Cytophagic histiocytic panniculitis with fever, cytopenia, liver failure, and terminal hemorrhagic diathesis

Cytophagic histiocytic panniculitis with fever, cytopenia, liver failure, and terminal hemorrhagic diathesis Christopher P. Crotty, M.D., and R. K. Winkelmann, M.D., Ph.D. Rochester, MN We have seen five adult patients with a clinical picture of recurrent histiocytic, cytophagic panniculitis, cytopenia, abnormal liver function tests, and a terminal, febrile bleeding diathesis. Originally thought to have Weber-Christian disease, these patients, we believe, represent a unique syndrome: lobular, histiocytic, cytophagic panniculitis. Erythrophagocytosis and cytophagocytosis are readily observed, but the cells do not show malignant features. Histiocytosis can be found at times in the bone marrow, lymph nodes, liver, spleen, and serosal tissues, as well as in the skin and subcutaneous tissues. The terminal hemorrhage in these patients is characterized by features of pancytopenia, liver failure, and intravascular coagulation. This disease may be separated from malignant histiocytosis by the chronic course, the primary involvement of the adipose tissue, and the benign histiocytes in the infiltrate. It has some similarities to other regional histiocytoses such as sinus histiocytosis, intestinal histiocytosis, and splenic histiocytosis. (J AM ACAD DERMATOL 4: 181194, 1981.)

Panniculitis may be due to trauma or infectious, physical or chemical, immunologic, or cellular proliferative disease. Malignant cell proliferations that present as panniculitis are often lymphoid in nature, and the diagnosis may be made by assessing the bulk, depth, and cytologic malignancy of the lesion. Histiocytic diseases that involve adipose tissue include malignant histiocytosis (histiocytic medullary reticulosis), histiocytosis X, and a recently recognized inflammatory, histiocytic panniculitis caused by histiocytic infiltration of fat lobules and termed "cytophagic panniculitis. "1,2 The cells of cytophagic panniculitis are benign histiocytes, which replace fat tissue and From the Department of Dermatology, Mayo Clinic and Mayo Foundation. Reprint requests to: Dr. C. P. Crotty, clo Section of Publications, Mayo Clinic, Rochester, MN 55901.

0190-9622/81/020181+14$01.40/0 © 1981 Am Acad Dermatol

produce edematous, hemorrhagic masses with fat necrosis. The course may be chronic, and infiltration of the reticuloendothelial and hematopoietic systems may lead to a progressive course with serositis, liver dysfunction, jaundice, and terminal hemorrhage. Our review of five cases has convinced us that this type of cytophagic panniculitis is rarely recognized, but with adequate biopsy material and clinical review it can be identified, and it should be treated as a primary histiocytosis. CASE REPORTS

Case 1 A 27-year-old woman presented at the Mayo Clinic in December, 1977, with a history of recurrent panniculitis, fever, oral ulcerations, and neutropenia. She was well until 1973, apart from the removal of "lumps" in her skin in 1970 which were called

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lipomas . In August , 1973, after she had returned from 3 months in Guam , scattered erythematous , painful nodules developed on her buttocks and legs and were associated with malaise and fever. This episode was called "allergic angiitis," and it responded after 4 to 6 week s to therapy with systemic steroids. She was maintained on low-dose systemic stero ids for mild recurrences of similar skin lesions in 1974. In August, 1975, she experienced further malaise, fevers daily to 40° C, and recurrence of similar skin lesions on her arms, buttocks, and legs. She also had a vaginal discharge with dyspareunia and lower abdominal pain. Use of steroids was discontinued, and antibiotics were given for pelvic infl ammatory disease. At this time her white blood cell count was 3 ,200/mm 3 . Biopsy of a skin nodule was i nterpreted as WeberChr istian panniculitis . In 1976 she had a pregnancy and a full -term, normal delivery; there was total remission of the recurring problem at that time, but her menstrual periods were abnormal and erratic since then . In November, 1977, she had a recurrence of the erythematous nodular subcutaneous ski n lesions on the abdomen and legs and spiking fever to 40° C in the early evenings . With hospitalization , splenomegaly was noted for the first time . The white blood count was 2,OOO/mm3 with a normal differential. Bone marrow showed erythroid hyperplasia . Liver enzymes were elevated . Treatment consisted o f hydroxychloroquine sulfate (Plaquenil) and sal icylates, which resulted in slight symptomatic relief. Her admission physical examination of the skin revealed multiple subcutaneous nodules on the upper and lower extremities and the trunk which were slightly erythematous and tender. She had multiple aphthouslike lesions of the hard palate , tongue, and buccal mucosa . There was tachycardia with a rate of 130 per minute with regular rhythm, and she had a midsystolic ejection murmur. The liver was palpable 2 em below the right costal margin and had a smooth edge. The spleen was palpated 8 ern below the left costal margin and was markedly tender. Pelv ic examination was negative. Abnormal x-ray and laboratory studies included wh ite blood count 1,500/mm3 with about 60% neutrophils and 30% lymphocytes . The hemoglobin concen trat ion was 9.0 gm/dl with hypochromic red blood cells. The value for alkaline phosphatase was slightly elevated at 373 U/1. The serum glutamic oxaloacetic transaminase (SGOT) was 15 times normal. Serum protein electrophoresis showed increased /l2-globulin. Computed tomography scan of the abdomen revealed

Journal of the American Academy of Dermatology

hepatosplenomegaly . Pathologic study of the leg lesion from 1973 showed mild superficial dermal lymphocytic perivascular infiltrate . The buttock nodule from 1977 was described as severe lobular panniculitis with granulomatous features. The biops y specimen from the leg lesion revealed vasculitis with infarction and nonspecific panniculitis . A bone marrow aspirate showed a hyperplastic reaction of the marrow with marked histiocytic phagocytosis of the erythrocyte and myeloid series. Bone marrow biopsy showed no evidence of lymphoma. Epidermal fluorescent antibodies from the skin lesion of the thigh showed agranular basement membrane with C3, IgM, fibrin, and IgA in the blood vessels , both superficial and deep . Normal studies included blood culture for brucella, fung i, bacteria, and tubercle bacillus from all body fluids, urinalysis, chemistry studies, thyroxine and free thyroxine, heavy metal screen , antinuclear antibody , lupus erythematosus clot test, rheum atoid factor, and complement studies , purified protein derivative (PPD) skin test, chest roentgenogram , upper and lower gastrointestinal x-ray studies, and proctoscopic examination; cultures for bacteria, fungi, and tubercle bacillus from skin lesions; hepatitis B antigen ; virus culture from the mouth; gonococcus, T strain mycoplasma, and Chla mydia from the cervix and gonococcus from the mouth and rectum; malaria smear and fungal serologic studies; immune complex determination by Clq radioimmunoassay; stool for ova and parasites; leptospirosis, cytomegalovirus, and toxoplasmosis serologic studies; and viral serology. The patient underwent laparotomy' because of the question of a lymphoproliferative disorder and had splenectomy, liver biopsy, and lymph node biopsies. The liver showed intact arch itecture with very slight portal tract lymphoid infiltrate . The spleen showed hyperplasia and expansion of sinusoidal pulp . Lymph nodes showed moderate reactive hyperplasia . No evidence of neoplasia was seen . Review of this tissue demon strated histiocytic proliferation with erythrophagocytosis. She was dismissed in late January, 1978, at which time she felt much improved. She remained well until April , when the fevers and subcutaneous nodules of the buttock s and extremities recurred. The aphthous lesions recurred in her mouth and on her vaginal mucosa. She denied other health problems, includ ing weight loss, abnormal bowel habits, and urinary d isturbance. Abnormal physical findings on this admission included the extensive aphthae of her oral mucosa and vaginal mu cosa and the subcutaneous nodules of her lower ex-

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tremities and buttocks; the liver margin spanned 12 em, with slight tenderness and a soft edge. Values for alkaline phosphatase were slightly increased and those for SGOT were 30 times normal. The white blood count was 4,500/mm 3 with a normal differential. The picture at this time was believed to be most consistent with a variant of Behcet's syndrome. Because of increased lethargy and some mental confusion and the fear of central nervous system involvement with Behcet 's syndrome, treatment was instituted with chlorambucil (Leukeran), 8 mg daily, and prednisone, 50 mg every other day. A few days later it was noted that she was improving mentally, but she noted some blood oozing from the aphthous lesion of her mouth. It was noted that her hemoglobin level had dropped from 10.2 to 7.8 grn/dl over a l-week period. Two days later, she had massive gastrointestinal bleeding that necessitated surgical Raux-en- Y gastrojejunostomy. Pathologic study of the stomach revealed multiple superficial mucosal ulcerations of 1 mm, Her clinical status continued to deteriorate rapidly because of uncontrolled gastrointestinal bleeding and respiratory complications, and the patient died in August, 1978. Autops y was refused.

Case 2 A 23-year-old woman presented with a documented lO-year history of leukopenia and intermittent fever of unknown cause. Four months before examination she acquired facial and periorbital edema and had daily fever. An examination elsewhere revealed chronic sinusitis and mild chronic active liver disease with hepatosplenomegaly. Her T cells measured 43%. Additional history revealed tender superficial and deep oral and perianal aphthous-like ulcerations present for 3 months and tender subcutaneous swellings for 2 months. Her clinical presentation was as an ill, febrile young woman with basilar rales and infiltration of both lower lung fields on the chest roentgenogram. Temperature was 38.9° C and spiked daily. The pulse was 110 and regular. The liver was 8 em below the midcostal line, and the spleen was 6 ern below the costal margin. Her admission hemogram revealed a white blood cell count of 2,200/mm 3 , with a normal differential count, and a hemoglobin concentration of 11.8 gm/dl. The serum iron was 37 jlg/dl. The total iron-binding capacity was 214 jlg/dl and saturation was 17%. The platelet count was 97 ,OOO/mm 3 . The erythrocyte sedimentation rate was normal and remained normal throughout the illness. The SOOT was 89 U/I and the alkaline phosphatase, 1,549 Ull. Total proteins were

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normal; albumin was 2.68 gm/dl and gamma globulin, 2.04 gm/dl. IgO was 18.64 mg/ml and IgM, 2.88 mg/dl. The rheumatoid factor was 1: 1,280. Her antistreptolysin 0 titer was 340 Todd units. Urinalysis, cryoglobulins, VDRL, blood chemistries, complement CH so, C3, and C4, thyroxine, and spinal fluid studies were normal. X-ray studies of the sinuses revealed pansinusitis with air and fluid levels. Blood, cerebrospinal fluid, urine, bone marrow, and skin biopsy cultures were negative for virus, mycoplasma, bacteria, acid-fast organisms, and fungus. The fever increased and liver function studies progressively worsened. Liver alkaline phosphatase reached a peak of 4,048 U!I and SOOT, 399 V/I within 2 weeks. Jaundice developed as the bilirubin values, which had been normal on admission, increased to 9 rng/dl, indirect. Bilirubin appeared in the urine. Liver and spleen scan revealed irregular hepatic uptake with some ill-defined filling defects and splenomegaly. It was interpreted as consistent with parenchymal liver disease. Antimitochondrial and smooth muscle antibody and hepatitis B antigen tests were negative. Review of the liver biopsy done elsewhere showed nonspecific reactive periportal hepatitis with Kupffer cell hyperplasia and focal fatty change. The biopsy suggested a lymphoproliferative disorder rather than primary liver disease. During her short hospital stay she acquired two new erythematous, subcutaneous, inflammatory masses, one in the right pectoral region at the anterior axillary line and one in the left inner region of the thigh below the inguinal fold. Both biopsy specimens showed infiltration of the panniculus with eosinophilic histiocytic cells of indeterminate histiocytic nature. Biopsy of the oral and perianal lesions showed submucosal lymphocytic inflammation suggestive of lichen planus. The bone marrow examination showed a normocellular marrow with megaloblastoid erythropoiesis. Plasma cells were slightly increased, and occasional multinucleated cells were observed. There was an increase in large, pale histiocytes, some suggestive of atypical storage disorder. A specific diagnosis was not given. One week after admission the prothrombin time increased to 50 seconds and responded only partially to vitamin K. A hemostatic survey revealed platelets, 94,000/mm 3 , prothrombin time, 15 seconds (control, 10 to 12 seconds), partial thromboplastin time, 103 seconds (control, 45 to 60 seconds), thrombin time, 33 seconds (control, 21 seconds), and reptilase time, 18 seconds (control, 15 seconds). Fibrinogen concentra-

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184 Crotty and Winkelmann

tion was low at 40 mg/dl and factors VII, X, XI, and XII were low. Fibrin split products were 5 fLg/ml of serum. These data were interpreted as consistent with severe liver disease. Five days later, the platelet count was 83 ,000Itnm a, the prothrombin and partial thromboplastin times were almost normal (14 and 64 seconds, respectively), and factor X was normal. Fibrinogen continued low at 60 mg/dl, thrombin time was prolonged at 33 seconds (control, 22 seconds), and reptilase was long at 21 seconds (control, 15 seconds). The patient continued with fever. A small pleural effusion evolved which contained unidentified cells. Blood cultures were positive for Staphylococcus aureus, and therapy with intravenous cephalothin (Keflin) was begun. Because of the ear, nose, and throat lesions, pulmonary lesions, progressive multisystem disease, and the granulomatous large cell appearance of the adipose pathology, lymphomatoid granulomatosis was considered, and prednisone, 60 to 120 mg, was given. One injection of intravenous cyclophosphamide (Cytoxan) was given. She had 3 days of improvement and then dyspnea developed, together with pulmonary and gastrointestinal hemorrhage. She had bloody stools with clots, lapsed into respiratory failure, and died. On the day of her death, 3 weeks after admission, her white blood cell count was I,IOD/mm a, hemoglobin, 8.8 gm/dl , platelets, 23,900/mm:1, and fibrin split products, 10 to 40 fLg/ dl. Autopsy showed pericardial, pleural, and peritoneal yellow fluid. The liver was enlarged to 2,730 gm, and the spleen weighed 610 gm. In the abdominal cavity were multiple enlarged mesenteric nodes; the retroperitoneal space was clear. Multiple petechial hemorrhages of the stomach mucosa were found, and coffee-ground material was present in the distal ileum. Multiple, large, fluctuant periaortic, mesenteric, axillary, mediastinal, and hilar nodes with a red and gray mottled cut surface were found. The vertebral marrow was firm and red-brown in color. All other organs were normal. Throughout the reticuloendothelial system in liver, spleen, marrow, and nodes were focal collections of histiocytes with erythrocytosis and lyrnphophagocytosis. The lymph node architecture was effaced with secondary dilation of subcapsular and medullary sinuses containing typical and atypical histiocytes. Many histiocytes were stuffed with multiple cells, cell nuclei, red blood cells, and vacuoles and resembled a "bean bag." Such bean bag cells had only red blood cells, only lymphocytes, or both cells filling up and distorting their cytoplasm. The nuclei of the histiocytes varied in size and had a homogeneous chromatin pattern. Some hyperchromatic nuclei were observed. No

mitoses or nuclear pleomorphism was observed. Focal lymphohistiocytic inflammation could be found in the heart, gastrointestinal tract, and subcapsular area of the kidneys. The unique histiocytes were observed in pulmonary alveoli together with the terminal pneumonitis. The final autopsy diagnosis was generalized histiocytic disease.

Case 3 A 26-year-old white man, a school custodian, experienced fever and splenomegaly in the spring of 1973 with subcutaneous nodules of the forehead and left antecubital fossa. Biopsy was consistent with panniculitis. Lymphoma workup was negative. Tetracycline, 6 gm daily, controlled the fever and skin lesions. In April, 1974, he was examined at the Mayo Clinic because of fever and continued multiple subcutaneous nodules over the forehead, upper arms, and abdomen. On examination the spleen was easily palpated 4 ern below the left costal margin; the liver and lymph nodes were not palpable. Admission laboratory results included the following. The white blood cell count was 3 AOO/mm:l with 62% neutrophils and 32% lymphocytes. Bone marrow study revealed a cellular marrow with no lymphoma. Delayed hypersensitivity skin tests showed a positive response to streptokinase-streptodornase and Candida albicans . There was type IV hyperIipoproreinernia. Biopsy done elsewhere showed a panniculitis with a focal increase in lymphocytic cells and reactive histiocytes. Cultures of urine, sputum, blood, lymph node, cerebrospinal fluid, and marrow were negative. X-ray films of the abdomen and chest and an excretory urogram were normal. Fungal serologic studies and titers for brucella and toxoplasmosis were negative. Antinuclear antibody and lupus erythematosus (LE) clot tests were negative. Pancreatic function with cholecystokinin-pancreozymin was normal, and trypsin and lipase output and amylase values were normal. The lymph node biopsy specimen was interpreted as dermopathic inflammation. Laparotomy on April 17, 1974, was unrewarding. Focal plasma cell infiltration and occasional histiocytic granulomas were seen in the splenic tissue, but cultures for all organisms were negative. Wound dehiscence occurred postoperatively. In early June, while the patient was receiving tetracycline, salicylates, and indomethacin, he experienced liver dysfunction with elevated SOOT (175 U/1) and alkaline phosphatase (3,120 U/I) and hypoalbuminemia (I.52 gm/dl). Anasarca to the level of the nipples and bilateral pleural effusions developed. Hyperlipemia (449 U/l) and hyperamylasuria (l,009 U/hour) were

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present, but no hyperamylasemia was noted. The lipid status changed to a moderately severe type I with elevated triglycerides (l, 170 mg/dl). Confusion, lethargy, ataxia, and bilateral ankle clonus developed. A mild disseminated coagulopathy was noted, and extensive truncal ecchymoses were observed. Cerebrospinal fluid examination was unrewarding. All medications were discontinued. Salt-poor albumin controlled the anasarca. The clinical picture improved, but an elevated temperature to 38.9° C continued. Mild ankle clonus persisted. The patient was dismissed on a regimen of acetaminophen (Tylenol) in July, 1974, the skin lesions having healed. He was readmitted to his local hospital in Septembel', 1974, with fever and panniculitis. Chylous pleural effusion was noted, and linitis plastica deformity was observed on x-ray examination of the stomach. Nontender skin nodules were noted on the ankles and antecubital fossae. He was started on steroids and cyclophosphamide, although the lymphoma workup was negative. He experienced Pseudomonas septicemia and died postoperati vely with a bleeding diathesis after parietal pleural stripping and decortication. The amylase and lipase values were normal. Autopsy revealed panniculitis with an atypical histiocytic component of the abdominal wall. Biopsies from the gastrointestinal tract, marrow, lung, and lymph node showed no malignancy, but benign cytophagic histiocytosis was observed in all tissues.

Case 4 An 81-year-old white woman was seen at the Mayo Clinic in February, 1979. She had been a healthy, active person until October, 1978, when a violaceous tender nodule developed over the left thigh and gradually enlarged. Other subcutaneous areas of the body became involved, including the breast, neck, and shoulder. In December, 1978, a biopsy elsewhere was interpreted as Weber-Christian disease. In January, 1979, she was hospitalized and found to have melena, a hemoglobin concentration of 10.7 grn/dl, white blood cell count of 3 ,OOO/mm:1, normal amylase, and platelet count of 114,OOO/mm 3 • No treatment was given. Subsequently she became febrile, confused, and bedridden. On physical examination, the patient was very confused and was oriented only to person. There were several large, flat, indurated, violaceous purpuric areas on the left anterior region of the thigh involving most of the thigh (Fig. 1), the right breast, and the left side of the neck. The biopsy site on the left side of the neck had not healed. Liver and spleen were not enlarged. There was no palpable lymphadenopathy. A hard, non-

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Fig. 1. Case 4. Inflammatory subcutaneous plaques of cytophagic panniculitis involving left thigh with secondaryecchymosis. pulsatile, nonmovable mass was palpated at the epigastrium by several examiners. Results of laboratory and x-ray studies were as follows: white blood cell count, 2,SOO/mm:1 with 74% neutrophils, 7% lymphocytes, and 1 % eosinophils, hemoglobin, 9.7 gm/dl, platelets, 84,OOO/mm3 , and erythrocyte sedimentation rate, 10 mm in 1 hour (Westergren). The alkaline phosphatase was 637 UII and SOOT,46 U/I. Lipase, amylase, and aI-trypsin inhibitor were normal. Bone marrow biopsy was read as slightly hyperceIIular with a focal small granulomatous lesion, and atypical amorphous perivascular deposits were seen. Amyloid stains were negative. Biopsy slides prepared elsewhere were interpreted as acute and chronic panniculitis consistent with erythema nodosum. Our biopsy from the left thigh was read as acute fat necrosis, consistent with enzyme panniculitis. The stool guaiac test was positive. Direct immunofluorescence of the skin biopsy was negative. Viral, bacterial, fungal, and acid-fast cultures of blood, gastric washings, urine, and thigh lesions were all negative. The chest roentgenogram was normal. An abdominal echocardiographic scan showed a normal pancreas, and no mass was seen in the epigastrium. A computed tomography body scan was normal. A negative purified protein derivative (PPD) test at intermediate and secondary strength was found. The liver and spleen scan was normal. Abnormal laboratory results included the following: activated partial thromboplastin time, 44.1 seconds, prothrombin time, 13.6 and 12.9 seconds, and decreased total protein in association with a slightly increased gamma globulin level of 1 .82 gm/dl. Tests for hemostasis showed low fibrinogen but no other evidence of intravascular coagulation and fibrinolysis.

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Chart I. Pathologic features in patients with cytophagic panniculitis Benign histiocytosis Lobular panniculitis Erythrophagocytosis and leukophagocytosis Necrosis of fat with edema and hemorrhage Occasional plasma cells, lymphocytes, and polymorphonuclear leukocytes Cytophagic histiocytes in liver, spleen, lymph node, bone marrow, myocardium, and lung Findings were considered consistent with a circulating inhibitor or acquired dysfibrinogenemia. The patient continued to have ecchymosis, and fever persisted. Focal seizure activity developed. She had a progressively downhill course. Increasing confusion resulted in a comatose state, and there was persistent fever until she died. Autopsy revealed a necrotizing panniculitis with subcutaneous and visceral histiocytosis involving lymph nodes and visceral fat. The pancreas was normal. There were focal hemorrhages and edema in both lungs.

Case 5 A 58-year-old white woman acquired cellulitis of the left lower leg in the fall of 1974. There was no resolution with antibiotics and bed rest. In January, 1975, swelling of the left inguinal lymph nodes with tender edematous erythematous plaques of the left leg developed. A 20-lb (9-kg) weight loss and fever ensued. A biopsy of the skin and subcutaneous tissue was consistent with Weber-Christian disease, and lymph node biopsy showed diffuse inflammatory hyperplasia. Cultures of the skin and lymph nodes were negative. She was started on therapy with prednisone, 20 mg three times a day, and there was some improvement, but the leg edema and inguinal adenopathy persisted. In February, 1975, the left inguinal biopsy site became infected and Streptococcus and Proteus organisms were cultured from the wound. At this time the albumin concentration was 1.6 gm/dl , and the liver function tests were grossly abnormal. Liver scan at the patient's local hospital was consistent with hepatocellular disease. The chest roentgenogram showed bilateral pleural effusions. Amylase concentration was 195 U/l. Her condition worsened, with fever, anorexia, peripheral edema, persistent infected and draining left inguinal lymph nodes, and reddened areas on the back and shoulders. At the Mayo Clinic in March, 1975, she was febrile, obese, and orthopneic. She had edema extending from

Journal of the American Academy of Dermatology

the lower limbs to the groin and had marked abdominal distention from ascites. There was an open, odoriferous, undermined left groin wound. A firm, indurated plaque, 2.5 em, was present in the upper, outer quadrant of the right breast, and a similar lesion was present in the inner quadrant of the left breast and was mildly tender. There was a 3-cm erythematous plaque on the posterior region of the right shoulder. There were also indurated erythematous plaques on the lower legs. Laboratory findings included hemoglobin, 11.1 gm/dl , white blood cell count, 6,900/mm:J with 90% neutrophils, creatinine, 3.95 mg/dl, platelets, 30,000/ mm", SOOT, 231 U/I, amylase, 453 U/1, and alkaline phosphatase, 627 U/1. Over the next 2 days, the white blood cell count decreased to 2,300/mm:J and hemoglobin to 10 gm/dl. Two days after admission, the patient became comatose. Her hemostatic survey showed a prothrombin time of 23 seconds with a control of 17 seconds, activated partial thromboplastin time, 66 seconds, fibrinogen, 70 mg/dl, negative protamine gel test, and fibrinolytic split products, 48 ~g/ml. Factor XIll was deficient. She underwent dialysis on March 6, 1975. New ecchymotic skin lesions of breast and hips continued to develop. She continued to have an elevated temperature, and coffee-ground aspirate was obtained from the nasogastric tube. Repeat biopsy of skin lesions showed fat necrosis. All blood and skin cultures were negative. Negative serologic tests for fungus and negative virus, fungus, and mycobacteria cultures were obtained. Agglutination titers for cytomegalovirus, toxoplasmosis, and brucella were negative. The patient remained comatose and died 4 days after admission. Autopsy revealed a histiocytic, cytophagic, subcutaneous, cutaneous, and visceral panniculitis. There were multiple mucosal hemorrhages. Pronounced ascites and bilateral pleural effusions were present. There was marked fatty liver infiltration with acute passive congestion and centrilobular necrosis. The pancreas showed fatty replacement. Histiocytosis with erythrophagocytosis was identified in skin, adipose tissue, spleen, and lymph nodes. There were also multiple peripheral pulmonary emboli and pale, swollen kidneys. Aggregates of benign histiocytes involved the pleura of the lung and obscured the lobules, and there was similar occupation of the subcapsular area of the kidney. PATHOLOGIC FEATURES (CHART I)

The panniculitis is primarily lobular (Fig. 2) in nature, involves contiguous fat lobules, and can

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Fig. 2. Case 5. Lobular panniculitis with nonspecific inflammation, fat necrosis, and hemorrhage. (Hematoxylin-eosin stain; original magnification, x 16.) Inset, Case 3. Cytophagic histiocyte in subcutaneous fat with erythrophagocytosis and lyrnphophagocytosis. (Hematoxylin-eosin stain; original magnification, x640.)

extend into the lower dermis as well. The histiocyte is the key feature in cytophagic panniculitis. Noncoherent histiocytes may be seen infiltrating subcutaneous and visceral fat, ringing fat cells, and engulfing red blood cells, platelets, nuclear debris, and inflammatory cells. Erythrophagocytosis may be present, but lymphophagocytosis seems to predominate in many cells. Some histiocytes are so stuffed with cells and cell particles that they are well called "bean bag" cells (Fig. 2, inset). The oval or reniform nuclei of the histiocytes vary in size and have homogeneous chromatin. Occasionally, a prominent nucleolus is observed. The cytoplasm of these cells, which is generous, is amphophilic or acidophilic and occasionally granular or vacuolated. The histiocytes are benign-appearing and have normal nuclei without heterochromatin and normal nuclear-tocytoplasmic ratios. Occasional hyperchromatic cells and normal mitoses are found. Langerhans' granules were not identified in the cell cytoplasm on electron microscopic examination of tissue from Patient 5. The histiocytes may be seen congregating around blood vessels in some biopsy specimens (Fig. 3), including those from ex-

tracutaneous sites. Foci of plasma cells may be prominent, and occasionally lymphocytes and neutrophils may be seen. Large areas of fat necrosis with edema and hemorrhage may be present and can obscure the diagnosis. Increased numbers of polymorphonuclear leukocytes are found in such areas. In one case, the histiocytes were present in a hyaline, granular syncytium with prominent erythrophagocytosis. Benign cytophagic histiocytes may also be found in liver, spleen, lymph node and marrow, myocardium, lung, mammary tissue, mesentery, and gastrointestinal tract. Throughout the reticuloendothelial system, focal collections of histiocytes with erythrophagocytosis and lymphophagocytosis may be seen. In the liver, fatty degeneration and hepatocellular necrosis with perivascular mononuclear infiltration of the portal triad and sinusoids can be seen. A hemorrhagic red pulp of the spleen with many large, pale histiocytes may be seen along with a focal plasma cell infiltration and occasional giant cell formation. Cytophagocytosis is observed as in other tissues. Erythrophagocytic histiocytes may involve the area of the malpighian corpuscles and

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Fig. 3. Case 1. Histiocytes with ample cytoplasm surrounding adventitia of blood vessel of fat. (Hematoxylin-eosin stain; original magnification, x640.)

Fig. 4. Case 5. Lymph node with effacement of normal architecture and widening of medullary sinus. Hyperchromatic cells are cytophagic histiocytes. (Hematoxylin-eosin stain; original magnification, x 64.)

essentially replace this normal structure of the spleen. The lymph node architecture may be effaced in the presence of secondary dilatation of subcapsular and medullary sinuses and typical cytophagic and hyaline histiocytes (Figs. 4 and 5). Cytophagocytosis may be prominent. Mesenteric, hilar,

carinal, axillary, pancreatic, and periaortic lymph nodes in our patients showed replacement of some or all structures by masses of histiocytes and cytophagic cells. Increased numbers of plasma cells and vascular proliferation may be prominent features also. The bone marrow may show only erythroid hy-

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Fig. 5. Case 2 . Erythrocytophagic hyalin ized histiocytes filling lymph node. (Hematoxylin-eosin stai n; ori ginal magn ification, x 250.)

Table I. Cli nical features in patients with cytophagic pannicu litis Age at onset (yr)

Sex

27

F

2

23

3

Patient No.

Enlargem ent Locatio n of skin lesions

Mucosal lesions

Ecchy. moses

Liver

5 yr

Arms, legs , buttocks

Oral, vaginal

+

F

10 yr

Thigh , chest, face

Oral, perianal

+

26

M

2 yr

Forehead, abo domen , arms , ankles

None

+

4

80

F

6 rna

Thigh , neck, shoulder, breast

None

+

+

5

56

F

6 rno

Breast, left hip , shoulder

None

+

+

Dura tion

perplasia , but there may be an increase in large , pale his tiocytes and giant cells with cytophagocytosis . In all instances, cul tures for virus , fungus, and mycobacteria and also amy loid stains have bee n negative. T here may be histiocytocellular infiltration of the interfascicular fibers of the myocardium (Fig. 6). Focal epicardial and subepicardial lymphocytes and atypic al histiocytic infiltra tes are also

I

Pleural effusio ns

Spleen

Fever

+

+

+

+

+

+

+

Death from h emorrhage

+

+

+

Death from h emorrhage, pu lmonary embolism

Course

D eath from hemorrhage

De ath from he morrhage, coma, sei zures

+

Death from hemorrhage , re nal failure

seen . His tiocy tic infiltration can be seen involving the adven titia of medium-sized bloo d vessels in the viscera or in subc utaneous tissue, as in Fig . 3 . The pericardial fat may contai n abnormal numbers of h istiocytes , lymp hocytes, an d occasional polymorphonuclear leukocytes, with focal fat necrosis and some areas of co mplete destructio n of fat cells . Intra-alveolar hem orrhage and focal intra-al veo-

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Dermatology

sinus infiltration with histiocytes, as noted in other regional and visceral lymph nodes. CLINICAL FEATURES (TABLE I)

Fig. 6. Case 5. Histiocytic infiltration of cardiac muscle and perivascular and interstitial tissue . (Hematoxylineosin stain ; original magnification , X400.)

lar atypical histiocytic infiltration are features of lung involvement. ln addition, hyaline membrane formation and pulmonary edema are seen, often with focal pleural thickening and hemorrhage. Entire lobules may be infiltrated by cytophagic cells. The pancreas of each of our patients was normal. Areas of fatty degeneration were found , but evidence of pancreatic malignancy or pancreatitis was not seen. Mammary tissue may show focal periductular infiltrates of lymphocytes and some benign histiocytes. The alimentary tract, including the jejunum , ileum , and appendix, can be congested with mucosal infiltrates of lymphocytes and benign histiocytes. This lymphohistiocytic infiltrate of the fat of the bowel is prominent, often with focal fibrous tissue replacement of the fat. Involved lymph nodes were identified in two patients in the biopsy specimen subcutaneous tissue (Fig . 7). There was subcapsular and medullary

In all five patients, the panniculitis was the presenting or major clinical feature. In Patient 2, however , recurrent fever and leukopenia had existed for 10 years before the development of panniculitis, and this probably represents a prodromal syndrome. The skin lesions were distributed in many areas of the body, including the lower legs, thighs, buttocks, arms, breast, and neck area. They were flesh-colored to red and 2 to 20 cm in size . The skin lesions were tender but not warm . Biopsy sites often drained for 3 to 6 weeks. Ecchymoses occurred late in the course of the disease in association with coagulation defects in areas of panniculitis or pressure surfaces. Mucous membrane ulcerations with a necrotic base occurred in oral, perianal, and vaginal sites in two patients. These ranged up to 3 em in size and healed slowly . No primary vesicle or pustule developed before the mucous membrane lesion appeared. A febrile course occurred, mediated by histiocytic pyrogens and pancytopenia, possibly a result of histiocytic phagocytosis. a Hepatomegaly and splenomegaly were present in the two chronic cases, and splenomegaly was found in Patient 3. There was no palpable lymphadenopathy. In all patients, progressive liver dysfunction developed in their last hospital stay, and two became jaundiced. Anasarca was present in two patients and pleural effusion in three patients . Renal failure developed in Patient 5. Hemorrhage from the gastrointestinal, urinary, and respiratory tracts and into the skin was part of the final episodes of life in all of the cases. Death occurred postoperatively with hemorrhage in Patients I and 3 . Death occurred with pneumonia in Patient 2, renal failure in Patient 5, and coma and seizure s with pneumoni a in Patient 4 . LABORATORY FINDINGS (TABLE II)

Leukopenia occurred in all patients; counts were not less than 1,500 cells/rum". Lymphopenia was observed. Anemia with hemoglobin values in

Volu me 4 Number 2 Feb ruar y. 1981

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191

Fig. 7. Case S. Subcutaneous lymph node involved with cytophagic histiocytes. (Hemat oxylin-eosin stain; original magnification , x 16.)

the range of 9 to 10 gmtdl was found in all patients at some time. Low level s of serum albumin and total protein were present in all patients. All patients had low levels of calc ium , but ionizable calcium was normal when determined . Gamm a globulin was elevated a t 2 .04 gm /dl in Patient 2, with an IgG value of 18 .6 mg /ml. The rheumatoid factor in this patient was 1: 1,280. All other tests for antibody or complement variation gave normal or negative results. Tests for cryoglobulin and circulating immune complexes with Clq-binding radioimmunoassays were negative in two patients. The erythrocyte sedi me ntation rate was normal in the four patients in which it was measured and ranged from 1 to 23 mm in 1 hour (Westergren), even during periods of fever. All five patients showed a progres sive increase in serum hepatic enzym es-glutamic oxaloaceti c acid transaminase and gamma glutamyl transferase-and in alkaline phosphatase. In the last 2 weeks of life, the values were 15 to 30 times normal in all these patients. The jaundiced patient s had increasing values for indirect bilirubin, which reach ed 12.3 mg/dl in Patient 2 . Hepatitis B antigen studies were negative. The last amylas e determination in Patient 1 was four times normal during the hemorrhagic terminal event. The lipase level was elevated only during the period of

anasarc a in Patient 3. In two patients , serum lipemia developed and was noted as cloudy serum , but it was not further characterized because of the termin al st atus of the se patients. Three of the five patients had thrombocytopenia, and in one there was thrombocytosis. In four of the patients , the level of fibrinogen was decreased. Fibrin-fibrinogen split products were increased in all patients. The protamine gel test was negative in four of the five patients. This lack of circulating fibrin monomer complexes was considered not compatible with intravascular coag ulation. Reduced levels of factors VII , X , XI, and XII were found in Patient 2 . Skin and blood cultures were negati ve in all patien ts for bacteri a , fung us , and typical and atypical acid-fast organisms , although Patient 2 hadS. aureus bacteremia in the last week of life . In addition , negative virus cultures , negative fun gal serologic studies, and neg ative or normal agglutination titers for brucella , cytomegalovirus, and toxoplasmosis were found . DISCUSSION

The clinical picture of cytophagic panniculitis is at the same time dramatic and confusing to the clinician. Other cases resembl ing ours have appeared in the literature w ith different nornencla-

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Crotty and Winkelmall1l

Table II. Laboratory findings in patients with cytophagic panniculitis Patient No. Test

Leukocytes, cells/ mm" Hemoglobin, gm/dl Platelets, cells/

I

Normal range

I

4 , 100-10,990 12-15 130-370 X 103

1,500

2

3

4

5

2,200/1 , 100

3,400/2, 100

2,500

2,300

9.7

11.1/10.0 30 X 103

11.8/8 .3 9/7.8 34/60 X 103 970/23 X 103

14.6/9.6 217/577 X 103

84

X

103

mm" Sedimentation rate, mm in I hr SGOT , U/l Bilirubin, total,

F (0-29) M (0-22) 8-20

3

23

<1.1

306 -630 3.6

89-399 0.9/12.3

44-175 1.2

Normal

76-196

373/4/0

1,549/4,048

48/3,120

394/637

627

138-404 32-80 17-19

1,260/2,410 20

26

248/356 1121449 26

245 69 20

195 97/14 23

25-36 <3 195-365

78 20/40 348/232

89 5/5 40/60

105 6/24 58/26

49 5 106

66 48 70

Neg

Neg

Pas

Neg

Neg

10 46-65

23 1

mg/dl

Alkaline phosphatase, U/l Amylase, U/I Lipase, U/I Prothrombin time, s

(Control 17) APTI, 's Fibrin spliI products Fibrinogen, mg/dl Protamine gel

APTT : activ ated parti al thrombop lastin time. SOOT: serum glutamic oxaloacetic transamin ase.

ture . We believe the cases of Miyasaki et al ," Henriksson et al," and Torres et al" represent this syndrome of cytoph agic panniculitis, and we find on rev iew of the tissue in the case of Henriksson et al confirmation of this concept. Friedman 's case" of "fatal panniculitis " had evidence of benign erythrophagocytic histiocytes involving the panniculus and evidence of multisystem involvement. The relatively long duration of disease (5 years ) , normal erythrocyte sedimentation rate , pancytopenia, reticuloendotheliomegaly, and febrile course were similar to the picture in our cases . The case of Koto et al, 8 described as congenital hemophagocytic reticulosis, had a similar clinical and pathologic picture with ultimate terminal pulmonary hemorrhage and pancytopenia. The str iking abnormality in this case was the benign histiocytic phagocytosis and diffuse organ involvement without destruction of organ parenchyma . The histiocytes showed no cytologic evidence of malignancy and no tendency to invade tissue or form nodules . Similarly , familia l hemophagocytic ret icul osis has been described . 9

Histiocytic medullary reticulosis or malignant histiocytosis may also present with subcutaneous invol vement and cytophagic cells. The course of histiocytic medullary reticulosis is usually rapid, and the histiocytes are recognizably malignant and atypical. Two of the cases described by Ho and Todd LO affected subcutaneous fat and, ultimately, involved multiple systems . Although malignant cells were not manifested in the panniculus , obvious histiocytic neopl asia was discovered in lymph nodes, in contrast to our patients. The skin lesions in these cases followed the onset of the systemic signs and symptoms . Clinically, the fever of cytophagic panniculitis may suggest an infectious cause, which must be ruled out with extensive bacteriologic studies. An erythrophagocytic histiocytic pic ture with pancytopenia has been described in acute brucellosis! ' and also in infectious mononucleosis and other viral diseases . Recently, a virus-associated hemophagocytic syndrome was described . t 2 Blood and skin viral, bacterial, and fungal cultures were negative in our cases, as were funga l serologic studies and agglutination titers.

Volume 4 Number 2 February. 1981

Hepatomegaly and splenomegaly with pan~ cytopenia are features of cytophagic panniculitis which may suggest lymphoma clinically . Malignant cells are not found in staging studies or in organ and marrow biopsies. Adult histiocytosis X J;; can also be confusing clinically when jaundice, cytopenia , and hemorrhage are features . Granulomatous inflammatory lesions with eosinophilia or xanthomatous changes, bone lesions, superficial skin lesions, and Langerhans' granules typify this disease . Adult Letterer-Siwe disease, reported by Chevrant-Breton , 1~ is characterized by a papular, confluent, and crusted skin eruption, with purpura as a late feature. Erythrophagocytosis may be observed in sev eral different disease states (Chart II). The observation by Warnke et al " that the malignant cells were phagocytic in only six of twenty-nine cases of malignant histiocytosis is important. This contrasts with the general belief that histiocytic medullary reticulosis is a malignant, phagocytic histioproliferative disease as defined by Rappaport. t(i Possibly benign, mature populations of histiocytes are more usually phagocytic. Regional histiocytosis is a developing concept implying that long-term localized proliferative infiltration of organs or regions may occur. 13 Cytophagic panniculitis has some similarities to other regional histiocytoses as found in the lymph node, intestine, or spleen (Chart III). Sinus histiocytosis with massive lymphadenopathy has been described by Rosai and Dorfman 17 and others . 18. 19 The sinu ses of the involved lymph nodes contain benign cytophagic histiocytes . Lymphocytophagocytosis is prominent in lymph node and skin lesions . After a protracted clinical course, recovery is complete, with resolution of the lymphadenopathy. The intestinal histiocytosis of Isaacson and Wright 20 is a regional histiocytosis that produces localized symptoms of malabsorption, obstruction, and perforation. A variable degree of cytologic malignancy may be observed. Vardiman et aFl described a chronic form of atypical histiocytosis involving the spleen only. Four patients had an erythrophagocytic histiocytic infiltrate of the spleen, one of whom was asymptomatic 15 months after splenectomy. We have

Cytophagic histiocytic panniculitis

193

Chart II. Erythrophagocytosis in histiocytosis Malignant histiocytosis (histiocytic medullary reticulosis) Familial lymphohistiocytic reticulosis Virus-associated histiocytosis Regional histiocytosis Cytophagic panniculitis Histiocytosis X (rare) Acute brucellosis

Chart III. Regional histiocytosis Lymph node!" Intestine'" Spleen" Panniculus1.2.22

Chart IV. Clinical course of cytophagic panniculitis Fever Recurrent panniculitis Mucous membrane ulcerations Reticuloendotheliomegaly Cytopenia Serous effusion Terminal hemorrhagic diathesis

observed benign splenic histiocytosis with dermatomyositis. Regional histiocytosis may represent benign or malignant disease. Although a transition from a benign to a malignant state was not observed in our cases, Ho and Todd 10 reported cases in which skin lesions were benign but visceral lesions were malignant. We expect this relationship but have not observed it in our material to date . Our cases show that over a period of time, regional histiocytosis of the panniculus can also diffusely involve other organ systems and produce a characteristic pancytopenic, hemorrhagic terminal episode. 22 SUMMARY (CHART IV)

Cytophagic panniculitis is characterized by a benign histiocytosis of adipose tissue producing large areas of fat necrosis , with edema and hemorrhage . The "bean bag " cell is the result of cytophagocytosis of red blood cells, leukocytes, platelets, and nuclear debris. The histiocytes appear in greater number but lack features of malignancy.

194

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Erythematous, deep, tender nodules and plaques are the initial clinical features of this fat involvement, which can be differentiated from WeberChristian and other panniculitis by adequate biopsy. Ultimately, space-occupying histiocytes may adversely affect liver' function. Release of proteolytic enzymes may result in cutaneous and visceral hemorrhage. A febrile course occurs, mediated by histiocytic pyrogens and pancytopenia, a result of histiocytic phagocytosis, along with mucosal ulcerations, serosal effusions, and reticuloendotheliomegaly over a long course. The duration of the disease can be as much as several years. The patients die a hemorrhagic death, with liver or renal failure (or both). At autopsy, multicentric foci of histiocytes and cytophagic cells are observed in bone marrow, liver, spleen, lymph nodes, and serosal surfaces. Malignant cells have not been observed. Cytophagic panniculitis and other regional histiocytosis may represent a portion of a spectrum of histiocytic disease that includes malignant histiocytosis, adult histiocytosis X, familial hemophagocytic reticulosis, and viral-associated hemophagocytic syndrome. REFERENCES I. Winkelmann RK: Cytophagic panniculitis: A unique form of histiocytic panniculitis with fever, cytopenia, serous effusion, and terminal hemorrhagic diathesis. Hautarzt. (In press.) 2. Winkelmann RK: Cytophagic panniculitis. G Ital Dermatol Venereol 115:175-177, 1980. 3. Chandra P, Chaudhery SA, Rosner F, et al: Transienl histiocytosis with striking phagocytosis of platelets, leukocytes, and erythrocytes. Arch Intern Med 135:989991, 1975. 4. Miyasaki K, Ooiso Y, Nakamura I, et al: An unusual case wh ich began with subcutaneous panniculitis followed by fever, severe hepatic involvement and hyperlipidemia. Acta Pathol Jpn 27:213-224, 1977. 5. Henriksson P, Hedner U, Nilsson 1M, et al: Generalized proteolysis in a young woman with Weber-Christian disease (nodular nonsuppurative panniculitis). Scand J Haematol 14:355-360, 1975.

Journal of the American Academy of Dermatology

6. Torres A, Pachon J, Martinez F, et al: Reaccion leucoeritroblastica, trombopenia y celulas gigantes multinucleadas en rnedula osea en un caso de paniculitis recidivante de Weber-Christian. Rev Clin Esp 148:615617,1978. 7. Friedman NB: Fatal panniculitis. Arch Pathol 39:42-46, 1945. 8. Koto A, Morecki R, Santorineou M: Congenital hemophagocytic reticulosis. Am J Clin Pathol 65:495-503, 1976. 9. Bell RJM, Brafield AJE, Barnes NO, et al: Familial haernophagocytic reticulosis. Arch Dis Child 43:601606, 1968. 10. Ho FCS, Todd D: Malignant histiocytosis: Report of five Chinese patients. Cancer 42:2450-2460, 1978. II. Zuazu J, Duran JW, Julia AF: Hemophagocytosis in acute brucellosis. N Engl J Med 301:1185-1186, 1979. (Letter to the editor.) 12. Risdall RJ, McKenna RW, Nesbit ME, et al: Virusassociated hemophagocytic syndrome: A benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 44: 993-1 002, 1979. 13. Winkelmann RK:· Adult histiocytic skin disease. G Ital Dermatol Venereol115:67-76, 1980. 14. Chevrant-Breton J: La maladie de Letterer-Siwe de I'adulte: Revue de la litterature. Ann Oermatol Venereol 105:301-305, 1978. IS. Warnke RA, Kim H, Dotfman RF; Malignant histiocytosis (histiocytic medullary reticulosis). I. Clinicopathologic study of 29 cases. Cancer 35:215-230, 1975. 16. Rappaport H: Tumors of the hematopoietic system, in Atlas of tumor pathology, Fascicle 8. Washington, DC, 1966, Armed Forces Institute of Pathology. 17. Rosai J, Dotfman RF: Sinus histiocytosis with massive lymphadenopathy: A pseudolymphomatous benign disorder; analysis of 34 cases. Cancer 30: I 174-1188, 1972. 18. Lampert F, Lennert K: Sinus histiocytosis with massive lymphadenopathy: Fifteen new cases. Cancer 37:783789,1976. 19. Thawerani H, Sanchez RL, Rosai J, et al: The cutaneous manifestations of sinus histiocytosis with massive lymphadenopathy. Arch Dermatol 114:191-197, 1978. 20. Isaacson P, Wright DH: Malignant histiocytosis of the intestine: Its relationship to malabsorption and ulcerative jejunitis. Hum PathoI9:661-677, 1978. 2 I. Vardiman JW, Byrne GE Jr, Rappaport H: Malignant histiocytosis with massive splenomegaly in asymptomatic patients: A possible chronic form of the disease. Cancer 36:419-427, 1975. 22. Winkelmann RK, Bowie EJW: Hemorrhagic diathesis associated with benign histiocytic, cytophagic panniculitis and systemic histiocytosis. Arch Intern Med. (In press.)