lamina and anthormy fibrils in adult human skin. J. Cell Biol. 51, 381--392 (1971) 4. Calnan, C. D., Porter, A. D.: Recessive epidermolysis bullosa with unusual features. Trans. St. John Hosp. Soc. 83, 62--65, (1954) 5. Cockayne, E. A. : Inherited abnormalities of the skin and its appendages. London: Oxford University Press 1933 6. Cornelius, C. E., Shelley, W. B. : Syndaetylism, dyschromia and the arsenical dilemma. Arch. Derm. 98, 107--110 (1968) 7. Crikelair, G. F., Hoehn, R. J., Domonkos, A. N., Binkert, B.: Skin homografts in epidermolysis bullosa dystrophica. Plast. reconstr. Surg. 46, 89--92 (1970)
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8. Didolka, M.S., Gerner, R.E., Moore, G.E.: Epidermolysis bullosa dystrophica and epithelioma of the skin. Cancer 38, 198--202 (1974) 9. Eastwood, D. S. : Autographing in the treatment of squamous cell carcinoma in epidermolysis bullosa dystrophica. Plast. reconstr. Surg. 49, 93--95 (1972) 10. Edland, R. W. : Dystrophic epidermolysis bullosa: Tolerance of the bed and response of multifoeal squamous cell carcinomas to ionizing radiation: Report of a ease. Amer. J. Roentgenol. 105, 644--647 (1969) 11. Francis, M. J. 0., Macmillan, D. C. : The extraction of polymeric collagen from biopsies of human skin. Biochim. biophys. Aeta (Amst.) 251,236 (1971) 12. Gardner, V. C. : Discussion of a case of epidermolysis bullosa. Arch. Derm. 62, 767 (1950) 13. Gedde-Dahl, T. J. : Epidermolysis bullosa. A clinical genetic and epidermiological study. Baltimore: The Johns Hopkins Press 1971 14. Goltz, R., Good, R.A.: Benign hyperglobulinemic purpura: Relation to Mikulicz's disease, sicea syndrome and epidermolysis bullosa dystrophica. Arch. Derm. 83, 26--39 (1961) 15. Halpern, L. K.: Development of squamous cell epithelioma in epidermolysis bullosa: Report of a case. Arch. Derm. Syph. (Chic.) 56, 517--522 (1947) 16. Hashimoto, K., Yamanishi, Y., Maeyeus, E., Dubbous, M.K., Tomotsei, K. : Collagenolytie activities of squamous cell carcinoma of the skin. 17. Kalusner, E. : Zungenkrebs als Folgezustand bei einem Falle yon epidermolysis bullosa. Arch. Derm. Syph. (Berl.) 116, 71--79 (1913) 18. Lazarus, G. S. : Collagenase and connective tissue metabolism in epidermolysis bullosa. J. invest. Derm. 58, 642--648 (1972) 19. Lazarus, G. S., Daniels, J. R., Brown, R. S., Bladen, H. A., Fullmer, H. M. : Degradation of collagen by human granulocyte collagenolytes system. J. clin. Invest. 47, 2622 (1968) 20. Leinbrock, A.: Epidermolysis bullosa dystrophica et albo-papuloidea (Pasini) et nlcerovegetans (cure carcinoma) mit diffuser tI~imangiomatose bei Schilddriisen-Dysfunktion; wesentlich ver~nderte Blut- und Stoffwechselbefunde. Hautarzt 7, 395--3047 (1956) 21. Michaeli, D., Fudenberg, H.N.: Incidence of antibodies to denatured collagen in rheumatoid arthritis. Arthr. and Rheum. 14, 404 (1971) 22. Pearson, R. : The mechanobullous diseases. Dermatology in medicine. McGraw-Hill Book Company, a Bladiston Publication 1971, p. 621 23. Rasponi, L. : I1 Cancro sull'epidermolisi bullosa distrofica. Arch. ital. Derm. 23, 19--37 (1950) 24. Reed, W.B., College,J., Francis, M. J. 0., Zachariae, H., Moles,F., Sher, M. A., Sneddon, J. B. : Autosomal recessive epidermolysis dystrophiea with epidermal neoplasm. Arch. Derm. (in press) 25. Reed, W. B., Torres-Rodriguez, V., Francis, M. J. 0., Ryan, T., Torres, Candido: Dysstropic epidermolysis bullosa with epidermal neoplasms with emphasis on a dermal collagen defect. Presented at the Annual Birth Defects--National Foundation Meeting 1974, Newport, California 1974 (in press) 26. Rockl, H. : Carcinom bei epidermolysis bullosa dystrophica. Hautarzt 7,463--464 (1956) 27. Roenigk, H. It., Ryan, I. G., Bergfeld, W. F.: Epidermolysis bullosa acquista. Arch. Derm. 108, 1--10 (1971) 28. Schiller, F.: Zungencarcinom bei epidermolysis bullosa dystrophica. Arch. klin. exp. Derm. 209, 643--651 (1960) 29. Sonneck, H. J., ttantzschel, K. : Uber einen Fall yon Epidermolysis bullosa dystrophica mit Oesophagus stenose und Kardiocarcinom. Hautarzt 12, 124--125 (1961) 30. Wechsler, H. L., Krugh, F. J., Domonkos, A. N., Scheen, S. R., Davidson, C. L. : Polydysplastic epidermolysis bullosa and development of epidermal neoplasms. Arch. Derm. 102, 374--380 (1970) 31. Wetteland, P., Hovding, G.: Squamous cell carcinoma in dystrophic epidermolysis bullosa. Acta derm.-venereol. (Stockh.) 86, 27--36 (1967) Dr. William R. Reed 1013 W. Olive Burbank, California 91506 U.S.A.
