Fatal panniculitis

Clinical r e v i e w s III IIIII

IIII

I

Fatal panniculitis Iris K. Aronson, M.D., Dennis P. West, M.S., Daina Variakojis, M.D., Frederick D. Malkinson, M.D., H. David Wilson, M.D., and Howard J. Zeitz, M.D. Chicago, IL, and Lexington, KY The Weber-Christian syndrome (relapsing nodular panniculitis) displays a clinical spectrum varying from short, self-limited, or intermittent disease episodes to persistent disease with fatal outcome. Inflamed adipose tissue is exclusively subcutaneous in some patients and is both subcutaneous and perivisceral in others. Inflammation of fat may induce a focal cutaneous or a systemic extracutaneous histiocytic proliferative response in which hemophagocytosis may be a frequent characteristic. Major causes of death--sepsis, hepatic failure, hemorrhage, and thrombosis--are identical in the patients with and without the systemic histiocytic proliferation. Inflammation in fat, of and by itself, may be associated with significant morbidity and mortality, regardless of specific histopathology or inciting factors. (J AM ACAD DERMA'roL12:535-551, 1985.)

The clinical syndrome known as Weber-Christian disease (WCD) was first reported by Pfeifer 1 in 1892. He described a 23-year-old woman with a 2-year history of recurrent nodules that left a depression on involution. In 1916 Gilchrist and Ketron 2 reported the case of an 8-year-old girl who developed similar lesions accompanied by fevers. Histopathologic changes included inflammation in adipose tissue with fat ingestion by phagocytic cells. In 1925 Weber 3 described a woman with a history of bromide ingestion, a positive Pirquet's reaction for tuberculosis, and three episodes in 1 year of tender subcutaneous nodules that he called From the Department of Dermatology, College of Medicine (Dr. Aronson, Mr. West), and the Department of Pharmacy Practice, College of Pharmacy (Mr. West), University of Illinois at Chicago Health Sciences Center, the Department of Pathology, Northwestern University (Dr. Variakojis), the Department of Dermatology, Rush Medical College (Dr. Malkinson), the Department of Pediatrics, University of Kentucky at Lexington (Dr, Wilson), and the Max Samter Institute of Allergy and Clinical Immunity, Grant Hospital of Chicago (Dr. Zeitz). Reprint requests to: Dr. Iris K. Aronson, Room 376 CME, Department of Dermatology, University of Illinois at Chicago Health Sciences Center, P.O. Box 6998, Chicago, IL 60680.

"relapsing nonsuppurative nodular panniculitis." In 1928 Christian4 described a 22-year-old woman who developed ten episodes in 10 years of subcutaneous nodules, accompanied by fevers, headache, nausea, vomiting, myalgia, and fatigue. Intervals between attacks varied from a few months to 3 years; deep, irregular depressions developed in the cutaneous surface after the episodes subsided. Christian added the term febrile to the name: "relapsing febrile nonsuppurative nodular panniculitis" (RFNSNP). In 1936 BrilP described a 19-year-old girl with a 3-year history of recurrent tender subcutaneous nodules, fever, weakness, and significant splenomegaly. Many of the lesions in this patient healed without leaving depressions. Brill used the term Weber-Christian disease, rather than RFNSNP, to describe this syndrome. The cases subsequently reported as WCD or RFNSNP displayed a clinical spectrum varying from short, self-limited, or intermittent disease episodes to persistent disease with fatal outcome. The inflamed adipose tissue was exclusively subcutaneous in some patients and both subcutaneous and perivisceral in others; it was suggested that

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cytes. Our experience with four similar patients is reported here, together with a summary of clinical and pathologic findings in fifty-two patients with fatal panniculitis who were identified by a literature review. CASE REPORTS Case 1

Fig. 1. Superficial erosions that developed in many lesions prior to death. the former be called "subcutaneous nodular panniculitis" or "Weber-Christian panniculitis" and the latter, "systemic panniculitis" or "systemic WCD."6'7 In some patients, WCD occurred in association with drugs, trauma, infections, diets, jejunoileal bypass, a-antitrypsin (slAT) deficiency, pancreatitis, connective tissue diseases, diabetes, or malignancy; the other patients had no identifiable disease associated with the panniculitis. Since clinical and histologic features were similar in most patients, it became apparent that WCD was not a disease entity but a syndrome resulting from a variety of causes. T M Although most of the published case reports are of patients with nonfatal WCD, this report concerns those patients who have had persistent or recurrent disease with a fatal outcome. Winkleman et al ~2'~3recently reported five patients with a fatal clinicopathologic syndrome that included panniculitis with involvement of adipose and other tissues by benign-appearing cytophagocytic histio-

A 30-year-old white woman noted small, nontender lumps in both calves in 1966. In 1969, she developed recurrent low-grade fevers, joint pain, and tender erythematous nodules on her lower legs that would appear every 4-8 months and last for 2 months. In 1975 the lesions spread to the thighs and upper extremities, became larger and more erythematous with draining, crusting, and ulceration, and were associated with weekly fevers. In the following 3 years the patient developed a variety of associated medical problems, including high fevers, fatigue, malaise, chills, headaches, cough, abdominal pains, diarrhea, nausea, vomiting, myalgias, acute psychotic episodes, anemia, and leukopenia. Skin biopsies revealed lobular and septal panniculitis with an inflammatory infiltrate consisting of lymphocytes, histiocytes, and cytophagocytic histiocytes. In April, 1979, the subcutaneous nodules became more widespread and ulcerated. The patient developed high spiking fevers, sweating, episodic dyspnea, bilateral pleural effusions, right upper quadrant tenderness, hepatosplenomegaly, schizoid behavior, upper extremity tremor, and decreased sensation in the lower extremities. Extensive laboratory evaluation revealed an elevated erythrocyte sedimentation rate (ESR) of 65 mm/hr, anemia, leukopenia (white blood cells, 8003,000/ram3), thrombocytopenia, intermittently elevated liver enzymes (3 to 5 times normal), and coagulation abnormalities. Antinuclear antibodies were not present, arid levels of complement and cq-globulin were normal. HLA loci were A10, w32, Bwl5, and w21. Peripheral blood smear revealed spherocytes, schistocytes, anisocytosis, helmet cells, erythrocyte fragments, and many nucleated erythmcytes. Antibodies to platelets and leukocytes were not detected, but leukocyte chemotaxis was abnormal. Results of Coombs' test were repeatedly negative. Liver biopsy demonstrated moderate fatty infiltration and some nonspecific portal inflammation. Bone marrow examinations revealed mild megaloblastic erythroid hyperplasia, a decreased granulocyte series, and a mild, diffuse increase in histiocytes. Treatment included the use of chloroquine, dapsone, prednisone, and cyclophosphamide. Severe thrombocytopenia developed, with subsequent bleeding

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Fig, 2. Photomicrograph of lymph node, showing dilated sinus with histiocytes containing many erythrocytes in their cytoplasm (erythrophagocytosis). (Hematoxylin-eosin stain; original magnification, X 400.)

Fig. 3. Photomicrograph of subcutaneous tissue with large, foamy histiocytes, scattered lymphocytes, and fat cyst formation. (Hematoxylin-eosin stain; original magnification, x 400.) that was unresponsive to transfusions and surgery, leading to the patient's death in late 1979. Autopsy revealed pleural and pericardial effusions, diffuse alimentary tract hemorrhage, and multiple bleeding sites throughout the body. Skin lesions were widespread with superficial ulcerations (Fig. 1). The liver demonstrated fatty infiltration and sinus congestion with erythrocytes. The spleen and lymph nodes showed sinus histiocytosis with erythrophagocytic histiocytes (Fig. 2). Bone marrow examination revealed

occasional erythrophagocytic histiocytes; the lungs showed hemosiderin-laden macrophages. Irnmunofluorescence microscopy of a skin lesion demonstrated granular deposits of Clq at the dermoepidermal junction and in dermal blood vessel wails. Case 2 A 34-year-old white woman developed painful subcutaneous nodules in the flank, abdominal wall, back, neck, and thighs in July, 1977. The nodules varied from

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Fig. 4. Photomicrograph of inflammatory reaction present in fat lobules, as well as in septal areas. Foamy histiocytes, fat cysts, and lymphocytes are present. (Hematoxylineosin stain; original magnification, × 100.)

Fig. 5. Photomicrograph of subcutaneous venule with extensive subendothelial infiltrate of mononuclear cells. (Hematoxylin-eosin stain; original magnification, x 100.) individual lesions 1 cm in diameter to a 15 × 5-cm plaque. The lesions were erythematous to violaceous in color, were nonulcerated, and were associated with fevers to 38.8 C, malaise, and fatigue. Past history included splenectomy at age 15 years for hemolytic anemia, a vague history of arthritis, and chronic recurring perineal condyloma acuminata of 3 years' duration~ recently treated with vaginal povidone-iodine douche.

Clinical and laboratory examination revealed hepatomegaly, mild elevation of liver transaminases (2 to 3 times normal), and marked increase in lactate dehydrogenase with elevation of all fractions. Liver bioPsY demonstrated focal necrosis and a mononuclear cell infiltrate. Elevated levels of complement components (Clq, C3) and cq-globulin were detected. Antinuclear antibodies were not present. The ESR was 2 ram/hr. Peripheral blood smear showed occasional spherocytes

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and a few acanthocytes. Biopsy of a subcutaneous lesion in November, 1977, revealed lobular and septal panniculitis with mononuclear cell infiltration of vessels (Figs. 3 to 5). Eosinophilic histiocytes with intracellular erythrocytes were present. Treatment included chloroquine, indometbacin, prednisone, and levamisole. In April, 1978, the patient developed anemia, leukopenia, and thrombocytopenia with variation in platelet size. Shortly thereafter, she died at home of an undetermined cause; autopsy was not obtained.

Case 3 A 30-year-old white woman, whose case history will be reported in detail elsewhere, developed recurrent small, nontender subcutaneous nodules in 1974 while following a diet supplemented with vitamins, iodide, and bromide. Although she stopped the diet and dietary supplements, the panniculitis persisted. Between 1977 and 1980, she developed infrequent large subcutaneous nodules and plaques that occasionally ulcerated and were associated with premenstrual fevers, fatigue, leukopenia, and elevation of liver enzymes. Multiple biopsies of the nodules revealed a waxing and waning subcutaneous and lower dermal infiltrate of polymorphic and pleomorphic cells alternating with completely mature mononuclear cells. Biopsies of bone marrow, the liver, and a lymph node did not reveal extracutaneous malignancy. Antinuclear and anticytoplasmic antibodies were not present; complement levels were normal Or elevated. Circulating atypical cells were not found on multiple examinations. Following a primary genital Herpes simplex infection in March, 1980, the nodular lesions became more widespread with development of superficial ulcerations (Fig. 6). Skin biopsy revealed small- and medium-vessel vasculitis, occasional erythrophagocytic histiocytes, and a pleomorphic and polymorphic dermal and subcutaneous lymphocytic infiltrate that was subsequently diagnosed as cutaneous T cell lymphoma (CTCL). Two months after therapy with prednisone and local radiation of two nodules, the patient developed high spiking fevers, neurologic symptoms, pancytopenia, hyperlipidemia, hypoalbuminemia, hepatic abnormalities, and transient coagulation abnormalities. The level of a 1AT was normal, and protease inhibitor (Pi) phenotyping revealed the normal M type. HLA typing revealed A2, w33, B14, and w44 loci. Bone marrow aspiration revealed erythrophagocytic hisfiocytes, and skin biopsy revealed atypical lymphocytes associated with erythrophagocytic histiocytes. The urine lysozyme level was

Fig. 6. Ulcerated cutaneous nodule in Patient 3. 63 mg/dl (normal = 0-3 mg/dl). Despite antibiotic treatment, transfusions, and chemotherapy, the patient died with Clostridium sepsis in October, 1980. Autopsy revealed hepatosplenomegaly, pericardial and pleural effusions, and numerous ulcerated cutaneous lesions. Microscopic findings included a dense cutaneous and subcutaneous infiltrate of coexisting large atypical lymphocytes and erythrophagocytic histiocytes. Hepatic changes included fatty metamorphosis, periportal inflammation, and hyperplastic Kupffer's cells containing vacuoles and erythrocytes. Examination of the spleen and lymph nodes demonstrated marked lymphoid depletion and dilated sinuses filled with erythrophagocytic histiocytes. No neoplastic ceils were seen in any extracutaneous organ.

Case 4 An 8-week-old white baby developed fevers and small erythematous indurated areas with central necrosis under the chin and in the groin in November, 1979. Despite antibiotics, the cutaneous lesions spread tothe mandibular area, chest wall, abdomen, and back. Large

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Table I. Symptoms in fifty-two patients with fatal panniculitis Symptom

Cutaneous lesions Fever Abdominal complaints* Neurologic symptomst Weakness Malaise Weight loss Cough and/or dyspnea Arthralgias and/or arthritis Retrosternal chest pain Night sweats Fatigue Chills Myalgias

No. of [ patients

% total

52 48 20

100 92 38

17 15 i5 1:1 11 9

33 29 29 21 21 17

8 7 6 5 4

15 13 12 10 8

*Nausea, vomiting, diarrhea, focal or diffuse abdominal pain and tenderness, abdominal distension. tHeadaehe, 29'3°'35'46'~mental confusion,7'n: '~ lethargy and/or drowsiness7'n'47 (Ritama and Krusius, footnote next col.) dysarthria, ataxia, ~2.37,4~coma, i3.29,37.46.49seizures, ~2,~6.20,4~hemiparesis,6'5° aphasia.

areas of necrosis, some open down to muscle, developed in the groin and extended to the umbilicus. Marked hepatomegaly was present. Mild left facial palsy developed, with Pseudomonas corneal infection secondary to poor lid closure. Extensive laboratory evaluation over the next 6 months disclosed an ESR of 6 mrn/hr and decreased levels of immunoglobulin G, transferrin, albumin, and haptoglobin. There were moderate to marked elevations of the second component of complement, liver trans. aminases (4 to 6 times normal), bilirubin, and triglycerides (>2000 mg/dl). Small stippled areas of subcutaneous calcification were noted on x-rays. Peripheral blood B and T lymphocytes were normal in quantity and function. Antinuclear antibodies and circulating immune complexes were not demonstrated. Results of a nitroblue tetrazolium test were normal. A neutrophil ehemotactic defect was observedwith decreased random and directed motility in response to chemotatic substances. Multiple antemortem cutaneous and subcutaneous biopsies revealed lobular panniculitis with focal necrosis and calcification, fibfinoid necrosis of medium-sized blood vessels in the lower dermis and fat, and infarction of the dermis and epidermis. Immunoglobulin M and

complement were present in the blood vessel walls. Electron microscopy of a small subcutaneous arteriole revealed endothelial degenerative changes with intracytoplasmic tubuloreticular inclusions resembling myxoviruses or paramyxovimses. Treatment included multiple antibiotics, vigorous debridement, cyclophosphamide, pulse methylprednisolone, dapsone, zinc, heparin, exchange transfusion, levamisole, dipyridamole, and superficial radiation. A transient response was noted only with high-dose steroid treatment. At 8 months of age the patient developed pneumococcal meningitis and died. Autopsy revealed meningitis; a variety of hepatic abnormalities (fatty liver, with fibrosis, lipofuchsin deposition, and hemosiderin in Kupffer's cells); congestion of the spleen, with lymphoid depletion, hemosiderin-laden macrophages, and a few erythrophagocytic histiocytes; and lymphoid depletion with absence of germinal centers in the lymph nodes. REVIEW OF THE LITERATURE

A literature search revealed 168 patients with panniculitis, fifty-two of whom died. 6.7.t0.n.~3.sa.,..~ The fifty-two patients with fatal panniculitis included thirty female and twenty-two male patients. Age at onset of panniculitis ranged from 3 weeks to 80 years.: Where race was noted, there were forty-one Caucasian and six Oriental patients. Apparent precipitating factors included trauma (nine patients), medication (seven patients), and a variety of infections (ten patients). Vaccination also has been associated with fatal panniculitis. 2°a~ Onset of disease

Although fever and/or nodules did not always appear simultaneously and were not seen during the entire disease course, these s y m p t o m s were usually the presenting complaints. In thirty-eight patients the onset of subcutaneous nodules was preceded by, concurrent with, or followed by fever within 6 weeks. In six patients, recurrent nodules with or without systemic symptoms appeared years before fever was noted. 6:9,a4,25'2s'43 In four pa"*Pantangco EE, Alimurung MM', Parkes-Weber-Christian disease: Report of a case in a Filipino. J Philippine Med Assoe 32:412421, 1956. tRitama V; Krusius FE: Generalized lipogranulornatosis (WeberChristian syndrome): Report of a ease with autopsy. Ann Med Int Fenniae 42:133-148, 1953.

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tients,t2,22, 40,* intermittent fever was present prior t o the appearance of nodules. Eight of these patients had various signs and symptoms prior to the onset of either fever and/or nodules: two had only nonspecific systemic complaints,5°'t two had thrombocytosis, TM and the other four had abdominal symptoms. 7'21'33'+5 Three patients developed subcutaneous nodules that later disappeared, 16.39,52

Clinical manifestations At some time during the course of their disease, all fifty-two patients had cutaneous lesions, most frequently on the extremities and buttocks (Tables I and II). The overlying skin color was either normal, pink, markedly erythematous, purple, bluish purple, or brown (hyperpigmentation), with mild to moderate scaling in some. The lesions were flat or raised and either discrete and well circumscribed or irregular and diffuse. They varied in consistency from indurated, firm, or even hard to soft and fluctuant. Fluctuant lesions resembling an abscess were present in six patients, t8'25'29'~4'42'53 The lesions were most commonly nodules of various sizes that either remained discrete or coalesced to form large "swellings" or indurated plaques up to 20 cm in diameter. At times, indurated cords extending from the main lesions were noted. The lesions appeared singly or more often in crops and could either persist or regress over a period of weeks or months. During periods o f disease activity, new nodules appeared while others persisted or regressed. Healing was often followed by localized skin depression and/or hyperpigmentation. Ulceration of cutaneous lesions developed in twenty-four patients. These lesions were extremely recalcitrant to treatment, and biopsy sites often drained for months. T M Mucous membrane lesions were noted in only three patients. ~2,35 Acute abdominal emergencies with small bowel perforation secondary to inflammation and/or ne*Ritama V, Krusius FE: Generalized lipogranulomatosis (WeberChristian syndrome): Report of a case with autopsy. Ann Med Int Fenniae 42:133-148, 1953. tPantangco EE, Alimurung MM: Parkes-Weber-Christian disease: Report of a case m a Filipino. J Philippine Med Assoc 32:412420, 1956.

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Table II. Clinical findings in fifty-two patients with fatal panniculitis Finding

Cutaneous lesions Fever Skin ulceration Hepatomegaly and/or splenomegaly Neurologic changes* Abdominal abhormalitiest Lymphadenopathy:~ Cardiac abnormalities§

No. of patients

% total

52 48 24 23

100 92 46 44

17 13

33 25

10 5

19 10

*Additional to those in Table I: clonus, 7't2'~1facial palsy, 3~oeulomotor paresis~ (Ritama and Krusius, footnote col, ~), peripheral neuropathy, 7 ~ 6 bilateral proptosis? 7 tTenderness, distension, increased bowel sounds, ileus, acute abdominal emergencies, masses. SPeripheral in seven patients; abdomtnat in three discovered at taparotomy.'2.2~.~ §Cardiomegaly, congestive failure, pericarditis, myocarditis. la,25.26,37,49

crosis occurred in four patients.31,33,45.53 Abdominal masses, found later, at autopsy, to consist of necrotic and inflamed adipose tissue, ~,St were palpated in two patients.

Laboratory data Leukopenia was transient, intermittent, or persistent, and it was severe (white blood cell count, 1,000/ram 3) in fourT M (Table III). HLA typing in two patients was not informative.

Clinical course Group 1. Patients in Group I had a rapid disease course (death occurred ~<21 months). All twentyfive patients (eleven female and fourteen male) died within 21 months after the onset of disease, including twenty who died in less than 1 year. Their ages at onset ranged from 3 weeks to 80 years. Twenty patients had a relentlessly persistent course; five had an intermittent course. Group 2. In group 2 the disease course was longer (death occurred t>2 years). The age at onset of the nineteen female and eight male patients in this group ranged from 6 to 69 years. Seventeen patients died in 2 to 5 years; ten survived for 6 to

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Table III. Reported laboratory findings m fifty-two patients with fatal panniculitis Finding

Anemia (Hg, 7-11 gm/dl) Leukopenia (WBC <4,000/ram 3) Leukocytosis (WBC >9,000/mm 3) Thrombocytopenia (< 100,000/mm 3) Thrombocytosis (>600,000/ram a) Erythrocyte sedimentation rate High Low

Hepatic abnormalities Hypoalbuminemia Coagulation abnormalities* Hyperlipidemia oqAT deficiencyt Tissue autoantibodies Cryoglobulins Low pmperdin levels Pulmonary radiographic abnormalities~:

No. of eases

Finding

29 27 8 12 3

Small bowel perforation with granulomas, vasculitis or infarcts Bone marrow Normal or nonspecific changes Erythrophagocytic histiocytes Foamy histiocytes Lymph nodes Reactive Erythrophagocytic histiocytosis Lymphorna Liver Fatty Hepatitis

7 12 26 15 10 5 3 3 2 1 17

WBC: White blood cell count. *References 12, 18, 21, 31, 32, 36, 48. "tReferences 18, 42. :~Transient densities, 4°'45'4s infiltrates, 6'~'1~'24'4~'53 pleural sion, 6,~2:~.a~,2~,42emphysema, la,2~ interstitial fibrosis. 37

Table IV. Antemortem pathologic findings in twenty-nine patients with fatal panniculitis No. of cases

4

20 2 2 3 2 1 1 1

Pathologic findings

effu-

18 years. Twenty-six patients had intermittent remissions and exacerbations; only one patient had relentlessly persistent disease. Impairment in general condition was not noted early in the disease but became more prominent with persistent fevers and recurrences.

Treatment Corticosteroids and/or adrenocorticotmpic hormone therapy induced some improvement, usually temporary, in fourteen of twenty-six patients. No apparent change in disease course was noted in the other twelve patients. 10,12,14.18,25,32,36,42,53Radiotherapy of the skin was administered to three patients, with notable results in one. 46 The broadspectrum protease inhibitor aprotinin 18,32and transfer factor 2° had little or no effect. Other treatment modalities (nonspecific supportive care, blood transfusions, cytotoxic agents, inorganic arsenic, gentian violet, gold, and antibiotics) were used sporadically, and the results of treatment could not be evaluated.

Antemortem pathologic findings were observed in twenty-nine patients (Table IV). In addition to the abnormalities in bone marrow, lymph nodes, liver, and small bowel, direct immunofluorescenee microscopy of skin lesions revealed IgM and IgA, the third component of complement, and fibrin in the basement membrane zone and blood vessels in one patient, lz Indirect immunofluorescence of subcutaneous tissue using rabbit antimeasles nucleocapsid antibody demonstrated antibody uptake in one patient in whom helical structures resembling paramyxovirus nucleocapsid were seen on electron microscopy. 2° Postmortem pathologic findings are summarized in Tables V to VII. Forty-two patients had detailed, histopathologic descriptions of cutaneous lesions, Epidermal involvement was usually minimal or nonspecific, except in those patients who had ulcerated lesions. Dermal abnormalities were noted in thirteen patients and included perivascular and periappendageal inflammation, 17'26'~5'38:°'44'46'* diffuse lower dermal inflammation, 2~'34'49 vasculitis,34,4J.* and infarction. 33 The main pathologic findings were in the sub*Pantangco EE, Alimurung MM: Parkes-Weber-Christian disease: Report of a case in a Filipino. I Philippine Med Assoc 32:412420, 1956.

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Fatal panniculitis

Table VI. Postmortem microscopic findings in forty-five patients with fatal panniculitis

Table V. Postmortem pathologic findings in forty-five patients with fatal panniculitis Finding

Subcutaneous fat involvement Perivisceral fat involvement Splenomegaly Hepatomegaly Lymphadenopathy Bone marrow abnormalities Lung abnormalities Pancreatic abnormalities Serosal abnormalities Gastrointestinal abnormalities Brain abnormalities Myocardial abnormalities Myositis Urinary tract Malignancy

No. of patients

42 30 19 16 6 12 15 12 19 15 7 8 6 8 4

543

% total

93 66 42 35 13 27 33 27 42 33 15 18 13 18 9

cutaneous fat and consisted of a moderate to intense polymorphic inflammatory infiltrate involving the fat lobules and connective tissue septa. The inflammatory cells included neutrophils, lymphocytes, plasma cells, histiocytes, and foamy histio. cytes. Irregularity or lack of uniformity was noted frequently, In some cases normal areas were adjacent to areas with necrotic cells31,4°; in other cases, single lobules were replaced by granulomatous tissue whereas adjacent lobules were completely uninvolved? 1 Similarly, single or adjacent lobules were in different stages of inflammation simultaneously, with focal acute neutrophilic inflammation in some areas and diffuse chronic lymphohistiocytic inflammation in others? 5,51 Fat necrosis in varying amounts was noted in twenty patients. Phagocytosis of erythrocytes or leukocytes (cytophagocytosis) was noted in seven patients.J2.15,~5,26,38.4° Involvement of perivisceraI fat, noted in thirty patients, ranged from microscopic changes to grossly visible changes that included scattered individual nodules ,gv,51,s: multiple nodules ,7,27,41,45,* widespread induration of the fat, 24'42'45and diffuse firm tumorlike infiltration of fat in shell-like or *Ritama V, Krusius FE: Generalized lipogranulomatosis (WeberChristian syndrome): Report of a case with autopsy. Ann Med Int Fenniae 42:133-148, 1953.

Anatomic location/findings

Liver Fatty changes Necrosis Inflammation Cirrhosis Bile duct proliferation Small vein thrombosis Foamy or erythrophagocytic histiocyte Spleen Histiocytic hyperplasia Lymphoid depletion Congestion Foamy or erythrophagocytic histiocytes Lymph nodes Histiocytic hyperplasia Lymphoid depletion Foamy or cytophagocytic histiocytes Bone marrow Diffuse histiocytosis Foamy or cytophagocytic histiocytes Fat necrosis and inflammation Myelofibrosis Lung Thrombosis (emboli) Vasculitis Granulomatous pneumonitis Foamy or cytophagocytic histiocytes Free fat Pancreas Peripancreatic or intralobular fat inflammation Fatty infiltration or replacement Pancreatitis Amyloid Cyst Serosa Pericardial inflammation Pleural effusion Ascites Gastrointestinal tract Wall inflammation, ulceration, infarcts, or vasculitis Carcinoma Hodgkin's disease Mesenteric panniculitis Brain Lipomas Pituitary histiocytosis Vasculitis Hemorrhage

No. of patients

29 13 12 6 4 1 10 8 11 7 11 10 5 14 2 4 6 1 5 2 4 6 3 6 3 2 1 1 16 14 8 9 1 1 6 3 1 1 1

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Table VIII. Immediate causes of death

Table VII. Summary of postmortem abnormalities of hisfiocytes and lymphocytes in forty-five patients with fatal panniculitis No.

Histiocytosis Cytophagocytosis Vacuolated, fat-filled or foamy macrophages (extracutaneous) Cytophagocytic and vacuolated macrophages Lymphocyte depletion (spleen and/or lymph node)

of

patients

% total

26 9 11

58 20 24

4

9

13

29

Infection Hemorrhage Hepatic failure Thrombosis Generalized malignancy Renal failure Myocardial infarction Intracranial liporna Respiratory failure Unknown Total

14 10 10 5 3 2 I 1 1 5 52

ciency,18 The cause of death was not determined in the remaining five patients. DISCUSSION

armoflike encasement around various organs. 6'16'28 Microscopic examination of the altered fat revealed varying degrees of inflammation, necrosis, and fibrosis. The inflammatory cells included lymphocytes, plasma cells, histiocytes (with and without ingested lipid), and a few neutrophils. Pleomorphic histiocytes, many of bizarre shape, were noted in one case, 6 and Hodgkin's disease was diagnosed in another) 8 Fibrosis was variable but usually minimal. Other changes included vasculitis6'33'41:* and bony metaplasia. 45 Cause of death

Terminal infections, including bacterialsepsis, peritonitis, meningitis, and pneumonia, were present in seventeen patients, ten of whom had been treated wtih systemic steroids, and were the probable cause of death in fourteen patients (Table VIII). Three Patients died with generalized malignancy, including Hodgkin's disease) ~ gastric carcinoma, 23 and malignant histiocytosis. 43 Myocardial infarction was due to pericardial fat involvement by panniculitis with marked secondary narrowing of the coronary arteries, 16 Central nervous system lipoma, present in three patients, appeared to be the cause of death in only o n e . 37 Respiratory failure was noted as the cause of death in one unautopsied patient who had oL1AT deft• Ritama V, Krusius FE: Generalized lipogranulornatosis (WeberChristian syndrome):Report of a case with autopsy. Ann Med Int Fenniae 42:133-148, I953.

i

This report summarizes the clinical and pathologic characteristics of four new and fifty-two previously published patients with fatal panniculitis. The findings suggest that although panniculitis may be an isolated local process in some patients, it also can be a local manifestation of a systemic disease process that leads to death in others. Involvement of extracutaneous adipose tissue is variable. The pathologic process may smolder for years, with remissions and recurrences, or may have a rapidly progressive fatal course. Frequent causes of death include infection, hemorrhage and/ or thrombosis, and hepatic failure. Three major factors associated with the onset or recurrence of panniculitis were trauma, drugs, and infection. Panniculitis appears to be similar to dermatologic reaction patterns (e.g:, erythema nodosum, erythema multiforme, leukocytoclastic angiitis) in being precipitated by drugs, infections, malignancy, or connective tissue diseases. Panniculitis may also occur as an idiopathic disorder. The onset of disease in our Patient 3 occurred after a stringent diet accompanied by supplements of amino acids, vitamins, iodides, and bromides, Low-calorie diets, nutritional abnormalities, and ingestion of iodide and bromide all have been associated previously with the onset of panniculitisIT'~8,st,54,55; it is unclear whether these factors actually precipitated the reaction or were associated only coincidentally. Most patients had an intermittent disease course

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with recurrent cutaneous manifestations, but some patients had a relentless process in which cutarteous lesions were continuously present, with individual lesions appearing and disappearing. Nodular, plaquelike, abscesslike, liquefying, or ulcerating cutaneous lesions were noted either simultaneously or sequentially in the course of the disease. With only three exceptions, the type of cutaneous lesion was not correlated with associated disease or prognosis. The three exceptions were (1) liquefaction with fluctuant lesions resembling abscesses in patients with alAT deficiency t8'42 (I. K. A.: personal observation in three cases to be reported elsewhere); (2) superficial ulcerations of the skin over a majority Of lesions prior to death 34,38 (Patients 1, 3, and 4); and (3) persistence of individual lesions without signs of regression in association with an unfavorable prognosis. Histopathologic studies of the subcutaneous fat generally revealed a mixed inflammatory infiltrate of histiocytes and lymphocytes, the latter being large or atypical in occasional patients. Plasma cells, neutrophils, and eosinophils were present in varying proportions in some of the patients. With time, the subcutaneous infiltrate either remained basically unchanged or developed a predominance of histiocytes or lymphocytes. Half of the fiftyt w o previously reported patients had focal extracutaneous or generalized histiocytosis, usually associated with phagocytosis of fat or erythrocytes, and all four of our patients had erythrophagocytic histiocytosis. Multiple organ system involvement was frequently present in patients with fatal panniculitis. Involvement of the gastrointestinal tract, the liver, and the nervous system was prominent in many patients. Abdominal complaints were present in twenty patients and were usually associated with a variety o£ gastrointestinal and/or mesenteric pathologic findings. Intestinal involvement was caused either directly by inflammation of the bowel or indirectly by spread of inflammation from the mesenteric fat; microscopic changes included infiltration by foam cells, granuloma formation, vasculitis with infarcts and ulcerations, and necrosis. Hepatic abnormalities were present in two thirds

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of the patients and varied from mild or diffuse fatty infiltration and inflammation to hepatic failure. Hepatic changes were common in patients with perivisceral panniculitis but were also noted in patients with exclusively subcutaneous panniculitis. The extensive antemortem hepatic fatty infiltration and portal inflammation in all four of our patients suggest that hepatic involvement in fatal panniculitis is not coincidental, but the reason that the liver is involved so frequently is not clear. One possible explanation is that panniculitis leads to destruction of adipose tissue, whereupon free fatty acids and triglycerides are liberated into the circulation and subsequently deposited in the liver. The extent of fatty deposition might depend on the capacity of the liver to metabolize mobilized free fatty acids. Inflammation and cirrhosis might develop in those patients in whom the level of mobilized fat exceeds the metabolic capacity of the liver. Since the liver plays an important role in the synthesis and remodeling of various lipoprotein classes, hepatic dysfunction might lead to secondary abnormalities in lipoprotein synthesis with subsequent further alterations of lipid metabolism.• Although central and/or peripheral neurologic changes were present in one third of the patients, the association of these symptoms with fatal panniculitis has not been specifically emphasized previously. Terminal neurologic manifestations, ineluding seizures and coma, were seen in many patients and resembled Reye's syndrome? ~'57Clinical changes in patients with Reye's syndrome include encephalopathy and elevated serum free fatty acid levels; histologic changes include serous atrophy of adipose tissue, foamy macrophages in the pulmonary alveoli, and visceral fatty changes, 58'~9 suggesting that mobilization of fat from adipose tissue by excessive lipolysis with reesterification and oxidation of fatty acids in variousorgans might be a major pathologic process, s° The neurologic symptoms in Reye's syndrome and in some patients with fatal panniculitis might result from the elevated serum levels of free fatty acids following destruction of adipose tissue. Abnormal lipid metabolism also might have been a factor in the development of the thrombotic events that occurred in some panniculitis patients. Long-chain fatty acids have been shown to induce

546

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transient thrombocytopenia6~ and to promote thrombus or clot formation. 62,6~ Intravenous infusions of long-chain saturated fatty acids have been shown to produce massive thrombosis and death in dogs. 64 It therefore seems possible that large increases in free fatty acids in localized areas of panniculitis or in plasma might result in intravascular thrombi with secondary tissue infarcts. Two of our patients developed terminal hyperlipidemia, as did five other patients with fatal panniculitis, x~,t3,2~,~9,~3Three of the seven patients had erythrophagocytic histiocytosis t2,~3(Patient 3), one had reticuloendothelial erythrophagocytosis without histiocytosis (Patient 4), and two had foam cell histiocytosis. 2~,39The seventh patient had no histiocytosis noted. 53 The mechanism underlying the lipid disorder in these seven patients is not known. One possible explanation is a reduction, secondary to inflammation and necrosis, of available lipoprotein lipase on the endothelial cells of adipose tissue capillaries. 65 In one study of eight patients with WCD, lipoprotein lipase activity was normal in all patients during remission but decreased dramatically 24 to 48 hours prior to the onset of new lesions. ~6 Since the liver plays an important role in lipoprotein metabolism, altered hepatic function is a second possibility. Other factors that might be related to terminal hyperlipidemia include decreased lipoprotein lipase synthesis by monocytes involved in the inflammatory process, 67 a circulating inhibitor of postheparin lipase, 68 and corticosteroid therapy. 69 Although hyperlipidemia is usually a terminal event when it occurs in patients with fatal panniculitis, local changes in lipid composition probably occur much earlier in areas of fat destruction. Local uptake of lipid by macrophages with subsequent circulation of these cells throughout the reticuloendothelial system might lead to an apparent systemic lipidosis. In addition, the local lipid changes in the fat, as well as in the reticuloendothelial system, might induce cell membrane alterations in erythrocytes, making them more susceptible to phagocytosis. When hyperlipidemia does develop, alterations may occur in the membranes of circulating erythrocytes, which continuously remodel their membrane lipid composition through passive exchange with plasma lipids; these alterations might then promote an increased fre-

Journal of the American Academyof Dermatology

quency of systemic erythrophagocytosis. With widespread local fat destruction and/or hyperlipidemia, alterations of leukocyte and platelet membranes might also develop, leading to cytophagocytosis with secondary anemia, leukopenia, and thrombocytopenia. Furthermore, when the macrophages are filled with fat or cells, their role in microbial phagocytosis, antibody production, and cell-mediated immunity might be compromised, leading to an increased susceptibility to infections, v° The experimental finding that fatty acids administered intravenously in mice exert a significant depressant effect on phagocytosis of colloidal carbon 7~ supports this hypothesis. However, since hyperlipidemia and lipoprotein abnormalities also have been reported in association with infections72 and lymphoreticular malignancies73 without panniculitis or erythrophagocytic histioeytosis, the exact relationship between hypedipidemia and fatal panniculitis remains uncertain. Malignancy was associated with panniculitis in five of the fifty-six patients summarized in this report. The tumors included gastric carcinoma, 23 malignant histioeytosis, 43 Hodgkin's disease, 2a lymphocytic lymphoma, 24 and CTCL (Patient 3). One additional patient had midline granuloma. 52 Panniculitis with angiocentric and angiodestructive infiltration of vessels in subcutaneous fat by mature and/or immature mononuclear cells has been reported previously in association with systemic lymphoreticular malignancy74; a similar relationship exists in the lung, where an angiocentric and/or angiodestructive polymorphous inflammatory cell infiltrate may precede the development or recognition of lymphoma.75.76 Mesenteric panniculitis (MP), sometimes referred to as mesenteric lipodystrophy or lipogranulomatosis of the mesentery, has been considered a variant of WCD, usually without the characteristic subcutaneous lesions. 77"85 Patients with MP frequently have an associated neoplastic process; in one group of fifty-three patients, sixteen (30%) had a malignancy. 83 Marked t~IAT deficiency was identified in three (5%) of the fifty-six patients with fatal panniculitis. 18.42In all three patients the a l A T deficiency was associated with the protease inhibitor (Pi) phenotype PiZ. In a review of 120 nonfatal cases of panniculitis (which will be the subject of a separate

Volume 12 Number 3 March, 1985

report), an additional eight patients with cdAT deficiency were identified; four (3%) of the 120 patients had marked deficiency and the PiZ phenotype86'8v (I. K. A.: personal observation). The frequency of severe cdAT deficiency of PiZ phenotype seems to be much higher in panniculitis patients (4%) than in the general population (~<0.1%),~8 which suggests that deficiency of this protein might predispose not only to severe emphysema89 and liver disease89-9~but also to panniculitis. Two frequently observed features of the panniculitis associated with alAT deficiency were (1) liquefaction of the subcutaneous lesions, with abscess formation and drainage, and (2) induction of lesions by trauma. With the exception of these two features, the clinical spectrum of panniculitis in patients with and without a 1AT deficiency was identical. Thus deficiency of this major protease inhibitor probably is not a cause per se of panniculitis but might predispose to dissemination of lesions and/or a poorer prognosis. 42 Six (1 1%) of the patients with fatal panniculitis were children. One of our patients (Patient 4) developed panniculitis at 2 months of age; the other reported infants with fatal panniculitis were 3 weeks, 3' 6 months, 44 and 7 months36 of age when the panniculitis began. One older child had panniculitis at age 6 years but died from hepatic failure without panniculitis 15 years later, TM and a 14year-old boy developed fatal panniculitis following immunization with live measles virus vaccine?° Major clinical manifestations in the six children included liver disease, hemorrhage, disseminated intravascular coagulation, severe nutritional deficits, and infections. Autopsies performed in three of the five previously reported patients with childhood panniculitis revealed foamy macrophages in the adipose tissue without generalized histiocytosis or erythrophagocytosis. '4'2°'36 Autopsy in our patient revealed major abnormalities in the liver, spleen, and lymph nodes; extensive reticuloendothelial siderosis with some evident erythrophagocytosis was suggestive of a chronic erythrophagocytic process even though marked histiocytosis was not evident. The syndrome that developed in these six children is similar to familial erythrophagocytic lymphohistiocytosis,92,93 an early childhood disease

Fatal panniculitis 547

characterizedby both hyperlipidemia and a rapidly progressive process resembling malignant histiocytosis. The hyperlipidemia noted in these patients is not present in unaffected family members, 94,95 Cutaneous involvement is usually nonspecific (erythema, maculopapular eruption), but extensive subcutaneous96 and periviscera194'9~98 panniculitis has been reported. At autopsy, diffuse infiltration by morphologically mature histiocytes and small lymphoeytes is usually observed, but large atypical lymphocytes also have been noted23,96,99"1°' The histiocytes may contain erythrocytes, various nucleated cells, nuclei, nuclear debris, and/or lipid material.l°2 Erythrophagocytosis may be minimal or prominent, as illustrated by two recently reported siblings who died with this syndrome; one sibling had generalized erythrophagocytic histiocytosis with hyperlipidemia, whereas the other had localized lymphohistiocytosis only of the central nervous system without erythrophagocytosis. ,03Cases with less prominent hemophagocytosis have generally been called "lymphohistiocytosis. ''96,'°°,'°' Many cases have been reported in which extensive antemortem investigations failed to reveal the widespread erythrophagocytosis noted at autopsy, suggesting that erythrophagocytosis in children with familial erythrophagocytic lymphohistiocytosis may become extensive only shortly before death. TM Panniculitis has also been associated with Beh~et's syndrome, pancreatic disease, connective tissue diseases, and malignant histiocytosis. Beh~et's syndrome, a frequently fatal chronic relapsing systemic inflammatory disease, is characterized clinically by iritis, orogenital ulceration, arthritis, thrombophlebitis, neurologic involvement, inflammatory bowel disease, and a variety of cutaneous lesions. 1°5,1°6Cutaneous lesions vary considerably but may include panniculitis with infiltration of lymphocytes, histiocytes, or bothl°7; cytophagocytosis has not been described as a characteristic histopathologic feature. Both pancreatitis and pancreatic malignancy have been associated with subcutaneous fat necrosis. ~°g,~°9These patients may also have polyarthritis, synovitis, bone marrow fat necrosis, and polyserositis.'°9'I'° Symptoms or signs of pancreatic disease may be absent in these patients. In the patients with fatal panniculitis summarized in this

Journal of the American Academy of Dermatology

548 Aronson et al

report, pancreatic or peripancreatic abnormalities were noted in twelve patients, although only three had obvious pancreatic findings that might have precipitated the panniculitis. Panniculitis may occur in association with systemic or discoid lupus erythematosus or with less well characterized" connective tissue diseases." TM Our Patient 1 had a typical lupus band present in skin lesions at autopsy; yet she had never displayed any clinical or serologic evidence of connective tissue disease. A patient of Crotty and Winkelmann12 with "cytophagic panniculitis" had granular deposits of IgM, IgA, and complement at the dermoepidermaljunction without any serologic evidence of connective tissue disease. The significance of the "lupus band"-like deposits in the skin of these patients is not known. Panniculitis also can be a major manifestation of malignant histiocytosis or histiocytic medullary reticulosis, which must be differentiated from reactive histiocytosis. Histologic criteria have been suggested to distinguish between malignant histioCytosis and reactive histiocytosis. 112In malignant histiocytosis the predominant histiocytes have atypical cytologic features characteristic of neoplastic cells, whereas in reactive histiocytosis the predominant cells have the cytologic characteristics of mature histiocytes, often with marked hemophagocytosis. Fatal reactive erythrophagocytic histiocytosis has been reported in association with malignancy, including lymphoma, leukemia, and gastric adenocarcinoma,7~'l~3;~5 and with a variety of viral infections.~6nS Our Patient 3 with CTCL developed hemophagocytic histiocytosis following a herpes simplex infection. Nonfatal reversible erythrophagocytic reactive histiocytosis has been associated with a variety of bacterial, parasitic, and viral infections. ~19"x~ Using the term virusassociated hemophagocytic syndrome, Risdall et al ~z3 described nineteen patients with a clinicopathologic syndrome simulating the features of malignant histiocytosis or histiocytic medullary reticulosis in association with active viral infections. Fourteen of the patients were receiving immunosuppressive therapy; supportive care and withdrawal of irnmunosuppressive drugs led to recovery in thirteen. Risdall et al suggested that this virus-associated hemophagocytic syndrome and

many of the cases reported as histiocytic medullary reticulosis may be closely related if not identical. ~2 The relationship of malignancy, infections, and panniculitis to the development of histiocytosis is intriguing but unclear. Jaffe et a175postulated that the erythrophagocytic syndrome they described in patients with T cell lymphoma was secondary to macrophage-stimulating lymphokines produced by the neoplastic T cells. It is possible that normal lymphocytes activated by infectious agents also might produce macrophage-stimulating lymphokines. In contrast, panniculitis has been associated with the presence of subcutaneous or lymph node erythrophagocytic histiocytes from 3 to 15 years prior to the development of the rapidly progressive and fatal generalized erythrophagocytic histiocytosis. Thus, although the mechanisms involved in the induction of erythrophagocytic histiocytosis are speculative at present, it is possible that both lymphokine and lipid-induced macrophage activation may play a role. In summary, panniculitis may develop as a secondary reaction precipitated by or in association with a variety of factors or as a primary (idiopathic) disease process without apparent cause. The panniculitis may be focal or systemic, and the associated inflammatory cells include histiocytes and lymphocytes. Inflammation in the fat may induce a focal extracutaneous or a generalized systemic histiocytic response, and hemophagocytosis is a frequent characteristic of the histiocytic infiltrate. The major causes of death (sepsis, hepatic failure, hemorrhage, or thrombosis) are identical in the patients with and without generalized histiocytic proliferation. It appears that inflammation in the fat, of and by itself, may .be associated with significant morbidity and mortality, regardless of the specific histopathology or inciting factors. A better understanding of the relationship between panniculitis and histiocytosis (with and without erythrophagocytosis) is an essential prerequisite to the development of a successful therapeutic regimen. REFERENCES 1. Pfeifer V: Uber einen fall yon herdweiser atrophic des subcutanin fettgewebes. Deutsches Arch klin Med 50:438-449, 1892. 2. Gilchrist TC, Ketron LW: A unique case of atrophy of

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the fatty layer of the skin preceded by the ingestion of the fat by large phagoeytic cell macrophages. Bull Johns Hopkins Hosp 27:291-294, 1916. Weber FP: A case of relapsing nonsuppurative nodular panniculitis showing phagocytosis of subcutaneous fat cells by macrophages. Br J Dermatol Syphilol 37:301311, 1925. Christian HA: Relapsing febrile nodular nonsuppurative panniculitis. Arch Intern Med 42:338-351, 1928. Brill IC: Relapsing febrile nodular nonsuppurative panniculitis (Weber-Christian disease). (Medical Papers Dedicated to Henry Asbury Christian.) Baltimore, 1936, Waverly Press, pp. 694-704. Milner RDG, Mitchinson MJ: Systemic Weber-Christian disease. J Clin Pathol 18:150-156, 1965. Steinberg B: Systemic nodular pannieulitis. Am J Pathol 29:1059-1081, 1953. Beerman H: Weber-Christian syndrome. Am I Med Sci 225:446-462, 1953. March ER, Turk RE, Scott CW: Medical grand rounds. South Med J 63:517-525, 1970. MeDonald A, Feiwel M: A review of the concept of Weber-Christian pannieulitis with a report of live eases. Br J Dermatol 80:355-361, 1968. McDonald A: Inflammatory diseases of the subcutaneous fat. Geriatrics 25:156-173, 1970. Crotty CP, Winkelmann RK: Cytophagic histiocytie panniculitis with fever, eytopenia, liner failure, and terminal hemorrhagic diathesis. J AM ACAD DERMATOL 4:181-I94, 1981, Winkelmann RK, Bowie EJW; Hemorrhagic diathesis associated with benign histioeytic, cytophagic panniculitis and systemic histiocytosis. Arch Intern Med 140:1460-1463, 1980. Allen-Mersh TG: Weber-Christian panniculitis and auto-immune disease: A case report. J Clin Pathol 29:144-149, 1976. Anthony JE Jr, Davidson JK: Relapsing febrile nodular nonsuppurative pannieulitis (Weber-Christian disease): Report of a ease with autopsy findings. J Med Assoc Ga 42:138-141, 1953. Arnold HA, Bainborough AR: Weber-Christian disease with visceral involvement: Case report and review of the literature. Can Med Assoc J 89:1138-1142, 1963. Bailey RJ: Relapsing febrile nodular nonsuppurative panniculitis (Weber-Christian disease). JAMA 109: 1419-1423, 1937. Balk E, Bronsveld W, Vander Deyl/AM, et al: Alpha,antitrypsin deficiency with vascular leakage syndrome and panniculitis. Neth J Med 25:138-141, 1982. Bjorrtstad RT: A fatal case of Weber-Christian disease. Aeta Derm Venereol (Stockh) 31:313-320, 1951. Buck BE, Yang LC, Caleb MH, et al: Measles virus panniculitis subsequent to vaccine administration. J Pediatr 101:366-373, 1982. Ciclitira PJ, Wight DGD, Diek AP: Systemic WeberChristian disease: A case report with ]ipoprotein profile and immunological evaluation. Br J Dermato11103:685692, 1980. Doel G: Bone involvement in Weber-Christian disease. Br J Radiol 36:140-142, 1963. Dostrovsky A, Kopel D, Tas J: A case of Weber-Chris-

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43. Sacher RA, Jacobson RJ, Lenes BA, Rath CE: Malignant histiocytosis simulating granulomatous disease. Am J Clin Pathol 74:180-185, 1980. 44. Sanford HN, Eubank DF, Stenn F: Chronic panniculitis with leucopenia (Weber-Christian syndrome). Am J Dis Child 83:156-163, 1952. 45. Schoen I, Reingold IM, Meister L: Relapsing nodular nonsuppurative panniculitis with lung involvement: Clinical and autopsy findings, with notes on pathogenesis. Ann Intern Med 49:687-698, 1958. 46. Shuman CR: Relapsing panniculitis (Weber-Christian disease): Review of literature and report of a case ineluding treatment with cortisone. Arch Intern Meal 87:669-681, 1951. 47. Spain DM, Foley JM: Nonsuppurative nodular panniculitis. Am J Pathol 20:783-786, 1944. 48. Spivak JL, Lindo S, Coleman M: Weber-Christian disease complicated by consumption coagulopathy and microangiopathic hemolytic anemia. Johns Hopkins Med J 126:344-349, 1970. 49. Taylor DE, Monroe WM, Taliaferro WL: Weber-Christian disease: Case report with autopsy findings. South Med J 46:1163-1168, 1953. 50. Tilden IL, Gotshalk HC, Avakian EV: Relapsing febrile nonsuppurative panniculitis: Report of two cases. Arch Dermatol Syphilol 41:681-688, 1940. 51. Ungar H: Relapsing febrile nodular inflammation of adipose tissue (Weber-Christian syndrome): Report of case with autopsy. J Pathol Bacterio158:175-185, 1946. 52, Wilkinson PJ, Hannan RRM, Tribe CR: Systemic nodular panniculitis with cardiac involvement, J Clin Pathol 27:808-812, 1974. 53. Yaffe HS: Liquefying panniculitis associated with arthritis and localized vasculitis of the ileum: Report of fatal case. Int J Dermatol 10:237-241, 1971. 54. Robson JRK, Self KS, Wadland W, et al: Relationship between zinc deficiency and Weber-Christian disease. Am J Clin Nutr 33:2221-2222, 1980. 55. Serf DJ: Weber-Christian disease after weight loss. South Med J 69:499-501, 1976. 56. De Vivo DC: Reye syndrome: A metabolic response to an acute mitochondrial insult. Neurology 28:105-108, 1978. 57. Schiff GM: Reye's syndrome. Annu Rev Med 27:447452, 1976. 58. Bourgeois C, Olson L, Comer D, et al: Encephalopathy and fatty degeneration of the viscera~ A clinicopathologic analysis of 40 cases. Am J Clin Pathol 56:558571, 1971. 59. Brown RE, Madge GE, Schiller HM: Observation on the pathogenesis of Reye's syndrome. South Med J 64:942-946, 1974. 60. Brown RE, Madge GE, Trauner DA, David RB: Lipid and lipoprotein studies in Reye's syndrome. Va Med 99:622-626, 1972. 61. Zbinden G: Transient thrombopenia after intravenous injection of certain fatty acids. J Lipid Res 5:378-384, 1964. 62. Botti RE, Ratnoff OD: The dot-promoting effect of soaps of long-chain saturated fatty acids. J Clin Invest 10:1569-1577, 1963. 63. Connor WE, Poole JCF: The effect of fatty acids on the formation of thrombi. Q J Exp Physio146:1-7, 1961.

Journal of the American Academy of Dermatology

4. Connor WE, Honk JC, Warner ED: Massive thrombosis produced by fatty acid infusion. J Clin Invest 42:860866, 1963. 65. Frederiekson DS, Levy RI: Familial hyperlipoproteinemia, in Stanbury JB, Wyngaarder JB, Fredefickson DS, editors: The metabolic basis of inherited disease, ed. 4. New York, 1978, McGraw-Hill Book Co., p. 614. 66. Frayer WC, Wise RT, Tsaltas TT: Ocular and adnexal changes associated with relapsing febrile nonsupuratire panniculitis (Weber-Christian disease). Trans Am Ophthalmol Soc 66:233-242, 1968. 67. Wang-Iverson P, Ungar A, Bliumis J, et al: Human monocytes in culture synthesize and secrete lipopmtein lipase. Biochem Biophys Res Commun 104:923-928, 1982. 68. Glueck CJ, Kaplan AP, Levy RI, et al: A new mechanism of exogenous hyperglyceridemia. Ann Intern Med 71:1051-1062, 1969. 69. Stem MP, Kolterman OG, Fries JF, et al: Adrenocortical steroid treatment of rheumatic diseases; Effects on lipid metabolism. Arch Intern Med 132:97-101, 1973. 70. du Toit DF, Villet WT, Heydenrych J: Fat emulsion deposition in mononuclear phagocytic system. Lancet 2:898, 1978. 71. DiLuzio NR, Blickens DA: Influence of intravenously administered lipids on reticuloendothelial function, J Reticuloendothel Soc 3:250-257, 1966. 72. Bertoli A, Greco AV, Caputo S, et al: Visceral leishmaniasis presenting with hypertriglyceridemia. Lancet 2:504-505, 1982. 73. Spiegel RJ, Schaefer EJ, Magrath IT, Edwards BK: Plasma lipid alterations in leukemia and lymphoma. Am J Med 72:775-782, 1982. 74. Christianson HB, Fine RM: Vasculitis with or without panniculitis in leukemia, lymphoma and multiple myeloma. South Med J 60:567-572, 1967. 75. Jaffe ES, Costa J, Fauci AS, et al: Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis. Am J Meal 75:741-749, 1983. 76. Liebow AA, Carrington CRB, Friedman PJ: Lymphomatoid granulomatosis. Hum Pathol 3:457-558, 1972. 77. Blom JMH, Verburg OW: Lipogranulomatosis of the mesentery. Radiol Clin North Am 45:132-139, 1976. 78. Grossman LA, Kaplan HJ, Preuss HJ, Herrington JL Jr: Mesentefic panniculitis. JAMA 183:318-323, 1963. 79. Herrington JL Jr, Edwards WH, Grossman LA: Mesenteric manifestations of Weber-Christian disease. Ann Surg 154:949-955, 1961. 80. Ogden WW, Bradburn DM, Rives JD: Mesenteric panniculitis: Review of 27 cases. Ann Surg 161:864-874, 1965. 81. Ormiston MC, Thomson, 1: Mesenteric panniculitis. Postgrad Med J 56:67-68, 1980. 82. Andersen IA, Rasmussen NR, Pedersen JK: Mesenteric panniculitis: A fatal case. Am J Gastroenterol 77:523525, 1982. 83. Kipfer RE, Moertel CG, Dahlin DC: Mesenteric lipodystrophy. Ann Intern Med 80:582-588, 1974. 84. Durst AL, Freund H, Rosenmann E, Birnbaum D: Mesenteric panniculitis: Review of the literature and presentation of cases. Surgery 81:203-211, 1977.

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85. Ogden WW II, Bradburn DM, Rives JD: Pannic~alitis of the mesentery. Ann Surg 151:659-665, 1960. 86, Breit SN, Clark P, Robinson JP, et al: Familial occurrence of ~x~-antitrypsin deficiency and Weber-Christian disease. Arch Dermatol 119:198-203, 1983. 87. Pottage JC Jr, Trenholme GM, Aronson IK, Harris AA: Panniculitis associated with histoplasmosis and alpha1-antitrypsin deficiency. Am J Med 75:150-153, 1983, 88. Laurell C-B, Sveger T: Mass screening of newborn Swedish infants for arantitrypsin deficiency. Am J Hum Genet 27:213-217, 1975. 89. Larsson C: Natural history and life expectancy in severe alpha-l-antitrypsin deficiency, PiZ. Acta Med Stand 204:345-351, 1978. 90. Berg NO, Erieksson S: Liver disease in adults with alpha-l-antitrypsin deficiency. N Engl J Med 287:12641267, 1972. 91. Sharp HL, Bridges RA, Krivit W, Freier EF: Cirrhosis associated with alpha-l-antitrypsin deficiency: A previously unrecognized inherited disorder. J Lab Clin Meal 73:934-939, 1969, 92. Farquhar JR, Claireaux AE: Familial hemophagocytie reticulosis. Arch Dis Child 27:519-525, 1952. 93. Perry MC, Harrison EG Jr, Burgert 0 Jr, Gilchrist GS: Familial erythrophagocytic lymphohistiocytosis; Report of two eases and clinicopathologic review. Cancer 38:209-218, 1976. 94, Ambruso DR, Hays T, Zwartjes, WF: Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin. Cancer 45:2516-2520, 1980, 95. Landrieu P, Choulot JJ: Reticulose hemophagocytalre avec hypertriglyceridemie. Arch Fr Pediatr 33:497-503, 1976, 96, Berard CW, Cooper RA, Freirech EF, Rabson AS: Disseminated histiocytosis associated with atypical lymphoid cells (lymphohistiocytosis). Cancer 19:14291437, 1966. 97. Hagberg B, Hultquist G, Svennerholm L, Voss H: Malignant hyperlipemia in infancy. Am J Dis Child 107:267-276, 1964. 98. Mozziconacci P, Nezelof C, Attal C, et al: La lymphohistiocytose famlliale, Arch Fr Pediatr 22:385-401, 1965. 99. MacMahon HE, Bedizel M, Ellis CA: Familial erythrophagocytie lymphohistiocytosis. Pediatrics 32:868879, 1963. 100. Nelson P, Santamaria A, Olson RL, Nayak NC: Generalized lymphohistiocytic infiltration. Pediatrics 27: 931-950, 1961. 101, Price DL, Woolsey JE, Rosman WP, Richardson EP: Familial lymphohistiocytosis of the nervous system. Arch Neurol 24:270-283, 1971. 102. Martian VJ, Sanerkins WG: Familial histiocytic reticulosis (familial haemophagocytic retieuloses). J Clin Pathol 16:65-69, 1963. 103. Shapiro DN, Hutchinson RJ: Familial histiocytosis in offsprings of two pregnancies after artificial insemination. N Engl J Med 304:757-759, 1981. 104, Bell RJM, Brafield AJE, Barnes ND, France NE: Fa-

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