Skin Manifestations of Systemic Diseases: Some Viscerocutaneous Syndrollles

Skin Manifestations of Systemic Diseases SOllle Viscerocutaneous Syndrollles

KURT WIENER, M.D.*

IN THE vast majority of dermatological cases, even in extensive and severe ones, one is, for all practical purposes, dealing with "mere" skin diseases. Other organs or the system as a whole generally remains free of discoverable related symptoms. In dermatology, topical treatment still is more important than systemic medication. Yet, this apparent autonomy of the skin is, of course, only relative. One should not forget that there are many syndromes affecting the skin and other organs as well. This article deals with a few of the rarer ones. ACRODERMATITIS ENTEROPATHICA (Fig. 129)

It would be worthwhile if dermatologists as well as pediatricians would reappraise their severe and therapy-resistant cases in children of eruptions mainly localized around the orifices with the possibility of acrodermatitis enteropathica in mind. The dermadromes of this entity are solid areas of erythema, vesicular, bullous and crusty exudation, more sharply defined than eczema usually is, but not without some satellites. There is a tendency for the lower lip and the cheeks to be affected while the upper lip and the nose remain free except in extreme cases. Thus, a horseshoe pattern around the mouth may result, suggestive of the grotesque mask of a clown. The eyelids, the perianal and gluteal areas show similar lesions which again are strikingly well defined. The eruption is not necessarily confined to the orifices, though it originates and persists there. In intermissions, perleche may be the only visible holdout of the disease. Well defined patches may occur over the extensor surfaces of elbows and knees, on the insteps, and on fingers and toes. Here, over the knuckles and in the interdigital spaces, bullae are often clearly visible. The periungual skin is red, scaly and crusty, and after some time the nails become severely dystrophic. The bullae on the mechanically exposed parts together with the dystrophy of the nails may suggest epidermolysis bullosa. The tongue may be swollen and furrowed. Total alopecia during the attacks and regrowth of hair in the remissions is characteristic. The disease takes an intermittent course with more or

* Dermatologist, M ount Sinai, Evangelical Deaconess and St. M ichael' 8 Hospitals, Milwaukee, Wisconsin. 689

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Fig. 129. Acrodermatitis enteropathica. (Courtesy Drs. A. Lodin and H. Gentele, Stockholm, Sweden and Acta Dermato-Venereologica.)

less complete remissions and relapses which sometimes tend to increase in severity. Diarrhea is the outstanding symptom; unhappy and cranky disposition and physical and mental retardation accompany the intestinal upset. Monilia found in the gastrointestinal tract and in the mouth and skin is more likely to be secondary than causative. Giardia lamblia has also been found in the stools. The blisters are formed by separation above the basal layer of the epidermis. They contain single and clumped prickle cells. Hyperkeratosis and parakeratosis with benign dyskeratotic cells in the stratum mucosum are features of older verrucous lesions (Piper). At least six fatal cases are on record, one at the age of eight years. One relatively mild case in a woman of 46 years has been described by Piper who suggests that more such cases may be around. In eight instances, several siblings were affected and consanguinity of the parents existed at least four times, a high percentage if one considers that not more than

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50 cases have become known. Erosions of the sigmoid seem to be the only significant necroptic findings. Of great interest is the effective treatment with diiodohydroxyquinoline or related compounds (Diodoquin, Enterovioform) by mouth, originally suggested by B. H. Schlomowitz, an internist of Milwaukee. This drug which is absorbed only in minimal quantities apparently disinfects or otherwise modifies the intestinal content. It should be given in large amounts, up to 1600 mg. daily, subdivided in four doses. The differential diagnosis has to consider epidermolysis bullosa hereditaria, eczema and moniliasis. The start and the localization around the orifices (perleches), the alopecia, the bouts of diarrhea, the intermittent course and the relatively low mechanical vulnerability will help to differentiate from epidermolysis; e.g., in epidermolysis bullosa the bullae are located over the bony prominences of the hands, rather than interdigitally as in acrodermatitis enteropathica. The bullous tendency, the nail involvement, alopecia, periorificial location with relatively sharp borders, the intermittent course, intestinal disturbance and the retardation are no common traits of infantile eczema. If systemic infection with Monilia is considered, it must be ascertained by repeated and massive laboratory findings and by immunobiological tests. The beneficial effect of treatment with one of the diiodohydroxyquinQline preparations is also a diagnostic help. Literature The titles listed throughout the article have been restricted to works that contain a sufficient bibliography to lead to the older literature. Danbolt, N. and Closs, K.: Acroderma.titis Enteropathica. Acta dermat.-venereol. 23: 127, 1942. (First observation.) Dillaha, C. J., Lorincz, A. L. and Havik, O. R.: Acrodermatitis Enteropathica. J.A.M.A. 152: 509, 1953. Piper, E. L.: Acrodermatitis Enteropathica in an Adult. A.M.A. Arch. Dermat. 76: 221, 1957. One Hundred Clinical Cases Presented at XI Internat. Congr. of Dermatology, Stockholm, 1957. Publ. by Acta dermat.-venereol., 1958.

PAPULOSIS ATROPHICANS MALIGNA (KOHLMEIER-DEGOS)

Only about ten instances of this characteristic syndrome, also known as thrombangiitis cutaneointestinalis disseminata, have become known since K6hlmeier, in 1941, described the first case which he interpreted as a cutaneous form of Buerger's disease. This conception has been abandoned and a new etiologic concept has not evolved. The disease, which seems to affect mostly young men, starts with a cutaneous phase and ends dramatically with sudden and usually fatal intestinal complications. The dermadrome is a scanty papular eruption which appears in slow crops. The lesions start as skin-colored or pale pink, round or oblong papules; they are at first only a few millimeters in size but grow, in weeks, to a centimeter or a little more. They become umbilicated and the edge infiltrated and edematous. A central scale-crust develops in the course of weeks and months. Finally it is shed; leaving a porcelain-white, atrophic, pocklike scar (Fig. 130).

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Fig. 130. Papulosis atrophicans maligna. (Courtesy of Dr. G. Miescher, Zurich, Switzerland and Der Hautarzt, Springer Verlag.)

The eruption appears on the trunk and the extremities but spares face, head and palms. The patient's general well-being is very little disturbed. However, from three weeks to three years after the beginning of the cutaneous phase, acute abdominal attacks occur with the symptoms of ileus and peritonitis. In most cases, these complications have been fatal. The autopsies showed multiple intestinal necrotic lesions which ranged from highly inflammatory subserous plaques to necroses with perforations. The skin lesions are best described as a white cutaneous infarct corresponding to a thrombosing fibrinoid endangiitis which affects mostly the arterioles but also the veins. Degos, R.: Malignant AtrophicPapulosis; a Fatal Cutaneo-Intestinal Syndrome. Brit. J. Dermat. 66: 304,1954. Stauffer, H. and Miescher, G.: Papulose atrophiante maligne (Degos) (Thrombangiitis Cutaneo-intestinalis Disseminata). Hautarzt 8: 4-7, 1957.

PYODERMA GANGRENOSUM

This is not an extremely rare condition. There appear erythematous nodules in the skin which grow fast and often develop a blister on top which covers the beginning of a rapid breakdown. The lesion grows with a painful, undermining edge leaving a necrotic ulcer. At first, these ulcers are round, but later they become arc or kidney shaped or serpiginous. There may be only one lesion, a few, or hundreds of them. The growth of the ulcer may stop at the size of a centimeter in diameter, or it may relentlessly melt down the skin of a whole region, such as the entire abdomen, a large part of the chest wall, or it may girdle the lower leg. Regional lymphadenopathy is insignificant~ Healing may occur at any stage, sometimes surprisingly fast. In other cases, the ulcer becomes chronic. The scars are severe. The tissues and blisters are either sterile or

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harbor micro-organisms which are likely to be secondary invaders, such as cocci, Escherichia coli or Pseudomonas aeruginosa. Often, a focus of infection exists. Ulcerative colitis is the most common association; it has been found in more than half of the cases. Among the noncolitic cases, severe rheumatoid arthritis is a conspicuous finding besides abscessed teeth, chronic empyema, and chronic lung abscess. Recently, two cases with hypogammaglobulinemia were observed and gammaglobulin injections proved helpful (Bloom et al.). In a considerable number of cases, no systemic association could be established. In colitis there is sometimes a striking parallelism between exacerbations and remissions of the intestinal and the skin condition. Injections and other small traumas may provoke new lesions. There ·is a considerable mortality. The treatment is primarily directed to the focus. A trial with steroids in combination with antibiotics and/or sulfonamides (Azulfidine) is indicated. Here it may be added that pyoderma gangrenosum is the most dramatic but not the most frequent dermadrome of ulcerative colitis. It occurs in only 2 per cent of the colitis cases. Aphthae and other mouth lesions are ten times, boils and other pyodermic infections eight times, urticaria and erythema nodosum three to four times more frequent. In approximately two-thirds of the cases, the skin is not affected at all (Samitz and Greenberg). Ayres, s. Jr. and Ayres, S. Ill: Pyoderma Gangrenosum with an Unusual Syndrome of Ulcers, Vesicles and Arthritis. A.M.A. Arch. Dermat. 77: 269, 1958. Bloom, D., Fisher, D. and Dannenberg, M.: Pyoderma Gangrenosum Associated with Hypogammaglobulinemia. A.M.A. Arch. Dermat. 77: 406, 1958. Canizares, 0.: Cutaneous Lesions of Rheumatic Fever. A.M.A. Arch. Dermat. 76: 702, 1957. Clark, D. M.: Pyoderma Gangrenosum. Australian J. Dermat. 3: 17, 1955. Flood, L. M. and Lively, H. S.: Skin Lesions in Chronic Ulcerative Colitis. Guthrie Clin. Bull. 24-: 151, 1955. Perry, H. o. and Brunsting, L. A.: Pyoderma Gangrenosum. A.M.A. Arch. Dermat. 75: 380, 1957. Samitz, M. H. and Greenberg, M. S.: Skin Lesions in Ulcerative Colitis. Gastroenterology 19: 476, 1951.

CHRONIC LEG ULCERS AND OTHER ULCERATIONS OF THE SKIN

Ulcerations without the eruptive and progressive character of pyoderma gangrenosum may occur on the lower legs of patients with colitis. They also may reflect the ups and downs of the intestinal trouble. Chronic ulcers of the lower legs are quite frequently associated with blood dyscrasias. They occur most often (25 to 75 per cent) in sickle cell anemia, but also in hemolytic icterus, Cooley's anemia (Mediterranean disease) , thrombocytopenic and nonthrombocytopenic purpura, pernicious anemia, in various forms of polycythemia, and also in Gaucher's disease. Hypersplenism seems to be the common denominator, though splenomegaly is more often seen without leg ulcers. The typical anemia patients with leg ulcers are young individuals of both sexes. Ulcerations on infiltrated plaques for which no other cause is known should always be investigated for leukemia or Hodgkin's disease. Torpid ulcers, mostly on the lower legs, occur in about one-half per cent of sufferers from rheumatoid arthritis. They develop only in active

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stages of the disease and may heal with the return of quiescence. They are supposed to originate from rheumatic nodules. Felty's syndrome (Fig. 131) (chronic rheumatoid arthritis, splenomegaly, leukopenia, and

Fig. '131. Felty's syndrome. Severe chronic arthritis, leg ulcers, also other ulcerations. Hepatosplenomegaly. (Courtesy of Drs. A. Lodin and H. Gentele, Stockholm, Sweden and Acta Dermato-Venereologica.)

anemia) may be complicated by ulcers of the lower legs. These lesions seem to be related to those in severe anemias and splenomegalies, but rheumatoid arthritis is among the known associations of pyoderma gangrenosum. Adrenal steroids may be tried. Hjorth, N.: Felty's Syndrome with Ulcer of Leg. Acta dermat.-venereol. 34: 67, 1954. Pascher, F. R. and Keen, R.: Chronic Ulcers of Legs Associated with Blood Dyscrasias. A.M.A. Arch. Dermat. 66: 478, 1952. Schoch, E. P.: Ulcer of Leg in Felty's Syndrome. A.M.A. Arch. Dermat. 66: 384,1952. Veikko, A. L, Lanie and Kanko, J. v.: Ulcerations of Skin in Rheumatoid Arthritis. Acta rheumat.Scandinav.1: 113, 1955.

ENCEPHALOTRIGEMINAL ANGIOMATOSIS (STURGE-WEBER DISEASE)

._ "According to a recent review of 35 cases from the Mayo Clinic (Peterman et al.), the outstandingifeatures of this congenital syndrome are convulsions and widespread nevi flammei (port-wine stains), a combination which occurs in almost 90 per cent of the reported cases. In about two-thirds of the cases, intracranial convolutional calcifications could be demonstrated roentgenographically. Somewhat less often there occur ocular involvement (especially glaucoma), intellectual impairment and hemiparesis of the side opposite to the facial nevus or the roentgenologic signs. One patient with a bilateral nevus was quadriplegic. Later in life

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many patients suffer severely from seizures, blindness and retardation, but about half of them lead a comfortable life due to anticonvulsants and ophthalmological treatment and in a few cases after successful neurosurgical procedures. Angiomatosis and calcification of the pia mater and secondary destruction of the cerebrum are salient pathologic findings. A syndrome comprising progressive cerebellar ataxia with onset in infancy, progressive telangiectasia of the bulbar conjunctivae and of the so-called butterfly area over the nose and cheeks has recently been described in eight cases. Sinopulmonary infection, abnormal eye movements and retardation of growth are other possible features. The relationship to other neurocutaneous diseases is not clear. Boder, E. and Sedgwick, R. P.: A. Familial Syndrome of Progressive Cerebellar Ataxia, Oculocutaneous Telangiectasia and Frequent Pulmonary Infection. Pediatrics 21: 526, 1958. Peterman, A. F., Hayles, A. B., Dockerty, M. B. and Love, J. G.: Encephalotrigeminal Angiomatosis (Sttirge-Weber Disease). J.A.M.A. 167: 2169,1958.

KLIPPEL-TRENAUNAV'S SYNDROME (Fig. 132)

This anomaly is usually discovered early in life by the presence of a large, strictly unilateral nevus flammeus on the trunk or, more often, on one leg. When the mother buys the first shoes she may find that the foot

Fig. 132. Klippel-Trenaunay syndrome. Telangiectatic nevus, varicose veins and hypertrophy of the left leg. (Courtesy ofUnive:rsitatsklinik fur Raut- und Geschlechtskrankheiten [Prof. Dr. J. Tappeiner], Vienna, Austria and Der Rautarzt, Springer Verlag.)

on the side of the nevus is larger than the other. When the patient has reached~:adult age, the triad: (1) hypertrophy of one leg, arm, or::even the

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whole side; (2) an extensive fiat, smooth angioma of port-wine stain type; and (3) varicose veins, is complete. The abnormality may affect both sexes. The hypertrophy of the bones invariably leads to considerable lengthening of the extremity. The affected leg has been seen to grow 5 to 7 cm. (2 to 3 inches) longer and the circumference of the thigh 4.5 cm. (almost 2 inches) larger than the other side. The affected leg and also other parts regularly show some thick convoluted varicose veins. Arteriovenous anastomoses can be detected by angiographic methods. On the nevus the skin temperature is as much as 4.5 8 C. (8.1 0 F.) warmer than that on the other side. The nevus flammeus may follow a pattern of spinal innervation. Its surface. may be smooth or made uneven by underlying varicose veins. The outline is not always sharp, and the color of the angiomatous area may vary. The patients suffer most from the unequal length of the legs. At higher temperatures, they complain of discomfort in the affected parts. Occasionally, leg ulcers in the nevus have been observed. Atrophy instead of hypertrophy of the extremity has been reported. . Ippen, H.: Systematisierte Angiektasie mit Gliedmassen atrophie. Hautarzt 8: 317, 1957. Lausecker, H.: Klippel-Trenaunay und Parkes-Weber Disease. Hautarzt 3: 70, 1952. Meier, M.: Das Klippel.. .T renaunay Syndrome. Schweiz. med. W chnschr. 8J,.: 736, 1954. Zelger, J.: Klippel-Trenaunay's Disease. Hautarzt 6: 165, 1955.

ANGIOKERATOMA CORPORIS DIFFUSUM (FABRY) (Fig. 133)

The onset of this rare condition is inconspicuous and occurs early in life. The fully developed eruption covers trunk and extremities, particularly the genitals, the groins and the inferior aspect of the buttocks. Other concentrations are seen in the belt area and the extensor sides of elbows and knees. The face and the mucosae are rarely affected. The eruption consists of highly monomorphous, discrete, pinhead-sized macules or slightly elevated papules of purple to black color which do not blanch under glass pressure. The general picture of this eruption remains the same throughout life. So far, this disease has been seen only in males. There were isolated and familial cases (three brothers). Quite regularly, the patients suffer from pains and spasms in hands and feet, persistent edema of the lower legs (which was not due to cardiorenal insufficiency), moderately raised blood pressure, cardiac enlargement and chronic albuminuria. Several biopsies and necropsies have shown that this anomaly is a systemic disorder affecting the smooth muscles, especially in the media of the blood vessels of the skin and of many internal organs, by deposits of a phosphatid lipid. As a result of the ubiquitous vascular changes, bizarre clinical symptoms can be expected besides those already named. Bone disturbances, retinal changes, and at least two cardiac deaths are known. Angiokeratoma corporis diffusum (Fabry) should not be confused with angiokeratoma neviforme (Fabry) which involves only one or more regions and which shows varicosities and multiple larger superficial cavernous angiomas which slowly come and go. More important is the differentiation from Rendu-Osler's disease. In this last-named diffuse vascular disease, the· face and upper part of the chest are mainly affected. Serious hemorrhages may originate from mucosal lesions in the nose and mouth.

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The skin lesions are more polymorphous than in angiokeratoma corporis diffusum, ranging from linear and punctate telangiectasias to vascular spiders and small angiomas. Pittelkow, R. N _, Kierland, R. R. and Montgomery, H.: Angiokeratoma Corporis Diffusum. A.M.A. Arch. Dermat. 72: 556, 1955. Ruiter, M.: Angiokeratoma Corporis Diffusum. A.M.A. Arch. Dermat. 68: 21, 1953.

PSEUDOXANTHOMA ELASTICUM

The skin part of this syndrome consists of pale yellow or sometimes darker plaques composed of discrete or coalescent, papular, flat, smooth, firm lesions which are frequently arranged in rows along the folds and, once developed, do not undergo further changes. The skin between the rows is often atrophic, reminiscent of striae. Connections between the rows may sometimes· create a pattern which has been compared to a

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knitted material or to the skin of a plucked chicken. ThEJ#~J)atches of pseudoxanthoma elasticum are found mostly on the sides of the neckJ in the axillae, occasionally in the groins or on the abdomen. In rare cases, almost the entire skin and also the adjacent mucosae may be involved. Commonly, the patches are about palm-sized, but they may be much larger. The onset of the dermatosis is insidious and most often noted in the third decade of life. There is neither itching nor pain. Both sexes are equally susceptible. Consanguinity of parents and a usually recessive type of heredity have been demonstrated. For a long".time, pseudoxanthoma elasticum was thought to be a harmless, benign d.ermatosis with only cosmetic implications, and interesting only by its unique histology. A broad band of thickened, fragmented, basophilic 'fibers, more likely of elastic than of collagen nature, is seen in the lower cutis, separated from the epidermis by a normal zone. Calcium deposits are' common and may reach clinically demonstrable size. In 1929, E. :Gronblad discovered that pseudoxanthoma elasticum of the skin is frequently accompanied by characteristic bilateral, ophthalmoscopic changes in the retina, namely a pattern of streaks radiating from a peripapillary ring and roughly following the blood vessels. These "angioid streaks" are one-half to four discs wide and usually reddish brown but may vary in color. Other concomitant ocular changes have been seen, and the vision is more or less disturbed in 70 per cent of the cases. The lesion is caused by elastica changes in Bruch's membrane beneath the retinal vessels. Mter the discovery of the syndrome pseudoxanthoma elasticum with angioid streaks (Gronblad-Strandberg syndrome) it could be expected that the degeneration of the elastic fibers would not affect skin and eye alone; typical changes in apparently normal skin were discovered. The elastic tissue in the blood vessels of many organs have since been found to take part in the degeneration. Serious bleeding, without blood changes, from the nose, the stomach and the uterus have been reported in patients with pseudoxanthoma. Dyspnea on exertion, intermittent claudication, and absence or weakness of peripheral pulses have been observed together with plethysmographic abnormalities. Many patients with pseudoxanthoma elasticum present stenosed or obliterated vessels at a comparatively early age (Bafverstedt and Lund). Patches histologically comparable with the skin changes have been discovered in the endocardiuni and pericardium. Diabetes, thyroid and other endocrine dysfunctions. seem to be more often associated with pseudoxanthoma than can be expected to occur by mere chance. Nevertheless, there are many instances of cutaneous pseudo..' xanthoma unaccompanied by other clinical symptoms and, with the sunjects in apparently unimpaired health. The syndrome of this form of elastic degeneration is probably 'still incomplete. Paget's disease of the bone which in 8 per cent is associated with angioid streaks has so far been observed only twice with pseudoxanthoma elasticum, possibly a new triad. Bii.fverstedt, B. and Lund, F.: Pseudoxa.nthoma Elasticum and Vascular Disturbances. Acta dermat.-venereol. 35:438, 1955. Kaplan, L .. and Hartmann, S. W.: Elastica Disease. Ar9h. Intern. Med. 94:489,1954. Loria,P. R., Kennedy, C. B., Freeman, J. A. and;Madd Hennington, V.: Pseudoxanthoma Elastioum. A.M.A. Arch. Dermat. 76: 609, 1957.

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Shaffer, B., Copelan, W. and Beerman, H.: Pseudoxauthoma Elastic\1m. A.M.A. Arch. Dermat. 76: 622, 1957. Szymanski, F. J. and Caro, M. R.: Pseudoxanthoma Elasticum. A.M.A. Arch. Derm. 71: 184, 1955.

PERIORAL PIGMENTED SPOTS ASSOCIATED WITH INTESTINAL POLYPOSIS (PEUTZ-JEGHERS' SYNDROME) (Figs. 134 and 135)

In 1921, Peutz observed in one family eight cases of a peculiar pigmentation of the face and the mucoust;membranes associated with intestinal polyposis. In 1949, Jeghers and his associates renewed the interest in this striking combination and up to now about 75 cases have been reported. Generalized polyposis intestinalis is a hereditary disease which

Fig. 134. Pigmented spots in familial intestinal polyposis. (Courtesy of Drs. K. Kitamura, R. Kojima, S. Sasagawa, Tokyo, Japan and Der Hautarzt, Springer Verlag.)

follows a dominant pattern of transmission. Great numbers of polyps of all sizes may cover the mucosa exclusively or predominantly of the small intestine frequently leading to bleeding, obstruction from intussusception or cancer. In these hereditary cases of polyposis,·pigmented spots around

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Fig. 135. Pigmented spots in familial intestinal polyposis. Bottom, Hyperpigmentation of basal cell layer (lower lip). (Courtesy of Drs. K. Kitamura, R. Kojima, S. Sasagawa, Tokyo, Japan and De~ Hautarzt, Springer Verlag.)

the mouth usually become visible in infancy. If fully developed, they appear as sharply outlined round, oval or irregular black to brown spots of pinhead to split-pea size mostly on and around the lips, especially the lower lip, but also in smaller numbers around the nostrils, on the eyelids, palms, soles and on the volar aspects of the fingers and about the toes. If the dermadrome is pronounced, the lips look as if they had been.spattered with tiny drops of India ink. Similar pigmented spots have been found in the mouth. If the patients are anemic from bleeding polyps, the pallor of their skin makes the unusual discoloration still more striking. The pigmentation tends to become less conspicuous later in life. Cases of generalized polyposis without the pigmentary disorder (which is sometimes called "lentiginosis") are known. The pigment is melanin.

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There are nonJamilial cases of polyposis which may develop much later in life and show diffuse or cWoasmatic brownish pigmentations of the face, alopecia and dystrophy and loss of nails. Diffuse hereditary polyposis oJ the colon does not seem to develop the black spots. However, it has been reported at least in two families associated with/amilial multiple sebaceous cysts. Members .of these families afflicted with sebaceous cysts do not always have polyposis. Bartholomew, L. G., Dahlm, D. C. and Waugh, J •.M.: Intestinal Polyposis Associated with Mucocutaneous Melanin Pigmentation (Peutz-Jeghers Syndrome). Proc. Staff Meet., Mayo Clin. 32: 675, 1957. CrQnkhite, L. W. Jr. and Canada, W. J.: Generalized Gastrointestinal Polyposis: Syndrome of Polyposis, Pigmentation, Alopecia, Onychodystrophy. New England J. Med. 252: 1011, 1955. Elconin, D. V. and Elconin, A. N.: Diffuse Polyposis of the Colon. Wisconsin M. J. 57: 289,1958. Kitamura, K., Koiima, R. and Sasagawa, S.: Zur Frage des Syndroms von Peutz-Jeghers. Hautarzt 8: 154, 1957. Oldfield, M.C.: Association of Familial Polyposis of Colon with Multiple Sebaceous Cysts. Brit J. Surge 4-1: 534, 1954.

DERMADROMES OF VISCERAL CANCER

Functioning Carcinoid (Carcinoid Syndrome)

The nature of this syndrome has only recently become clearer. The carcinoids are metastasizing tumors mostly of the small bowel which, apparently only ina fraction of the cases, produce large amounts of serotonin (5-hydroxytryptamine). This substance is found normally in the serum in a concentration of 0.4 mg. per cc. and in the urine its metabolites range.from 2 to 9 mg. per 24 hour specimen. In the so-called functioning carcinoid, these values may rise to 15 mg. and 800 mg. respectively. The main clinical symptoms of the functioning carcinoid are respiratory distress resembling asthma with stridor, and reduced mobility of the valves of the right heart which may lead to decompensation, frequent watery diarrheas and other gastrointestinal symptoms. Anyone of these symptoms may be absent, either at times or permanently. In the skin, a characteristic flush, or as a French author aptly called it, a "vascular storm," has been observed many times (Kierland et al.). The flush affects the face, the neck and particularly the classic flush area of the neck V. It usually subsides after ten minutes, but may last up to 30 minutes and also affect much more terrain or even the entire body surface. The patient has a feeling of heat and stiffness in the flush areas and there may be complaints about paresthesias in the fingers. The scleras are injected. The erythema tends to be cyanotic in some spots and bright red or bluish-red in others so that a patchy coloring results. The fading starts in the center and progresses peripherally, leaving gyrate and serpiginous patterns. Such attacks may occur occasionally or many times daily. They may be spontaneous or precipitated by eating, palpation of the tumor, enemas and other trigger factors. Gradually, the patient takes on a plethoric facies as though having polycythemia vera, but the blood findings remain normal. The microscopic findings (Montgomery and Kierland) show dilatation of veins and capillaries .and some thickening of the vessel walls, including the arterioles. There is chronic inflammation. The functioning carcinoid syndrome was seen in 3 percent

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of 199 cases studied by the Armed Forces Institute of Pathology (J. C. Shafer in discussion to Kierland). Apparently, at least some of the patients had the flush. Shafer also mentions the occurrence of pellagrinoid changes which can be explained by the fact that 60 per cent instead of the normall per cent of the daily tryptophan intake is used up to produce serotonin so that not enough remains to synthesize nicotinic acid and protein. Geoffrey and J ouanneau: Carcinoidosis Symposium. La semaine des hopitaux. 34.: 647, 1958. Kierland, R. R., Sauer, W. G. and Dearing, W. H.: Cutaneous Manifestations of the Functioning Carcinoid. A.M.A. Arch. Dermat. 77: 86,1958.

Acanthosis Nigricans

This rare dermatosis appears in the axillae (see Fig. 138, page 721), the nape of the neck, the genitals, the groins and inner thighs, the navel, but in exceptional cases also in other parts which are subject to maceration, folding and friction. The lips and the oral mucosa may participate. The eruption consists of pinhead to split pea-sized, mostly discrete, flat, rounded papules. According to the degree of development, a few or many of these papules, especially those in the large folds, start to vegetate. Thus, large moderately papillomatous beds traversed by deep furrows may ensue. Some pigmentation is present from the beginning, but the more pronounced the papillomatous proliferation is, the darker is the color. There are mild degrees of acanthosis nigricans which occur in obese brunette women and disappear with weight reduction. Helen O. Curth called attention to these cases and called them pseudo-acanthosis nigricans. She analyzed the available material and established that if acanthosis nigricans appears later in life or even shortly after puberty the patient is almost certain to have or to get internal cancer. This is most frequently a highly malignant abdominal adenocarcinoma, though association with such apparently peripheral neoplasms as dermatofibrosarcoma protuberans has been seen. The dependence of the dermatosis on the neoplasm is also demonstrated by disappearance of the skin lesions after removal and their reappearance after recurrence of the tumor. If acanthosis nigricans makes its appearance before or at puberty, it does not indicate cancer. There are, however, a few cases which do not follow this pattern. The greatest difficulty arises from the usually mild cases of pseudo-acanthosis nigricans in adult women. The histopathologist is unable to draw a sharp line. The difficulty becomes still greater through the existence of some clinically related rare dermatoses (Kesten) . Yet, the appearance of acanthosis nigricans in an adult remains an alarming signal. The benign or juvenile form is often associated with developmental or endocrine anomalies such as hypercorticoidism, hypogonadism, obesity, diabetes, etc. At least one of the juvenile cases has later developed a fatal diffuse basophilism of the pituitary (Rothman). Despite the small area of overlapping, the general divergence of the prognostic significance of the two types remains an important fact. While the pathogenesis of acanthosis nigricans is still unknown, it seems that the dermatosis is the response to an inciting agent which originates from hormonal imbalance or from the neoplasm or from some

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unknown source. The susceptibility of the skin to respond in this way is rare and a hereditary factor may be important. The great significance of the adult form of acanthosis nigricans lies in the fact that it is the only known noncancerous skin change which almost certainly indicates visceral cancer. Curth, H. 0.: Significance of Acanthosis Nigricans. A.M.A. Arch. Dermat. 66: 80, 1952. Curth, H. 0.: Dermatoses and Malignant Internal Tumors. A.M.A. Arch. Dermat. 71: 95, 1955. Kesten, B. M. and Jamel, D. H.: Pseudoatrophoderma Colli, Acanthosis Nigricans and Confluent and Reticular Papillomatosis. A.M.A. Arch. Dermat. 75: 525, 1957. Marafion, G. and Alvarez Cascos, M.: Die gutartige jugendliche "Acanthosis nigricans"ihr Zusammenhang mit den angeborenen Missbildungen. Acta Dermat.-Venereol. 37: 249, 1957. Melczer, N. and Dvorsky: Acanthosis Nigricans bei Dermatofibroma protuberans, etc. Hautarzt 8: 54, 1957. Sheldon, S. A. and Curtis, A. G.: Juvenile Acanthosis Nigricans, etc. A.M.A. Arch. DermaL 72: 63, 1955.

Dermatomyositis and Scleroderma in Relation to Cancer

A relationship exists between dermatomyositis and carcinoma. Such an association was found in 6.7 per cent of 276 "classic" cases of dermatomyositis from the Mayo Clinic. This percentage is much lower than previous ones in smaller series. In this unique series, there were twice as many females as males. The adenocarcinomas of breast and colon are predominant. The appearance of the cancer may precede, accompany or follow the outbreak of dermatomyositis. Among 125 cases of progressive and generalized scleroderma, eight associated malignancies were found which is about the same incidence (6 per cent). There were less than 2 per cent in 235 cases of localized scleroderma.

Treatment of the malignancy has been followed by improvement of the dermatomyositis but recurrences of the cancer did not seem to stimulate the disease with the same regularity as seen in acanthosis nigricans (Curth).

Christianson, H. B., Brunsting, L. A. and Perry, H. 0.: Dermatomyositis. A.M.A. Arch Dermat. 74: 581, 1956. Curth, H. 0.: See Acanthosis Nigricans. Schuermann, H.: Maligne Tumoren bei Dermatomyositis und progressiver Sclerodermie. Arch. Dermat. u. Syph. 192: 575, 1951. Sheard, C. Jr. and Knoepfler, P. T.: Dermatomyositis and Incidence of Associated Malignancy. A.M.A. Arch. Dermat. 75: 224, 1951.

Nonspecific Dermatoses Sometimes Associated with Internal Cancer

Pruritus without visible lesions, general hyperpigmentation and also prurigo-like eruptions (small, quickly excoriated papules) have many

times been seen to accompany visceral, in particular gastrointestinal and hepatic, cancers and lymphoblastomas-especially Hodgkin's disease. Bullous eruptions resembling dermatitis herpetiformis, urticaria, purpura, eczema, exfoliative dermatitis, gyrate, migrating erythemas and such combinations as purpuric dermatitis with widespread superficial necrosis have been described, but they are rare and in the absence of large series it is difficult to ascertain or prove their nature as dermadromes of

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cancer. Sometimes they precede the malignancy so closely that they could act as a warning signal. They may subside with successful surgery and reappear if the cancer recurs. In some instances, the biopsy from a clinically nonspecific exanthem showed carcinomatous infiltration. The pronounced tendency toward multiple peripheral thromboses in cancer of the pancreas is known. An extremely rare event is the diffuse bluishblack discoloration of the face, neck and hands in metastasizing malignant melanoma. Icterus and pruritus in massive invasion of the liver or obstruction of the biliary system, secondary pellagroid symptoms occasionally seen in gastric cancer and the pallor of a patient with a bleeding malignancy can also be looked upon as dermadromes of visceral cancer. For practical purposes, it is important to recognize that all known dermadromes of visceral cancer are rare. One may see hundreds of internal cancer cases without encountering a single instance of the conditions described. Curth, H. 0.: See Acanthosis Nigricans.

Skin Metastases froIn Visceral Cancer

These are infrequent (1 to 3 per cent). While any otherwise unexplained cutaneous or subcutaneous nodule may prove to be a metastasis of a visceral cancer, a certain pattern of the distribution of secondaries is recognizable. One must assume that the dispersal takes place via the blood stream with the liver as a first station. The scalp is a favorite location. The literature gives the impression that the seeds from urogenital malignancies, e.g., seminomas and prostatic cancers, have a special tendency to germinate in the scalp where they may resemble sebaceous cysts or in advanced stages turban tumors. Such cases with a large number of metastatic tumors almost exclusively in the scalp suggest a special mechanical catch mechanism or particularly favorable thermal or chemical conditions in this area. But this special scalp predisposition must be present only in certain persons, since in the vast majority of metastasizing cancers no scalp metastases occur. Cancer of the breast frequently produces skin metastases in the neighborhood of the primary lesion or of the operative scar. Carcinoma of the stomach may produce cutaneous and subcutaneous nodules in any part of the body, but predominantly of the trunk. Cutaneous metastases from other malignancies occur occasionally. It is a general experience that skin metastases of visceral cancers do not spell impending death. The patient may live for an unexpectedly long time, even several years (Schiff). Sometimes, e.g., in differentiated adenocarcinomas, it is possible to approximate the primary site from the pathological structure of the metastatic nodule. Gonzago, R.: Metastatic Cancers of the Skin. Portugal med. 36: 641, 1952. Abstr. Exc. Med. 7: 395, 1953. Montgomery, H. and Kierland, R. R.: Metastases of Carcinoma to Scalp. Arch. Surge J,.O: 672, 1940. Schiff, B. L.: Tumors of Testis with Cutaneous Metastases to Scalp. A.M.A. Arch. Dermat. 71: 465,1955. Wiener, K.: Skin Manifestations of Internal Disorders (Dermadromes). St. Louis, C. V. Mosby Co., 1947. 425 E. Wisconsin Avenue Milwaukee 2, Wisconsin