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Life-threatening complications in the cancer patient part II
LIFE-THREATENING COMPLICATIONS IN THE CANCER PATIENT PART II BY ALAN D. TURNBULL, M.D.
0147-0272/79/10001-69505.00 9 1979, Year Book Medical Publishers, Inc.
TABLE OF CONTENTS LIFE-THREATENING DERMAVOLOGIC COMPIJCATZO~S OF CANCER . . . . . . . . . Scalded Skin Syndromes (SSS) . . . . . . . . . . . . . . . . . . . . E r y t h e m a Multifc r m e {EM) . . . . . . . . . . . . . . . . . . . . . Craft-vs.-Host Disease (GVHD) . . . . . . . . . . . . . . . . . . . SUPP(:RTIVE TRANFUSION--THE PRESENT ~TATE OF 7FE ART . . . . . . . . . . . Platelet Transfusions . . . . . . . . . . . . . . . . . . . . . . . Polymorphonuclear (PMN) Transfusions . . . . . . ". . . . . . . . . . C O M B I N E D R E N A L A N D HEPATIC FAILURE: TIIE POTENTIAL OF SERIAL HEMODIALYSIS A N D MASSZVE E X C H A N G E PLASMAPHERESIS. *. . . . . . . . . DISORDERS OF HEMOSTASIS IN M A L I G N A N C Y . . . . . . . . . . . . . . . . Quantitative Platelet Disorders . . . . . . . . . . . . . . . . . . . . Treatment of Thrombocytopenia and Thrombocytosis . . . . . . . . . . . . Qualitative Platelet Disorders . . . . . . . . . . . . . . . . . . . . Va~ c u l a r D i s o r d e r s . . . . . . . . . . . . . . . . . . . . . . . . H y p e r c o a g u l aI:le S t a t e s . . . . . . . . . . . . . . . . . . . . . . . Hypocoagulable States . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . U R I N A R y TRACT EMERGENCIES IN THE C A N C E R PATIENT . . . . . . . . . . . Ureteral C~ stzuction . . . . . . . . . . . . . . . . . . . . . . . . Hemaluria . . . . . . . . . . . . . . . . . . . . . . . . . . . C~ncer in the Solitary K i d n e y . . . . . . . . . . . . . . . . . . . . Ir tastin~l C bstrt:cti(n . . . . . . . . . . . . . . . . . . . . . . . LIFE-THREATENING COMPLICATIONS IN THE GYNECOLOGIC C A N C E R PATIENT . . . . . Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Va~ c u l a r D i s o r d e r s . . . . . . . . . . . . . . . . . . . . . . . . Uzemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . H E A D .~ND NECK E ~ m Z G E ~ C Z E S . . . . . . . . . . . . . . . . . . . . . Airway C[ stlucti( n . . . . . . . . . . . . . . . . . . . . . . . . ttemorrh~ge . . . . . . . . . . . . . . . . . . . . . . . . . . . ABDOMINAL EMERGENCIES . . . . . . . . . . . . . . . . . . . . . . . Hemorrhagic Gastritis . . . . . . . . . . . . . . . . . . . . . . . Actte Cholecystitis . . . . . . . . . . . . . . . . . . . . . . . . Mesenteric Vascular Occlusicn . . . . . . . . . . . . . . . . . . . . Occult Abdominal Abscess . . . . . . . . . . . . . . . . . . . . . . Spontaneous Liver Rutture . . . . . . . . . . . . . . . . . . . . . Perforated Viscus . . . . . . . . . . . . . . . . . . . . . . . . . Obstruction ~rd lleus . . . . . . . . . . . . . . . . . . . . . . . Intestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . Right Lower Quadrant ~Syndrome" . . . . . . . . . . . . . . . . . . Left Upper Quadrant "Syndrome" . . . . . . . . . . . . . . . . . . . Anereclal Complications . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . THORACIC EMERGENCIES . . . . . . . . . . . . . . . . . . . . . . . Spontaneous Pneumothorax . . . . . . . . . . . . . . . . . . . . . EEcph~ g e a l E m e r g e n c i e s . . . . . . . . . . . . . . . . . . . . . . Pericardial Effusion . . . . . . . . . . . . . . . . . . . . . . . . Superkr Vena Cava Syndrome . . . . . . . . . . . . . . . . . . . . Pulmonary EmBolism . . . . . . . . . . . . . . . . . . . . . . . Aspiration Pneumonia . . . . . . . . . . . . . . . . . . . . . . . Massive Hemoptysis . . . . . . . . . . . . . . . . . . . . . . . . Massive Pleural Effusions . . . . . . . . . . . . . . . . . . . . . . Acute Empyema . . . . . . . . . . . . . . . . . . . . . . . . . lung Abscesses . . . . . . . . . . . . . . . . . . . . . . . . . Complications of Pulmonary Resection . . . . . . . . . . . . . . . . . T i m CRITICALLY ILL C A N C E R PATIENT--PHILOSOPHICAL ASPECTS . . . . . . . . .
5 5 8 9 13 13 15 18 21 21 22 `)3 23 24 25 26 27 ')7 `)8 28 29 30 30 32 33 34 36 36 39 42 42 44 45 45 46 47 48 49 49 49 51 51 53 E3 ~4 55 56 ~7 ~9 60 61 (2 (3 (3 (6
CONTRIBUTING AUTHORS DR. GRAZIANO CARLON ASSISTANT ATTENDING ANESTHESIOLOGIST Co-DIRECTOR SPECIAL CARE UNIT MEMORIAL SIX)ANKETTERINGCANCER CENTER INSTRUCTOR OF ANESTHESIOLOGY CORNELLUNIVERSITYMEDICALCOLLEGE NEW YORK,NEW YORK DR. ARLANFULLER FELLOW, DEPARTMENT OFSURGERY DIVISION OFGYNECOLOGY MEMORIAL SLOANKETTERING CANCERCENTER DR, ALVIN FREIMAN DIRECTOR, ECGLABORATORY ATTENDING PHYSICIAN CARDIOPULMONARYSERVICE MEMORIAL SLOAN KETTERINGCANCER CENTER ASSOCIATEPROFESSOROF MEDICINE CORNELLUNIVERSITYMEDICALCOLLEGE DR. HARRYGRABSTALD ATTENDING SURGEON, UROLOGY SERVICE MEMORIAL SLOAN KETrERING CANCER CENTER PROFESSOROF UROLOGY CORNELLUNIVERSITYMEDICALCOLLEGE DR. MARIAN ISAACS ASSOCIATE ATTENDING PHYSICIAN CLINICALPHYSIOLOGYSERVICE MEMORIAL SLOANKETTERING CANCER CENTER ASSISTANT PROFESSOR OFMEDICINE CORNELL UNIVERSITY MEDICALCOLLEGE DR. SANFORD J. KEMPIN ASSISTANT ATTENDING PHYSICIAN HEMATOLOGY SERVICE DIRECTOR, COAGULATION LABORATORY
MEMORIAL SLOANKETTERING CANCERCENTER ASSOCIATE PROFESSOR OFMEDICINE CORNELL UNIVERSITY MEDICAL COLLEGE DR.LILIANREICH ASSOCIATE A~rENDING PHYSICIAN HEMATOLOGY-LYMPHOMA SERVICE MEMORIAL SLOANKEar'ERING CANCERCENTER CLINICAL ASSISTANT PROFESSOR OF MEDICINE CORNELL UNIVERSITY MEDICAL COLLEGE DR. BIJAN SAFAI ACTING CHIEF, DEPARTMENT OF DERMATOLOGY ASSISTANTATTENDINGPHYSICIAN MEMORIAL SLOAN KETrERING CANCER CENTER ASSISTANT PROFESSOROF MEDICINE (DERMATOLOGY) CORNELL UNIVERSITY MEDICAL COLLEGE DR.WILLIAMSHAPIRO ATTENDING NEUROLOGIST HEAD, COTZIAS LABORATORY OF NEURO-ONCOLOGY MEMORIAL SLOANKETTERING CANCER CENTER PROFESSOR OF NEUROLOGY CORNELL UNIVERSITY MEDICAL COLLEGE DR. MAURICE SHILS DIRECTOR oI~NUTRITION ATTENDING PHYSICIAN MEMORIAL SLOAN KETTERING CANCERCENTER ASSOCIATE PROFESSOR OFMEDICINE CORNELL UNIVERSITY MEDICAL COLLEGE DR. CAROLSINGER ASSISTANT ATTENDING PHYSICIAN INFECTIOUS DISEASE SERVICE DEPARTMENT OFMEDICINE 3
MEMORIAL SLOAN KETTERINGCANCER CENTER ASSISTANT PROFESSOROF I~IEDICINE CORNELLUNIVERSITYMEDICALCOLLEGE
DR. ELLIOT STRONG ATTENDINGSURGEONAND CHIEF, HEAD AND NECK SERVICE MEMORIAL SLOAN KETTERINGCANCER CENTER PROFESSOROF SURGERY CORNELLUNIVERSITY~VIEDICALCOLLEGE
DR. ALAN D. TURNBULL ASSOCIATEATTENDINGSURGEON GASTRIC AND MIXEDTUMOR SERVICE ASSOCIATE ATTENDING ANESTHESIOLOGIST Co-DIRECTOR, SPECIALCARE UNIT MEMORIAL SLOAN KETTERINGCANCER CENTER ASSOCIATE PROFESSOR O'F SURGERY CORNELLUNIVERSITY]~[EDICALCOLLEGE
is Associate Attending Surgeon and Anesthesiologist, Director of the Critical Care Facility of Memorial Sloan Kettering Cancer Center and Associate Professor of Surgery at Cornell University Medical College in New York City. Certified in surgery both in Canada and the United States, he was trained in general surgery at the Royal Victoria Hospital in Montreal after graduating from McGill University School of Medicine. During his residency he earned a Master's degree in surgical physiology. Following a fellowship in surgical oncology and thoracic surgery at Memorial Hospital, he completed his training in cardiac surgery at the New York Hospital. Dr. Turnbull joined the attending staff of Memorial Hospital in 1971, charged with the responsibility of establishing a multidis: ciplinary intensive care unit. He is active in the clinical practice of general and thoracic cancer surgery, with research interests in the prevention and treatment of lifethreatening complications of cancer therapy.
LIFE-THREATENING DERMATOLOGIC COMPLICATIONS OF CANCER BIJAN SAFAI, M.D. A VAST NUMBER OF SKIN CONDITIONS are directly related to or indirectly caused by an underlying m a l i g n a n t neoplasm. This chapter provides a brief review of the major skin disorders t h a t may cause life-threatening problems for cancer patients.
SCALDED SKIN SYNDROMES (SSS) There are several clinical syndromes in which the skin looks and feels as though it has been scalded by boiling water. These include the staphylococcal-induced scalded skin syndrome (SSS), drug-induced SSS and idiopathic SSS. Severe erythema multiforme as well as graft-vs.-host disease m a y present a similar clinical picture. Staphylococcal SSS is also known as staphylococcal epidermolyric toxin syndrome (SETS) and it is caused by infection with 5
dermopathic strains of S t a p h y l o c o c c u s a u r e u s that are often b u t not always members of bacteriophage group II (types 3A, 3B, 3C, 55 and 71). These strains are unusual in that they do not normally cause boils, carbuncles, osteomyelitis or septicemia b u t are capable of producing skin eruptions of SETS. Staphylococcal impetigo is a localized b u t more common form of infection with dermopathic strains of S . a u r e u s . The epidermolytic toxins produced by these strains are proteins with molecular weights of approximately 28,000; they are distinct from other staphylococcal e~/otoxins such as hemolysins or enterotoxins. These toxins are rem a r k a b l y specific and affect the epidermis exclusively in h u m a n s and some animal models. Staphylococcal epidermolytic toxin syndrome is recognized by its clinical features and characteristic histopathology (intraepidermal cleft formation), and is confirmed by isolation of a dermopathic strain of S. a u r e u s . This syndrome is usually seen in infants and young children but rarely occurs in adults. Adult patients usually are immunosuppressed or have renal failure, visceral malignancy or other debilitating illnesses. A male preponderance in distribution is of particular interest. The syndrome appears with the sudden onset of widespread erythema and tenderness followed by loosening and peeling of large areas of skin, exposing dark red, rare, oozing and painful surfaces. Healing occurs without scarring in 1 0 - 1 4 days because peeling develops at a very superficial level. Drug-induced SSS is considered to be the true '~toxic epidermal necrolysis" (TEN) syndrome I, 2 and represents an adverse reaction to drugs. Sheets of epidermis are shed in association with a febrile, toxic and often fatal systemic illness. Many medications have been associated with this syndrome, including sulfonamides; sulfones, pyrazolones, barbiturates, antibiotics and antiepileptics. The pathogenesis of drug-induced SSS is unclear b u t has been assumed to be a hypersensitivity reaction. Unfortunately, there is no laboratory test or animal model that can provide insight into the cause of this disease. A systemic toxin such as lymphotoxin released by lymphocytes could cause this type of widespread epidermal cytolysis. Scalded skin syndrome occurring in patients with severe illnesses is a more difficult problem since these patients usually are receiving a variety of necessary medications. It is possible that one or more of these drugs m a y be responsible for the scalding or these drugs may act synergistically with one another or with a product of infection or tumor. Lymphomas are among the more common diseases in which the SSS is seen. The histopathology of drug-induced SSS includes obliteration, of epidermal structures, eosinophilic and glossy appearance of the cytoplasm of keratinocytes, and pyknotic nuclei. The epidermis separates from the dermis as these cells die. Idiopathic SSS has been reported in elderly patients with no 6
history of ingested medication and no evidence of staphylococcal SSS. Unfortunately, they are prone to recurrent and increasingly severe attacks of SSS that m a y result in death. DIAGNOSIS
A skin biopsy specimen is taken as soon as possible to avoid misinterpreting the healing stage of a subepidermal blister as an intradermal split. Identification ofdermopathic strains of staphylococci is necessary to confirm the diagnosis of SETS. Unfortunately, the results m a y become available too late to be used in the selection of therapy. Factors other than S. aureus and drugs that cause scalding of skin must also be considered.
Differential Diagnosis Thermal or chemical burns should be excluded. Carbon monoxide and barbiturate poisoning m a y result in localized blister formation in unconscious states b u t do not resemble the spreading erythema followed by loss of skin seen in,SSS. Histologically, SETS has been mistaken for pemphigus vulgaris, but direct immunofluoresence is negative in SETS. In the glucagonoma syndrome, necrolysis is a histologic feature of the involved skin b u t the clinical manifestation resembles chronic infected eczema with intertrigo. Although there is a close overlap between the StevensJohnson syndrome and TEN, the eruption appears usually a few days after the onset of illness in the Stevens-Johnson syndrome. Rarely, graft-vs.-host disease m a y also appear as scalded skin. PROGNOSIS
The prognosis of SSS depends on its cause. With rare exception, children with SETS recover, but the prognosis of adult SETS is guarded and depends on the underlying illness (i.e., internal malignancies) and effectiveness of therapy. Some patients die as a result of unusually pathogenic strains of bacteria or debilitating illnesses. In drug-induced SSS the prognosis is not as good, and a 20% mortality has been reported. Scalded skin syndrome complicating severe illnesses and idiopathic SSS have a poor prognosis and the estimated mortality in this group is about 50%. TREATMENT
There is no specific treatment. Intensive support is required until spontaneous recovery occurs. In SETS, a penicillinase-resistant antibiotic should be initiated early in the course of the disease. Indiscriminate use of antibiotics m a y result in selective overgrowth of pathogens. In drug-induced SSS, all potentially offending medication should be stopped and as few others pre7
scribed as possible. Corticosteroids given for systemic effect are of value in the drug-induced and idiopathic forms, especially if administered early and in adequate doses, but should not be used in SETS. GENERAL SUPPORTIVE MEASURES
Good nursing care is of the utmost importance and is the key to survival. Electrolyte and fluid balance and postural drainage of bronchial secretions are critical. If swallowing is impossible, a nasal feeding tube is preferable to intravenous infusions because of the risk of septicemia. Special attention is given to oral hygiene and to the eyes and conjunctivae. Analgesics may be needed to relieve pain caused by loss of skin over a large portion of the body. Bacterial growth in the denuded areas is life-threatening to the patient. Potassium permanganate baths and intermittent moist compresses with 0.5% silver nitrate solution followed by topical application of corticosteroid cream are of great value. Debridement of necrotic slough may also be necessary.
ERYTHEMA MULTIFORME (EM) Erythema multiforme (EM) is a distinct clinical and pathological entity that can be precipitated by a variety of agents and is widely accepted as a hypersensitivity syndrome resulting from antigen-antibody reactions. 3 Various types of skin reactions may occur from the same etiologic agent and conversely many agents may induce the same skin or mucous membrane eruption. The multiformity in its broadest sense is the characteristic feature of this syndrome and attacks may be recurrent. In 1922, Stevens and Johnson ~described an acute form of EM in which the involvement of mucous membranes and blister formation was the main feature. Stevens-Johnson syndrome is characterized usually by a sudden onset, sometimes with prodromal complaints or signs of fever, malaise, headaches, rapid weak pulse, rapid respiration, prostration and joint pain. Stomatitis with bleeding and ulceration, bilateral conjunctivitis, corneal ulcers and rhinitis with epistaxis are common. Other organs may also be involved. Renal involvement is manifested by albuminuria, hematuria and elevated blood urea levels. Eosinophilic pneumonopathy has been reported. Gastrointestinal disturbances, arthritis, convulsions, coma, cardiac arrhythmia, pericarditis, myositis, hepatopathy and septicemia may occur. The cause of EM is unknown. Numerous etiological agents have been implicated, including herpes simplex virus, Mycoplasma pneumonia and several pharmacological agents such as sulfa drugs and diphenylhydantoin. It may also be seen in association with systemic infections, collagen diseases and visceral malignancies. 8
PATHOLOGY
The principal inflammatory changes are found in the upper dermis and consist of dilation of blood vessels with perivascular infiltration of round cells and extravasated erythrocytes. Marked edema of the dermis may result in formation of vesicles and bullae that contain serum, round cells, eosinophils and other polymorphonuclear cells. Epidermal changes may be mild or severe and may consist of edema and cleft formation. PATHOGENESIS
The pathogenesis of EM remains unclear. Recent studies have demonstrated the presence of immune complexes in the blister fluid and fixed to the blood vessel walls in the upper dermis. These findings suggest that the symptom complex of EM is a reaction precipitated by immunologic mechanisms. 4
PRO(JNOSIS The disease is sometimes fatal, with an estimated mortality of 18%; it infrequently causes blindness. DIFFERENTIAL DIAGNOSIS
Different forms of EM may simulate other dermatoses. The Stevens-Johnson syndrome may be difficult to distinguish from severe cases of pemphigus vulgaris, bullous pemphigoid and dermatitis herpetiformis. This syndrome is distinguished from SSS by the absence of large sheets of loose peeling skin. TREATMENT
The multitude of possible etiologic factors in EM prevents specific therapy. In severe cases the use of corticosteroids for systemic effect may be helpful and lifesaving. Appropriate antibiotics for systemic effect should be given for prevention or treatment of secondary infections. Those supportive measures described for the SSS are equally essential for successful therapy of the StevensJohnson syndrome.
GRAFT-VS.-HOST DISEASE (GVHD) Human allogeneic bone marrow transpl~tnts are being employed with increasing frequency in the management of congenital immunodeficiency diseases, leukemias, aplastic anemia and severe radiation exposure. The entity known as graft-vs.-host disease (GVHD) is a major and often fatal complication of this procedure. 5-7 9
The first knowledge of GVHD dates back to animal experiments reported during the 1950s and 1960s. Wasting and skin lesions were observed following transplantation of unmatched bone marrow into a mouse whose own marrow had been destroyed by radiation. Subsequently, a successful therapeutic transplantation was performed in an individual who had been accidentally exposed to large doses of ionizing radiation. The increasing success of bone marrow transplantation has also led to increasing numbers of cases of GVHD. Graft-vs.-host disease develops following transplantation of immunologically competent incompatible lymphocytes into a recipient who is immunologically incompetent and incapable of rejecting them. The transplanted donor lymphocytes survive in their new host and may become aggressive, producing damage to various tissues and organs in the host. Despite careful in vitro matching of major histocompatibility loci and mixed leukocyte cultures, some of the manifestations of GVHD develop in approximately 70% of bone marrow transplant recipients. The earliest signs of GVHD are seen 7 - 1 4 days following transplantation. Skin eruption is usually the earliest and often only obvious manifestation of GVHD. A faint erythematous maculopapular eruption rapidly spreads to involve large areas of skin and becomes confluent. Fever and malaise may develop and hepatosplenomegaly, lymphadenopathy and diarrhea are seen in many cases. Tenderness of the liver and abnormal liver functions are included among the primary manifestations of GVHD. The cutaneous eruption becomes progressively worse and skin may peel off in large sheets. Liver functions become profoundly abnormal and high fever and bloody diarrhea develop. The outcome of severe GVHD is usually death, but in the majority of cases the acute phase is mild and well tolerated with full recovery. Chronic GVHD develops in approximately 10% of patients who have received transplants. Manifestations include debilitating skin disorders, chronic active liver disease, malabsorption, oral and ophthalmic involvement, weight loss and recurrent infection. Cutaneous manifestations in chronic GVHD consist of a generalized hypopigmented or hyperpigmented eruption and dryness of the skin. Cutaneous scleroderma, xerophthalmia, xerostomia, SjSgren's syndrome and lichen planus-like eruptions are also seen. The protean manifestations of chronic GVHD include chronic active skin disease, malabsorption, oral and ophthalmic involvement, weight loss and recurrent infections. Chronic GVHD may develop after gradual progression of the acute form or it may occur a few months following bone marrow transplantation in patients who have shown no evidence of early GVHD. A variety of infections, drugs, multiple transfusions and radiation are complicating factors. lo
The histopathologic changes of acute GVHD in skin include disruption and destruction of epidermal cells. In acute GVHD the basal cells in the epidermis show marked vacuolar degeneration and cleft formation in the lower epidermal layers. In severe cases, the epidermis resembles toxic epidermal necrolysis. The necrotic cells appear as hyaline or mummified bodies in the epidermis or upper dermis and are a characteristic finding in GVHD. Edema of the epidermis and inflammatory infiltrates of the dermis are seen and skin appendages (nails, hair and sweat glands) are similarly affected. In chronic GVHD, the disruption of epidermal cells is more pronounced and the dermis is also involved. The basal cell layer shows hydropic degeneration and the dermis shows thickening of collagen bundles with a ground-glass appearance. Mononuclear infiltration is found in the middermis. PATHOGENESIS
The pathogenesis of GVHD is not known. It is widely believed that the various manifestations of GVHD are caused by cell-mediated mechanisms. The pathologic changes are produced by an immunologic attack of the graft against the various tissues and organs of the host. The presence of tissue-fixed immunogIobulins or complement in the dermoepidermal junction or in blood vessel walls suggests the pathogenic importance of humoral immune mechanisms2 Cutaneous changes of GVHD may resemble the findings of other skin diseases, such as lupus erythematosus, scleroderma, lichen planus or toxic epidermal necrolysis. TREATMENT
T r e a t m e n t of GVHD includes corticosteroid therapy for systemic effect and chemotherapy with drugs such as cyclophosphamide. Antithymocyte globulin also has been used. Other supportive measures are dictated by the clinical presentation and severity of the disease. ROBERT C. HICKEY: Dermatologic diseases are important in cancer care. On review of this manuscript by Dr. Herman J. Schultz, a Houston dermatologist also working within a cancer center, it was pointed out that Dr. Safai has described largely life-threatening complications of cancer therapy; Dr. Schultz would add the disabling and correctable zinc deficiency/acrodermatitis enteropathica-like eruption that is the sequel of long-term parenteral hyperalimentation. Added also might be dermatomyositis and acanthosis nigricans, among other unique dermatologic entities.
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REFERENCES 1. Rasmussen, J. E.: Toxic epidermal necrolysis: A review of 75 cases in children, Arch. Dermatol. 111:1135, 1975. 2. Lyell, A.: A review of toxic epidermal necrolysis in Britain, Br. J. Dermatol. 79: 662, 1967. 3. Stevens, A. H., and Johnson, F. C.: Am. J. Dis. Child. 24:526,1922. 4. Safai, B., Day, N. K., and Good, R. A.: Erythema multiforme: Report of 2 cases and speculation on immune mechanisms involved in the pathogenesis, J. Clin. Immunol. Immunopathol. 7:379, 1977. 5. Shulman, H. M., et al.: Chronic cutaneous graft-versus-host disease in man, Am. J. Pathol. 91:545, 1978. 6. Kersey, J. H., et al.: Graft-versus-host reactions following transplantation in allogeneic hematopoetic cells, Hum. Pathol. 2:389, 1971. 7. Slavin, R. E., and Santos, G.: The graft-versuS-host reaction in man after bone marrow transplantation: Pathology, pathogenesis, clinical features and implication, Clin. Immunol. Immunopathol. 1:472, 1973. 8. Tosi, M. D., et al.: Deposition of IgM and complement at the dermo-epidermal junction in acute and chronic cutaneous graft-versus-host disease in man, J. Immunol. 120:1485, 1978.
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0147-0272/79/10001-69505.00 9 1979, Year Book Medical Publishers, Inc.
TABLE OF CONTENTS LIFE-THREATENING DERMAVOLOGIC COMPIJCATZO~S OF CANCER . . . . . . . . . Scalded Skin Syndromes (SSS) . . . . . . . . . . . . . . . . . . . . E r y t h e m a Multifc r m e {EM) . . . . . . . . . . . . . . . . . . . . . Craft-vs.-Host Disease (GVHD) . . . . . . . . . . . . . . . . . . . SUPP(:RTIVE TRANFUSION--THE PRESENT ~TATE OF 7FE ART . . . . . . . . . . . Platelet Transfusions . . . . . . . . . . . . . . . . . . . . . . . Polymorphonuclear (PMN) Transfusions . . . . . . ". . . . . . . . . . C O M B I N E D R E N A L A N D HEPATIC FAILURE: TIIE POTENTIAL OF SERIAL HEMODIALYSIS A N D MASSZVE E X C H A N G E PLASMAPHERESIS. *. . . . . . . . . DISORDERS OF HEMOSTASIS IN M A L I G N A N C Y . . . . . . . . . . . . . . . . Quantitative Platelet Disorders . . . . . . . . . . . . . . . . . . . . Treatment of Thrombocytopenia and Thrombocytosis . . . . . . . . . . . . Qualitative Platelet Disorders . . . . . . . . . . . . . . . . . . . . Va~ c u l a r D i s o r d e r s . . . . . . . . . . . . . . . . . . . . . . . . H y p e r c o a g u l aI:le S t a t e s . . . . . . . . . . . . . . . . . . . . . . . Hypocoagulable States . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . U R I N A R y TRACT EMERGENCIES IN THE C A N C E R PATIENT . . . . . . . . . . . Ureteral C~ stzuction . . . . . . . . . . . . . . . . . . . . . . . . Hemaluria . . . . . . . . . . . . . . . . . . . . . . . . . . . C~ncer in the Solitary K i d n e y . . . . . . . . . . . . . . . . . . . . Ir tastin~l C bstrt:cti(n . . . . . . . . . . . . . . . . . . . . . . . LIFE-THREATENING COMPLICATIONS IN THE GYNECOLOGIC C A N C E R PATIENT . . . . . Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Va~ c u l a r D i s o r d e r s . . . . . . . . . . . . . . . . . . . . . . . . Uzemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . H E A D .~ND NECK E ~ m Z G E ~ C Z E S . . . . . . . . . . . . . . . . . . . . . Airway C[ stlucti( n . . . . . . . . . . . . . . . . . . . . . . . . ttemorrh~ge . . . . . . . . . . . . . . . . . . . . . . . . . . . ABDOMINAL EMERGENCIES . . . . . . . . . . . . . . . . . . . . . . . Hemorrhagic Gastritis . . . . . . . . . . . . . . . . . . . . . . . Actte Cholecystitis . . . . . . . . . . . . . . . . . . . . . . . . Mesenteric Vascular Occlusicn . . . . . . . . . . . . . . . . . . . . Occult Abdominal Abscess . . . . . . . . . . . . . . . . . . . . . . Spontaneous Liver Rutture . . . . . . . . . . . . . . . . . . . . . Perforated Viscus . . . . . . . . . . . . . . . . . . . . . . . . . Obstruction ~rd lleus . . . . . . . . . . . . . . . . . . . . . . . Intestinal Bleeding . . . . . . . . . . . . . . . . . . . . . . . . Right Lower Quadrant ~Syndrome" . . . . . . . . . . . . . . . . . . Left Upper Quadrant "Syndrome" . . . . . . . . . . . . . . . . . . . Anereclal Complications . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . THORACIC EMERGENCIES . . . . . . . . . . . . . . . . . . . . . . . Spontaneous Pneumothorax . . . . . . . . . . . . . . . . . . . . . EEcph~ g e a l E m e r g e n c i e s . . . . . . . . . . . . . . . . . . . . . . Pericardial Effusion . . . . . . . . . . . . . . . . . . . . . . . . Superkr Vena Cava Syndrome . . . . . . . . . . . . . . . . . . . . Pulmonary EmBolism . . . . . . . . . . . . . . . . . . . . . . . Aspiration Pneumonia . . . . . . . . . . . . . . . . . . . . . . . Massive Hemoptysis . . . . . . . . . . . . . . . . . . . . . . . . Massive Pleural Effusions . . . . . . . . . . . . . . . . . . . . . . Acute Empyema . . . . . . . . . . . . . . . . . . . . . . . . . lung Abscesses . . . . . . . . . . . . . . . . . . . . . . . . . Complications of Pulmonary Resection . . . . . . . . . . . . . . . . . T i m CRITICALLY ILL C A N C E R PATIENT--PHILOSOPHICAL ASPECTS . . . . . . . . .
5 5 8 9 13 13 15 18 21 21 22 `)3 23 24 25 26 27 ')7 `)8 28 29 30 30 32 33 34 36 36 39 42 42 44 45 45 46 47 48 49 49 49 51 51 53 E3 ~4 55 56 ~7 ~9 60 61 (2 (3 (3 (6
CONTRIBUTING AUTHORS DR. GRAZIANO CARLON ASSISTANT ATTENDING ANESTHESIOLOGIST Co-DIRECTOR SPECIAL CARE UNIT MEMORIAL SIX)ANKETTERINGCANCER CENTER INSTRUCTOR OF ANESTHESIOLOGY CORNELLUNIVERSITYMEDICALCOLLEGE NEW YORK,NEW YORK DR. ARLANFULLER FELLOW, DEPARTMENT OFSURGERY DIVISION OFGYNECOLOGY MEMORIAL SLOANKETTERING CANCERCENTER DR, ALVIN FREIMAN DIRECTOR, ECGLABORATORY ATTENDING PHYSICIAN CARDIOPULMONARYSERVICE MEMORIAL SLOAN KETTERINGCANCER CENTER ASSOCIATEPROFESSOROF MEDICINE CORNELLUNIVERSITYMEDICALCOLLEGE DR. HARRYGRABSTALD ATTENDING SURGEON, UROLOGY SERVICE MEMORIAL SLOAN KETrERING CANCER CENTER PROFESSOROF UROLOGY CORNELLUNIVERSITYMEDICALCOLLEGE DR. MARIAN ISAACS ASSOCIATE ATTENDING PHYSICIAN CLINICALPHYSIOLOGYSERVICE MEMORIAL SLOANKETTERING CANCER CENTER ASSISTANT PROFESSOR OFMEDICINE CORNELL UNIVERSITY MEDICALCOLLEGE DR. SANFORD J. KEMPIN ASSISTANT ATTENDING PHYSICIAN HEMATOLOGY SERVICE DIRECTOR, COAGULATION LABORATORY
MEMORIAL SLOANKETTERING CANCERCENTER ASSOCIATE PROFESSOR OFMEDICINE CORNELL UNIVERSITY MEDICAL COLLEGE DR.LILIANREICH ASSOCIATE A~rENDING PHYSICIAN HEMATOLOGY-LYMPHOMA SERVICE MEMORIAL SLOANKEar'ERING CANCERCENTER CLINICAL ASSISTANT PROFESSOR OF MEDICINE CORNELL UNIVERSITY MEDICAL COLLEGE DR. BIJAN SAFAI ACTING CHIEF, DEPARTMENT OF DERMATOLOGY ASSISTANTATTENDINGPHYSICIAN MEMORIAL SLOAN KETrERING CANCER CENTER ASSISTANT PROFESSOROF MEDICINE (DERMATOLOGY) CORNELL UNIVERSITY MEDICAL COLLEGE DR.WILLIAMSHAPIRO ATTENDING NEUROLOGIST HEAD, COTZIAS LABORATORY OF NEURO-ONCOLOGY MEMORIAL SLOANKETTERING CANCER CENTER PROFESSOR OF NEUROLOGY CORNELL UNIVERSITY MEDICAL COLLEGE DR. MAURICE SHILS DIRECTOR oI~NUTRITION ATTENDING PHYSICIAN MEMORIAL SLOAN KETTERING CANCERCENTER ASSOCIATE PROFESSOR OFMEDICINE CORNELL UNIVERSITY MEDICAL COLLEGE DR. CAROLSINGER ASSISTANT ATTENDING PHYSICIAN INFECTIOUS DISEASE SERVICE DEPARTMENT OFMEDICINE 3
MEMORIAL SLOAN KETTERINGCANCER CENTER ASSISTANT PROFESSOROF I~IEDICINE CORNELLUNIVERSITYMEDICALCOLLEGE
DR. ELLIOT STRONG ATTENDINGSURGEONAND CHIEF, HEAD AND NECK SERVICE MEMORIAL SLOAN KETTERINGCANCER CENTER PROFESSOROF SURGERY CORNELLUNIVERSITY~VIEDICALCOLLEGE
DR. ALAN D. TURNBULL ASSOCIATEATTENDINGSURGEON GASTRIC AND MIXEDTUMOR SERVICE ASSOCIATE ATTENDING ANESTHESIOLOGIST Co-DIRECTOR, SPECIALCARE UNIT MEMORIAL SLOAN KETTERINGCANCER CENTER ASSOCIATE PROFESSOR O'F SURGERY CORNELLUNIVERSITY]~[EDICALCOLLEGE
is Associate Attending Surgeon and Anesthesiologist, Director of the Critical Care Facility of Memorial Sloan Kettering Cancer Center and Associate Professor of Surgery at Cornell University Medical College in New York City. Certified in surgery both in Canada and the United States, he was trained in general surgery at the Royal Victoria Hospital in Montreal after graduating from McGill University School of Medicine. During his residency he earned a Master's degree in surgical physiology. Following a fellowship in surgical oncology and thoracic surgery at Memorial Hospital, he completed his training in cardiac surgery at the New York Hospital. Dr. Turnbull joined the attending staff of Memorial Hospital in 1971, charged with the responsibility of establishing a multidis: ciplinary intensive care unit. He is active in the clinical practice of general and thoracic cancer surgery, with research interests in the prevention and treatment of lifethreatening complications of cancer therapy.
LIFE-THREATENING DERMATOLOGIC COMPLICATIONS OF CANCER BIJAN SAFAI, M.D. A VAST NUMBER OF SKIN CONDITIONS are directly related to or indirectly caused by an underlying m a l i g n a n t neoplasm. This chapter provides a brief review of the major skin disorders t h a t may cause life-threatening problems for cancer patients.
SCALDED SKIN SYNDROMES (SSS) There are several clinical syndromes in which the skin looks and feels as though it has been scalded by boiling water. These include the staphylococcal-induced scalded skin syndrome (SSS), drug-induced SSS and idiopathic SSS. Severe erythema multiforme as well as graft-vs.-host disease m a y present a similar clinical picture. Staphylococcal SSS is also known as staphylococcal epidermolyric toxin syndrome (SETS) and it is caused by infection with 5
dermopathic strains of S t a p h y l o c o c c u s a u r e u s that are often b u t not always members of bacteriophage group II (types 3A, 3B, 3C, 55 and 71). These strains are unusual in that they do not normally cause boils, carbuncles, osteomyelitis or septicemia b u t are capable of producing skin eruptions of SETS. Staphylococcal impetigo is a localized b u t more common form of infection with dermopathic strains of S . a u r e u s . The epidermolytic toxins produced by these strains are proteins with molecular weights of approximately 28,000; they are distinct from other staphylococcal e~/otoxins such as hemolysins or enterotoxins. These toxins are rem a r k a b l y specific and affect the epidermis exclusively in h u m a n s and some animal models. Staphylococcal epidermolytic toxin syndrome is recognized by its clinical features and characteristic histopathology (intraepidermal cleft formation), and is confirmed by isolation of a dermopathic strain of S. a u r e u s . This syndrome is usually seen in infants and young children but rarely occurs in adults. Adult patients usually are immunosuppressed or have renal failure, visceral malignancy or other debilitating illnesses. A male preponderance in distribution is of particular interest. The syndrome appears with the sudden onset of widespread erythema and tenderness followed by loosening and peeling of large areas of skin, exposing dark red, rare, oozing and painful surfaces. Healing occurs without scarring in 1 0 - 1 4 days because peeling develops at a very superficial level. Drug-induced SSS is considered to be the true '~toxic epidermal necrolysis" (TEN) syndrome I, 2 and represents an adverse reaction to drugs. Sheets of epidermis are shed in association with a febrile, toxic and often fatal systemic illness. Many medications have been associated with this syndrome, including sulfonamides; sulfones, pyrazolones, barbiturates, antibiotics and antiepileptics. The pathogenesis of drug-induced SSS is unclear b u t has been assumed to be a hypersensitivity reaction. Unfortunately, there is no laboratory test or animal model that can provide insight into the cause of this disease. A systemic toxin such as lymphotoxin released by lymphocytes could cause this type of widespread epidermal cytolysis. Scalded skin syndrome occurring in patients with severe illnesses is a more difficult problem since these patients usually are receiving a variety of necessary medications. It is possible that one or more of these drugs m a y be responsible for the scalding or these drugs may act synergistically with one another or with a product of infection or tumor. Lymphomas are among the more common diseases in which the SSS is seen. The histopathology of drug-induced SSS includes obliteration, of epidermal structures, eosinophilic and glossy appearance of the cytoplasm of keratinocytes, and pyknotic nuclei. The epidermis separates from the dermis as these cells die. Idiopathic SSS has been reported in elderly patients with no 6
history of ingested medication and no evidence of staphylococcal SSS. Unfortunately, they are prone to recurrent and increasingly severe attacks of SSS that m a y result in death. DIAGNOSIS
A skin biopsy specimen is taken as soon as possible to avoid misinterpreting the healing stage of a subepidermal blister as an intradermal split. Identification ofdermopathic strains of staphylococci is necessary to confirm the diagnosis of SETS. Unfortunately, the results m a y become available too late to be used in the selection of therapy. Factors other than S. aureus and drugs that cause scalding of skin must also be considered.
Differential Diagnosis Thermal or chemical burns should be excluded. Carbon monoxide and barbiturate poisoning m a y result in localized blister formation in unconscious states b u t do not resemble the spreading erythema followed by loss of skin seen in,SSS. Histologically, SETS has been mistaken for pemphigus vulgaris, but direct immunofluoresence is negative in SETS. In the glucagonoma syndrome, necrolysis is a histologic feature of the involved skin b u t the clinical manifestation resembles chronic infected eczema with intertrigo. Although there is a close overlap between the StevensJohnson syndrome and TEN, the eruption appears usually a few days after the onset of illness in the Stevens-Johnson syndrome. Rarely, graft-vs.-host disease m a y also appear as scalded skin. PROGNOSIS
The prognosis of SSS depends on its cause. With rare exception, children with SETS recover, but the prognosis of adult SETS is guarded and depends on the underlying illness (i.e., internal malignancies) and effectiveness of therapy. Some patients die as a result of unusually pathogenic strains of bacteria or debilitating illnesses. In drug-induced SSS the prognosis is not as good, and a 20% mortality has been reported. Scalded skin syndrome complicating severe illnesses and idiopathic SSS have a poor prognosis and the estimated mortality in this group is about 50%. TREATMENT
There is no specific treatment. Intensive support is required until spontaneous recovery occurs. In SETS, a penicillinase-resistant antibiotic should be initiated early in the course of the disease. Indiscriminate use of antibiotics m a y result in selective overgrowth of pathogens. In drug-induced SSS, all potentially offending medication should be stopped and as few others pre7
scribed as possible. Corticosteroids given for systemic effect are of value in the drug-induced and idiopathic forms, especially if administered early and in adequate doses, but should not be used in SETS. GENERAL SUPPORTIVE MEASURES
Good nursing care is of the utmost importance and is the key to survival. Electrolyte and fluid balance and postural drainage of bronchial secretions are critical. If swallowing is impossible, a nasal feeding tube is preferable to intravenous infusions because of the risk of septicemia. Special attention is given to oral hygiene and to the eyes and conjunctivae. Analgesics may be needed to relieve pain caused by loss of skin over a large portion of the body. Bacterial growth in the denuded areas is life-threatening to the patient. Potassium permanganate baths and intermittent moist compresses with 0.5% silver nitrate solution followed by topical application of corticosteroid cream are of great value. Debridement of necrotic slough may also be necessary.
ERYTHEMA MULTIFORME (EM) Erythema multiforme (EM) is a distinct clinical and pathological entity that can be precipitated by a variety of agents and is widely accepted as a hypersensitivity syndrome resulting from antigen-antibody reactions. 3 Various types of skin reactions may occur from the same etiologic agent and conversely many agents may induce the same skin or mucous membrane eruption. The multiformity in its broadest sense is the characteristic feature of this syndrome and attacks may be recurrent. In 1922, Stevens and Johnson ~described an acute form of EM in which the involvement of mucous membranes and blister formation was the main feature. Stevens-Johnson syndrome is characterized usually by a sudden onset, sometimes with prodromal complaints or signs of fever, malaise, headaches, rapid weak pulse, rapid respiration, prostration and joint pain. Stomatitis with bleeding and ulceration, bilateral conjunctivitis, corneal ulcers and rhinitis with epistaxis are common. Other organs may also be involved. Renal involvement is manifested by albuminuria, hematuria and elevated blood urea levels. Eosinophilic pneumonopathy has been reported. Gastrointestinal disturbances, arthritis, convulsions, coma, cardiac arrhythmia, pericarditis, myositis, hepatopathy and septicemia may occur. The cause of EM is unknown. Numerous etiological agents have been implicated, including herpes simplex virus, Mycoplasma pneumonia and several pharmacological agents such as sulfa drugs and diphenylhydantoin. It may also be seen in association with systemic infections, collagen diseases and visceral malignancies. 8
PATHOLOGY
The principal inflammatory changes are found in the upper dermis and consist of dilation of blood vessels with perivascular infiltration of round cells and extravasated erythrocytes. Marked edema of the dermis may result in formation of vesicles and bullae that contain serum, round cells, eosinophils and other polymorphonuclear cells. Epidermal changes may be mild or severe and may consist of edema and cleft formation. PATHOGENESIS
The pathogenesis of EM remains unclear. Recent studies have demonstrated the presence of immune complexes in the blister fluid and fixed to the blood vessel walls in the upper dermis. These findings suggest that the symptom complex of EM is a reaction precipitated by immunologic mechanisms. 4
PRO(JNOSIS The disease is sometimes fatal, with an estimated mortality of 18%; it infrequently causes blindness. DIFFERENTIAL DIAGNOSIS
Different forms of EM may simulate other dermatoses. The Stevens-Johnson syndrome may be difficult to distinguish from severe cases of pemphigus vulgaris, bullous pemphigoid and dermatitis herpetiformis. This syndrome is distinguished from SSS by the absence of large sheets of loose peeling skin. TREATMENT
The multitude of possible etiologic factors in EM prevents specific therapy. In severe cases the use of corticosteroids for systemic effect may be helpful and lifesaving. Appropriate antibiotics for systemic effect should be given for prevention or treatment of secondary infections. Those supportive measures described for the SSS are equally essential for successful therapy of the StevensJohnson syndrome.
GRAFT-VS.-HOST DISEASE (GVHD) Human allogeneic bone marrow transpl~tnts are being employed with increasing frequency in the management of congenital immunodeficiency diseases, leukemias, aplastic anemia and severe radiation exposure. The entity known as graft-vs.-host disease (GVHD) is a major and often fatal complication of this procedure. 5-7 9
The first knowledge of GVHD dates back to animal experiments reported during the 1950s and 1960s. Wasting and skin lesions were observed following transplantation of unmatched bone marrow into a mouse whose own marrow had been destroyed by radiation. Subsequently, a successful therapeutic transplantation was performed in an individual who had been accidentally exposed to large doses of ionizing radiation. The increasing success of bone marrow transplantation has also led to increasing numbers of cases of GVHD. Graft-vs.-host disease develops following transplantation of immunologically competent incompatible lymphocytes into a recipient who is immunologically incompetent and incapable of rejecting them. The transplanted donor lymphocytes survive in their new host and may become aggressive, producing damage to various tissues and organs in the host. Despite careful in vitro matching of major histocompatibility loci and mixed leukocyte cultures, some of the manifestations of GVHD develop in approximately 70% of bone marrow transplant recipients. The earliest signs of GVHD are seen 7 - 1 4 days following transplantation. Skin eruption is usually the earliest and often only obvious manifestation of GVHD. A faint erythematous maculopapular eruption rapidly spreads to involve large areas of skin and becomes confluent. Fever and malaise may develop and hepatosplenomegaly, lymphadenopathy and diarrhea are seen in many cases. Tenderness of the liver and abnormal liver functions are included among the primary manifestations of GVHD. The cutaneous eruption becomes progressively worse and skin may peel off in large sheets. Liver functions become profoundly abnormal and high fever and bloody diarrhea develop. The outcome of severe GVHD is usually death, but in the majority of cases the acute phase is mild and well tolerated with full recovery. Chronic GVHD develops in approximately 10% of patients who have received transplants. Manifestations include debilitating skin disorders, chronic active liver disease, malabsorption, oral and ophthalmic involvement, weight loss and recurrent infection. Cutaneous manifestations in chronic GVHD consist of a generalized hypopigmented or hyperpigmented eruption and dryness of the skin. Cutaneous scleroderma, xerophthalmia, xerostomia, SjSgren's syndrome and lichen planus-like eruptions are also seen. The protean manifestations of chronic GVHD include chronic active skin disease, malabsorption, oral and ophthalmic involvement, weight loss and recurrent infections. Chronic GVHD may develop after gradual progression of the acute form or it may occur a few months following bone marrow transplantation in patients who have shown no evidence of early GVHD. A variety of infections, drugs, multiple transfusions and radiation are complicating factors. lo
The histopathologic changes of acute GVHD in skin include disruption and destruction of epidermal cells. In acute GVHD the basal cells in the epidermis show marked vacuolar degeneration and cleft formation in the lower epidermal layers. In severe cases, the epidermis resembles toxic epidermal necrolysis. The necrotic cells appear as hyaline or mummified bodies in the epidermis or upper dermis and are a characteristic finding in GVHD. Edema of the epidermis and inflammatory infiltrates of the dermis are seen and skin appendages (nails, hair and sweat glands) are similarly affected. In chronic GVHD, the disruption of epidermal cells is more pronounced and the dermis is also involved. The basal cell layer shows hydropic degeneration and the dermis shows thickening of collagen bundles with a ground-glass appearance. Mononuclear infiltration is found in the middermis. PATHOGENESIS
The pathogenesis of GVHD is not known. It is widely believed that the various manifestations of GVHD are caused by cell-mediated mechanisms. The pathologic changes are produced by an immunologic attack of the graft against the various tissues and organs of the host. The presence of tissue-fixed immunogIobulins or complement in the dermoepidermal junction or in blood vessel walls suggests the pathogenic importance of humoral immune mechanisms2 Cutaneous changes of GVHD may resemble the findings of other skin diseases, such as lupus erythematosus, scleroderma, lichen planus or toxic epidermal necrolysis. TREATMENT
T r e a t m e n t of GVHD includes corticosteroid therapy for systemic effect and chemotherapy with drugs such as cyclophosphamide. Antithymocyte globulin also has been used. Other supportive measures are dictated by the clinical presentation and severity of the disease. ROBERT C. HICKEY: Dermatologic diseases are important in cancer care. On review of this manuscript by Dr. Herman J. Schultz, a Houston dermatologist also working within a cancer center, it was pointed out that Dr. Safai has described largely life-threatening complications of cancer therapy; Dr. Schultz would add the disabling and correctable zinc deficiency/acrodermatitis enteropathica-like eruption that is the sequel of long-term parenteral hyperalimentation. Added also might be dermatomyositis and acanthosis nigricans, among other unique dermatologic entities.
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REFERENCES 1. Rasmussen, J. E.: Toxic epidermal necrolysis: A review of 75 cases in children, Arch. Dermatol. 111:1135, 1975. 2. Lyell, A.: A review of toxic epidermal necrolysis in Britain, Br. J. Dermatol. 79: 662, 1967. 3. Stevens, A. H., and Johnson, F. C.: Am. J. Dis. Child. 24:526,1922. 4. Safai, B., Day, N. K., and Good, R. A.: Erythema multiforme: Report of 2 cases and speculation on immune mechanisms involved in the pathogenesis, J. Clin. Immunol. Immunopathol. 7:379, 1977. 5. Shulman, H. M., et al.: Chronic cutaneous graft-versus-host disease in man, Am. J. Pathol. 91:545, 1978. 6. Kersey, J. H., et al.: Graft-versus-host reactions following transplantation in allogeneic hematopoetic cells, Hum. Pathol. 2:389, 1971. 7. Slavin, R. E., and Santos, G.: The graft-versuS-host reaction in man after bone marrow transplantation: Pathology, pathogenesis, clinical features and implication, Clin. Immunol. Immunopathol. 1:472, 1973. 8. Tosi, M. D., et al.: Deposition of IgM and complement at the dermo-epidermal junction in acute and chronic cutaneous graft-versus-host disease in man, J. Immunol. 120:1485, 1978.
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