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VOLUME 18 NUMBER 5 PART 2 MAY 1988

I II I I

Toxic epidermal necrolysis in a patient affected by mixed essential cryoglobulinemia Antonio Solinas, M.D.,* Francesca Cottoni, M.D.,** Francesco Tanda, M.D. ,*** and Andreina Tocco, M.D.**** Sassari, Italy

A patient with mixed essential cryoglobulinemia and polysystemic involvement developed cutaneous lesions characterized by erythematopurpuric maculae and blisters over his entire body. Such lesions appeared during the course of treatment with prednisone and cyclophosphamide when penicillin was added to the therapeutic regimen. The diagnosis of drug-related toxic epidermal necrolysis was made on the basis of clinical history and histologic features. The possible relationship with the underlying immunologic aberration and the active immunosuppression is discussed. (J AM ACAD DERMATOL 1988;18: 1165-9.)

The clinical spectrum of mixed essential cry- oglobulinemia includes skin lesions, arthralgias, and myalgias with renal and hepatic involvement. 1

Skin lesions are mostly represented by purpura, Raynaud's phenomenon, and leg ulcers. 2"3 Renal involvement includes diffuse and focal prolifera- tive glomerulonephritis. These disorders seem to represent an immune complex type of vasculi- tis, 4 and, in fact, mixed cryoglobulins are cold- precipitable rheumatoid factors that interact with complement: Moreover, IgM, IgG, and comple- ment components have been localized in cutaneous and renal lesions.

In view of this pathogenesis, prednisone and cyclophosphamide have been employed in the treatment of these patients:

We report here a case of a patient with typical initial findings of mixed essential cryoglobulin- emia and later development of penicillin-related toxic epidermal necrolysis during the course of treatment with prednisone and cyclophosphamide.

From the Istituto di Patologia Mediea,* the Istituto di Clinica Der- matologica,** the Istituto di Anatomia Patologica,*** and the Servizio di Immunopatologia,**** Universit~t di Sassari.

Reprint requests to: Dr. Antonio Solinas, Istituto di Patologia Medica, Viale S. Pietro, 12, 07100 Sassari, Italy.

CASE REPORT

A 62-year-old man was admitted to our hospital in March 1983 because of fever and arthralgias. He had been well until 8 years before admission, when he no- ticed palpable purpuric, nonpruritic lesions on his legs, The purpura had an intermittent course with sponta- neous recovery, and he did not seek medical advice. One year before admission, he was admitted to another hospital because of dysphonia. A biopsy specimen of his right vocal cord showed the features of squamous cell carcinoma. He received a course of radiotherapy, which was followed by complete remission. Physical examination on that occasion showed that his liver was palpable 3 cm below the costal margin. Laboratory tests revealed a nine-fold increase of alanine transaminase. The immunoglobulin levels were as follows: IgG, 2260 mg/dl (normal, 650-1500); IgM, 640 mg/dl (normal, 40-230); and IgA, 169 mg/dl (normal, 60-300). Results of hepatitis B surface antigen assay were negative. No evidence of metastases was obtained. Three months before admission the patient developed intermittent fe- ver (38 ° to 39 ° C), polyarthralgias, and productive cough. He was started on a regimen of penicillin and gentamicin. No amelioration was observed, and he was referred to our hospital.

On physical examination the patient's skin was hy- potrophic and anelastic, with areas of dyschromia on both legs and reduction of body hair. No purpuric le- sions were observed. Lymph nodes were not enlarged.

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The chest examination revealed a prolonged expiratory phase with wheezing. The patient's heart rate was 90 beats/roAn, and blood pressure was 180/100 mm Hg. His liver was palpable 6 cm below the costal margin, his spleen was not palpable, and there was no ascites. Genitalia were normal, and findings of the neurologic examination were normal. There was no evidence of a relapse of the carcinoma of the vocal cord as determined by laryngoscopy. Raynaud's phenomenon was not elic- ited by exposure to cold.

Laboratory tests showed that the white blood cell count was 10,600/mm 3, with the differential count as follows: neutrophils, 81%; eosinophils, 1%; lympho- cytes, 16%; and monocytes, 2%. The platelet count and the liver function test results were normal. Creatinine clearance was 40 mllmin (normal, 70-120), and uri- nalysis revealed microscopic hematuria. The level of C3 fraction of complement was 153 mg/dl (normal, 83-177), and the C4 fraction was undectable (normal, 15-45). The IgG level was 1440 mg/dl, and the IgM level was 662 mg/dl. Non-organ-specific autoantibod- ies and antibodies to double-stranded deoxyribonucleic acid were not detected. Sputum, blood, and urine cul- tures were repeatedly negative.

The chest x-ray film showed moderately increased transradiancy. Total body gallium scan did not reveal metastases. The electrocardiogram showed supraven- tricular and ventricular extrasystoles and flattened T waves on peripheral and left precordial leads. Bone marrow smears and culture were normal. The cryoglob- ulin search was positive, with a cryocrit of 7%. Im- munoelectrophoresis of the cold precipitate was nega- tive for gamma, mu, kappa, and lambda chains.

A liver biopsy specimen was obtained and showed the features of chronic nonspecific reactive hepatitis. A kidney biopsy was refused. A skin biopsy specimen from the left leg showed atrophy of the epidermal layer with deposition of iron in the papillary dermis. Im- munofluorescence findings were negative.

The diagnosis of mixed essential cryoglobulinemia with polysystemic involvement was made, and the pa- tient was started on a regimen of prednisone, 100 mg every second day, and cyclophosphamide, 150 mg/day. His temperature declined to normal values, and creat- inine clearance went up to 60 ml/min. An attempt to discontinue cyclophosphamide was followed by a re- lapse with fever and arthralgias. A maintenance sched- ule of prednisone, 25 mg every second day, and cyclo- phosphamide, 100 rag/day, was therefore instituted.

Bimonthly controI evaluations after the patient was discharged showed that lddne3r function was stable and the white blood cell and platelet counts were within normal limits. No purpuric lesions were observed. In

spite of the clinical amelioration, cryocrit levels and the composition of cryoprecipitate did not show any change. C4 levels also remained below the normal range. Fourteen months after discharge the patient com- plained of rigors, arthralgias, and continuous fever. He was started on a regimen of penicillin, 1 gm/day, by his family physician. A rash developed 3 days after the beginning of therapy, and the patient was admitted to the dermatology department.

On physical examination the patient appeared se- verely ill. His temperature was 39 ° C, blood pressure was 160/90 mm Hg, pulse rate was 120 beats/rain, respiratory rate was 30/min. Skin lesions initially con- sisted of erythematopurpuric maculae spread over his entire body, reminiscent of target lesions of erythema multiforme (Fig. 1). They rapidly became confluent and were followed by the explosive appearance of large blisters, which easily ruptured and left large denuded areas. The histologic features of these lesions are re- ported below. Laboratory tests showed that the white blood cell count was 7500/mm 3, with the following differential count: neutrophils, 69%; eosinophils, 18%; basophils, 8%; and lymphocytes, 5%. Immunoglobulin levels were as follows: IgG, 445 mg/dl; IgM, 38 mg/dl; and IgA, 29 mg/dl. The C3 level was 12 mg/dl, and the C4 level was 9.04 mg/dl. Alanine transaminase showed a fourfold increase, and the serum creatinine level was 1.5 mg/dl. There was no evidence of infection. Because of the severe skin lesions, the dosage of prednisone was increased to 1 gin/day and cyclophosphamide was given in a dose of 100 rag/day. Cimetidine was given to prevent gastric bleeding.

Three days after the patient's admission, the white blood cell count was 1700 mm 3, with the following differential count: neutrophils, 77%; lymphocytes, 19%; and monocytes, 4%. An analysis of peripheral blood lymphocyte subsets by monoctonal antibodies disclosed that T lymphocytes were decreased to 50/mm 3 (normal, 1300-2300), with a CD4 + (helper-inducer) to CD8 + (cytotoxic-suppressor) ratio of 0.19 (normal, 1.1 to 3.5). In spite of adequate blood volume expansion, serum creatinine levels progressively increased within 5 days. Melena supervened, and the patient died 7 days after admission. Postmortem examination was refused.

HISTOLOGIC FINDINGS

A skin biopsy was performed on the second day after the patient's admission to the dermatology department. The skin sections were characterized by slight atrophy with scattered areas of basket-weave-like hyperkera- tosis and focal hypergranulosis. Necrosis of the indi-

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Toxic epidermal necrolysis in essential cryoglobulinemia 1167

Fig. 1. Appearance of the skin at presentation. Erythematopurpuric target lesions are scattered over the entire body, including the soles, and tend to be confluent. Fig. 2. Massive necrosis of keratinocytes, forming a subepidermal blister. Fig. 3. Vacuolar degeneration of the basal cells and extravasated erythrocytes in the papillary dermis and the epidermis.

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vidual keratinocytes was observed both at the dermo- epidermal junction and in the lower third of the mal- pighian layer. The necrotic keratinocytes showed a pyknotic nucleus and eosinophilic, hyalinized cyto- plasm. Some necrotic keratinocytes tended to be con- fluent, leading to the formation of subepidermal blisters (Fig. 2). Vacuolar degeneration of the basal cells was also observed at the dermoepidermal junction, and in the papillary dermis a diffuse, lichenoid type of infil- tration, consisting mainly of lymphocytes and scanty plasma cells, was present. This infiltration tended to involve the epidermis, particularly in the areas of ne- crotic keratinocytes. Many extravasated erythrocytes were present both in the papillary dermis and in the epidermis (Fig. 3). Vacuolar alterations, necrotic ker- atinocytes, and lymphocytic infiltration were also ob- served along the external sheath of the pilosebaceous apparatus. The mid dermis showed only a slight peri- vascular infiltration. The reticular dermis was normal. Irnmunohistologic study of the same specimen by direct immunofluorescence revealed a granular deposition of IgA, IgM, and C3 around the vessels and a granular deposition of C3 and fibrinogen at the dermoepidermal junction.

DISCUSSION

We have described the case of a patient with mixed essential cryoglobulinemia with multisys- tern involvement. The typical immunologic char- acteristic of this disorder is an immunoglobulin hyperproduction in which the T lymphocyte sup- pressors are probably functionally defective. 7 The treatment suggested in such cases consists of a combination of prednisone and cyclophospha- mide, which is employed in similar clinical con- ditions, such as glomemlonephritis occurring dur- ing the course of systemic lupus erythematosus and leukocytoclastic vasculitis.

Prednisone and cyclophosphamide given to our patient led to progressive immunosuppression. The described cutaneous alterations occurred in this clinical setting.

In the differential diagnosis of these lesions, systemic lupus erythematosus, erythema multi- forme, toxic epidermal necrolysis, and graft- versus-host disease must be considered. 8

Neither clinical nor laboratory criteria, however, justified the diagnosis of systemic lupus erythe- matosus. In contrast with our findings, the histo- logic lesions of systemic lupus erythematosus are

normally distinguished by a marked liquefaction degeneration of the basal layer cells, whereas ne- crosis of single keratinocytes is not equally no- ticeable. Moreover, the collagen bundles usually appear thickened because of the precipitation of fibrinoid material on them and because of edema of the papillary dermis. The diagnosis of erythema multiforme is suggested both by the initial mac- roscopic appearance of the cutaneous lesions and by numerous histologic aspects (see necrotic ker- atinocytes and the infiltrate type). Hydropic de- generation, on the other hand, which is charac- teristic of erythema multiforme, was not present in this case. Moreover, the immunoglobulin de- posit was observed at the dermoepiderrnal junction and not around the vasal wails, as usually found in erythema multiforme. Drug-related toxic epi- dermal necrolysis should be considered the most accurate diagnosis. In favor of this diagnosis is the patient's anamnestic data, consisting of the use of an antibiotic some days before the appearance of the lesion, the transient eosinophilia, and the histologic findings. The pathogenesis of toxic epi- dermal necrolysis is not known, although Saurat 9 considers this lesion to be the result of an acute lymphocytoxic reaction directed against the epi- dermis. This process is characterized by the se- lection of cytotoxic T clones with specificity against the keratinocytes, with a concomitant de- fect of the specific suppressor T lymphocytes. The administration of drugs such as antibiotics has been associated with the pathogenesis of toxic epi- dermal necrolysis, but it has not always been pos- sible to determine the moving cause, lO The case we have described shows that toxic epidermal ne- crolysis may also occur during the administration of immunosuppressive drugs. We cannot state whether the immunoregulative defect caused by the mixed cryoglobulinemia, or the immunosup- pressive treatment itself, contributed in this par- ticular case to the pathogenesis of the cutaneous lesions. The analysis of the lymphocyte subsets in the peripheral blood showed a global reduction of the T lymphocytes and a definite inversion of the CD4 +/CD8 ÷ ratio, and these effects could prob- ably be attributed to the relative increase of the cytotoxic T lymphocytes.

It may be presumed that, through the effect of

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Toxic epidermal necrolysis in essential cryoglobulinemia

immunosuppression, a lymphocyte clone was se- lected with specificity against the keratinocytes. A similar condition is found after cyclosporine treat- ment in rats that have undergone autologous bone marrow transplantation. H This assumption is in- directly confirmed by the absence of response to the increasing doses of prednisone and cyclo- phosphamide. Finally, whether or not the anti- biotic that was administered had a trigger effect continues to be an unanswered question.

REFERENCES

i. Gorevic PD, Kassab H J, Levo Y, et al. Mixed cryoglob- ulinemia: clinical aspects and long term follow-up of 40 patients. Am J Med 1980;69:287-308.

2. Brouet JC, Clauvel IP, Danon F, et al. Biologic and clinical significance of cryoglobulins. Am J Med 1974;57:775-89.

3. Olsen T. Peripheral vascular disease, necrotizing vas- culitis, and vascular-related disease. In: Moschella SL, Hurley HJ, eds. Dermatology. Philadelphia: Saunders, 1985:1066-7.

4. Cream JJ. Cryoglobulins in "~asculitis. Clin Exp Immunol 1972;10:117-26.

5. Zinnermann HH. Cryoglobulins and pyroglobulins. In: Litmans GW, Good RA, eds. Immunoglobulins, New York: Plenum Medical, 1978:323-43.

6. Mathison DA, Condemi JJ, Leddy JP, et al. Purpura, arthralgia and IgM-IgG cryoglobulinernia with rheuma- toid factor activity: response to cyclophosphamide and splenectomy. Ann Intern Med 1971;74:383-90.

7. Meroni PL, Barcellini W, Messina C, De Bartolo G, Capsoni F, Invernizzi F. Defective suppressor cell activ- ity in essential mixed cryoglobulinemia. J Clin Lab Im- munol 1982;8:177-82.

8. Safai B, Good RA. Immunodermatology. New York: Plenum Medical, 1981:238-47.

9. Saurat JH, Piguet PF. Human and murine graft versus host disease: potential models for the study of immu- nologically mediated skin disease. Br J Dermatol 1984; 27:213-8.

10. Chan HL. Observation on drug-induced toxic epidermal necrolysis in Singapore. J AM ACAD D~RMATOL 1984; 10:973-8.

11. Hess AD, Horwitz L, Beschomer WE, et al. Develop- ment of graft versus host disease like syndrome in cy- elosporine treated rats after syngeneic bone marrow trans- plantation. J Exp Med 1985;61:718-30.

III I II I II II

Klippel-Trenaunay syndrome Somaia Fathy Mahmoud, M.D.,* Mohamed O. E1-Benhawi, M.Sc.,* M. Hany E1-Tonsy, M.D.,* and S. M. Kalantar, M.D.** Doha, Qatar

An unusual and extreme case of Klippel-Trenaunay syndrome is presented. The patient has an extensive capillary hemangioma involving the right side of the body, increases in the length and girth of the right lower limb, gross varicosities of the superficial venous system, and complete absence of the deep venous system of the right lower extremity, with suprapubic shunt of the venous blood to the contralateral external iliac vein. Secondary manifestations are increased sweating and compensatory scoliosis. (J AM ACAD DERMATOL 1988;18:1169-72.)

In 1900, Klippel and Trenaunay 1 described a clinical syndrome with three major findings: hem-

From the Departments of Den,natology* and Radiology,** Hamad General Hospital.

Reprint requests to: Dr. Somaia Fathy Mahmoud, Department of Dermatology, Hamad General Hospital, P.O. Box 3050, Doha, Qatar,

angiomas, hypertrophy of soft tissue and bone with overgrowth of the involved extremity, and varicose veins. This syndrome is often mentioned together with "haemangiectatic hypertrophy," described by Parkes Weber z,3 in 1907 and 1918.

Additional reported complicating features are thrombophlebitis, cellulitis, edema of the limb,

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