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Fatal systemic cytophagic histiocytic panniculitis: A histopathologic and immunohistochemical study of multiple organ sites
Fatal systemic cytophagic histiocytic panniculitis: A histopathologic and immunohistochemical study of multiple organ sites Charles Perniciaro, MD,a R. K. Winkelmann, MD, PhD,b and Dennis R. Ehrhardt, MDc Jacksonville, Florida, Scottsdale, Arizona, and Hila, Hawaii The presence of hemocytophagic histiocytosis within subcutaneous tissue has been termed "cytophagic histiocytic panniculitis" (CHP). CHP may occur as a feature of hematopoietic malignancies or infections, particularly viral. In some patients with CHP, an underlying illness cannot be identified. We describe a young man with a rapidly fatal systemic illness characterized by CHP. Lymphoma was not present, and an infectious agent could not be identified. Immunohistochemical stains of tissue obtained at autopsy from multiple organ sites confirmed the presence of histiocytes and T lymphocytes within adipose tissue. (J AM ACAD DERMATOL 1994;31:901-5.) Cytophagic histiocytic panniculitis (CHP) is the nomenclature coined to describe histologic phagocytosis of cytologically benign lymphocytes and other cellular blood elements by histiocytes within adipose tissue. 1 The disease was initially presumed to be fatal,because all five of the original patients described by Crotty and Winkelmann2 died as a result of hemorrhagic complications. Recently pri~ mary T-cell lymphoma has been identified in some patients with the CHP phenomenon. 3, 4 Other patients with CHP have viral infections, most notably with Epstein-Barr virus. 5 In rare cases, patients with CHP have only cutaneous lesions and a benign clinical course without systemic illness. 6 One patient with CHP and a B-ceillymphoma has also been described. 7 We describe a rapidly fatal case of systemic CHP involving multiple organs in a 20-year-old man who had no known viral infections. Although immunohistochemical studies confirmed phagocytosis of T cells by histiocytes, there was no evidence of lymphoma. From the Department of Dermatology, Mayo Clinic Jacksonville"; the Department of Dermatology, Mayo Clinic Scottsdaleb; and the Department of Pathology, Hilo Hospital.c Reprint requests: Charles Perniciaro, MD, Department of Dermatology, Mayo Clinic Jacksonville, 4500 San Pablo Rd., Jacksonville, FL 32224.
Copyright © 1994 by the American Academy of Dermatology, Inc.
0190-9622/94 $3.00 + 0 16/4/54673
CASE REPORT
A previously healthy 20-year-old Hawaiian man slipped and bruised his left leg. Two days later swelling occurred in the left thigh and chills and fever to 39° C developed. The patient was hospitalized and treated with intravenous clindamycin for presumed cellulitis. On admission findings included diffuse swelling with ecchymosis of the left thigh and mild hypogastric tenderness. No lymphadenopathy was present. During hospitalization intermittent fever persisted to 40° C, and a progressive, severe, generalized myalgia developed. The creatine phosphokinase concentration (all skeletal muscle fraction) increased to 10,967 IU/L (normal, 24 to 195 IU/L). A muscle biopsy specimen showed a few scattered degenerating fibers undergoing phagocytosis, but no significant inflammation, vasculitis, or atrophy was found. Although initial blood counts were normal, pancytopenia developed. The hemoglobin value decreased from 17.6 gm/dl on admission to 8.9 gm/dI23 days later, and there was a corresponding decrease in the leukocyte count from 6700/mm 3 to 3200/mm3 and a decrease in the platelet count from 169,Ooo/mm3 to 104,OOO/mm3• A peripheral blood smear on admission showed a few atypical lymphocytes. The differential cell count was normal. Prothrombin time was increased to 15.7 seconds (control, II to 13.5 seconds), partial thromboplastin time was elevated to 38 seconds (control, 20 to 32 seconds), and fibrinogen was decreased to 26 mg/dl (normal, 153 to 389 mg/dI). D-Dimerwasincreased to 2.0 to 4.0 jLg/rnl of serum (normal, <0.5 J.Lg/ml). The percentage of factor IX was decreased to 28% (normal, 50% to 150%). A bone marrow biopsy specimen showed markedly decreased cellularity but no evidence of lym-
901
Journal of the American Academy of Dermatology November 1994
902 Perniciaro et al.
Fig. 1. Characteristic "beanbag" cells of cytophagic histiocytic panniculitis. These cells represent histiocytes that have phagocytized lymphoid cells, erythrocytes, or cellular debris. (Hematoxylin-eosin stain; X53.)
phoma or infection. Cultures were negative for bacteria, fungi, and acid-fast organisms. 'Liver function values increased during the illness: aspartate aminotransferasewas 150 U jL (normal, 7 to 35 U /L) on admission and peaked at 654 U /L on the fourteenth hospital day. Similar to this increase were those of alkaline phosphatase (peak, 426 U IL; normal, 50 to 130 U/L), total bilirubin (peak, 1.6mg/dl;normal, 0.1 to 1.0 mg/dl), and i'-glutamyltransferase (peak, 346 lUlL; normal, 15 to 85 lUlL). The serum calcium concentration was decreased slightly on admission to 8.5 mg/dl (nonnal, 8;8 to 10.5 mg/dl) and decreased to 7.1 mg/dl by the second hospital day. A computed tomographic scan of the abdomen showed hepatosplenomegaly without focal masses or lymphadenopathy. The following values were negative or normal: erythrocyte sedimentation rate, glucose, creatinine, urea nitrogen, a11:JUmin, uric acid, phosphorus, amylase, neutrophil cytoplasmic antibody, antinuclear antibody, rheumatoid factor, thyroid-stimulating hormone, antistreptolysin titer, 'Monospot test (1gM heterophile), hepatitis B surface antigen, H1V antibody, leptospirosis titer, febrile agglutinIns to typhoid antigens (0 and H), parathyroid antigens (A and B), Brucella abortus, Proteus Ox-19, and thyroid-stimulating hormone. Results were also normal for the following studies: urinalysis, radiograph of the left femur, chest radiograph, gallium scan, electromyelogram, electrocardiogram, and bacterial cultures from urine, blood (aerobic and anaerobic), and left thigh. On the eighteenth hospital day, therapy with prednisone, 60 mg daily, was started. During the subsequent
°
13 days, febrile episodes decreased and the patient was discharged; at that time the dosage of prednisone was 30 mg daily. Ten days later generalized ecchymoses developed and thepatient collapsed at home. Resuscitation was unsuccessful. METHODS We reviewed hematoxylin-eosin-stained material prepared from tissue obtained at autopsy from the following sites: skin and subcutaneous tissue, spleen, stomach, heart, hilar lymph nodes, muscle, bone marrow, liver, and adrenal gland. Except for the liver and adrenal gland, additional sections were recut from the original paraffin blocks and were stained with a standard streptavidin-biotin technique with the following antibodies: Leu-22 (CD43, Dako, Carpenteria, Calif.), UCHL-I (CD45RO, Dako) , L26 (CD20, Dako), Ber-H2 (CD30, Dako), Leu-Ml (CD IS, Becton-Dickinson, Mountain' yiew, Calif.), KP-1 (CD68, Dako), and lysozyme (Biogenex, San Ramon, Calif.). A modified streptavidin-biotin techniqueS was used to stain the sections with polyclonal CD3 (Dako).
RESULTS The adipose tissue in the skin and adjacent to multiple organs (adrenal gland, stomach, heart, and muscle) displayed similar histopathologic findings: an infiltrate of large histiocytes with medium-sized, benign-appearing lymphoid cells. Within the skin biopsy specimen, no abnormalities were detected in the epidermis and dermis. Lymphoid cells formed rings around intact adipocytes.
Journal of the American Academy of Dermatology Volume 31, Number 5, Part 2
Perniciaro et al. 903
Fig. 2. Numerous cytophagic histiocytes within hilar lymph node. (Hematoxylin-eosin stain; X53.)
Most of the lymphoid cells stained positive with T-cell stains (UCHL-I, Leu-22, CD3) and negative with the B-cell stain (L26). However, up to 20% of the lymphoid cells in adipose tissue did not stain with any of the lymphocyte stains. The histiocytes were cytologically benign and contained abundant eosinophilic cytoplasm with small, eccentrically placed nuclei. Histiocytes stained prominently with the macrophage stain KP-I and weakly with UCHL-l. These cells did not stain with lysozyme. Some sections showed distinct cytophagocytosis by histiocytes of lymphoid cells and karyorrhectic debris (Fig. 1). Erythrophagocytosis was prominent in some areas. In histiocytes that had ingested lymphocytes, debris from these cells caused the cytoplasm of the histiocytes to stain positive with T-cell stains. Nonphagocytizing histiocytes did not stain with T- or B-Iymphocyte stains. Cytophagic changes were limited to the skin and adnexal adipose tissue. Except for the spleen and lymph nodes, the parenchyma of all organs examined was not involved. Sections from the liver indicated severe fatty change and focal hepatocellular necrosis with a minimal lymphoid infiltrate, primarily around central lobular veins. The portal areas did not show any abnormalities. The spleen showed an expansion of red pulp, and the sinusoids were stuffed with erythrocytes, lymphoid cells, histiocytes, and cytophagic cells. The lymphoid cells within these sinusoids did not stain with T- or B-cell stains. Cytophagia, particularly erythrophagia, was prominent in the spleen. Specimens taken from the hilar lymph nodes had sinus histiocytosis with almost total effacement of normal nodal architecture by large histiocytes with abun-
dant eosinophilic cytoplasm and small nuclei (Fig. 2). As in the adipose tissue, these histiocytes stained positive with KP-I and negative with the lymphocyte stains. The few lymphoid follicles remaining within the node contained small, benign-appearing lymphoid cells that stained positive with L26 in the germinal centers and positive with T-cell stains around the mantle. Cytophagia was present within the node, but the ingested lymphocytes did not stain with T- or B-cell stains. There was no evidence of lymphoma. The bone marrow specimen taken at autopsy was 75% cellular and contained abundant histiocytes (KP-l positive). Cytophagia was also prominent in the marrow. The cytoplasm of some histiocytes contained multiple lymphocytes, erythrocytes, or both (Fig. 3). Although lymphoid cens within the marrow did not stain with T- or B-cell stains, the megakaryocytes stained weakly positive with the T-cell stain CD3. Staining with Ber-H2 was negative in all sections except for rare isolated lymphoid cells. Some phagocytized debris within histiocytes stained positive with Leu-MI, but no positive Reed-Sternberg-like cells were identified.
DISCUSSION
CHP was originally described in 1980 as a disorder 'of morphologically benign histiocytes that invaded adipose tissue and phagocytized lymphocytes and other cells. 1 Additional patients were subsequently reported with the clinical course and histologic features of CHP.2, 7 These patients had an ill-
904 Perniciaro et al.
Journal of the American Academy of Dermatology November 1994
Fig. 3. Bone marrow biopsy specimen with prominent cytophagia by large histiocytes (arrows) of lymphoid cells and erythrocytes. (Hematoxylin-eosin stain; X84.)
ness characterized by a hemophagocytic syndrome (fever, hepatosplenomegaly, liver function abnormalities, and death from a hemorrhagic diathesis). None of these patients had lymphoma at the time of death, with the exception of one patient with a B-cell malignancy. Electron microscopy performed in one patient showed no evidence of viral inclusions. Several authors presumed CHP to be a form of malignant histiocytosis. 9, 10 We now recognize that true histiocytic malignancies (malignancies of macrophage lineage) are rare. I I, 12 Many disorders previously classified as histiocytic lymphomas are actually T-cell lymphomas. 13 Recently a subcutaneous variant of T-cell lymphoma has been identified. 3, 4 One characteristic feature of subcutaneous T-cell lymphoma is the presence of reactive phagocytic histiocytes within adipose tissue, resembling CHP. Patients frequently die of hemorrhagic complications. A hemophagocytic syndrome has also been identified as a sequela of infections with at least 18 different organisms. 14 Viral infections have been most commonly described, particularly with Epstein-Barr virus, cytomegalovirus, and HIV-l. The clinical course in some patients was rapidly fatal; others fully recovered. Patients with documented evidence of Epstein-Barr virus have been reported with CHP.5 Our patient had screening tests for Epstein-Barr virus, HIV-1, and other infectious agents. No definite
infections were found. Nonetheless, the rapidly fatal clinical course in our previously healthy patient suggests the possibility of an infection. Studies for molecular genetics analysis were not performed, but the cytologic characteristics of the histiocytes and lymphocytes we observed did not allow us to make a diagnosis of malignancy. Fatal cases of generalized CHP have been described by others as "fatal Weber-Christian disease,,15 and "fatal panniculitis."16 These cases are similar to the case we describe and may represent a reaction to infection or subcutaneous T-cell lymphoma. CHP has also been reported in one patient with a B-celllymphoma. 7 In rare patients, CHP has an apparent benign clinical course. 9 Reversible phenytoin-induced hemophagocytic histiocytosis was reported by Gutierrez-Rave Pecero et al. 17 The lipotropic predilection of CHP remains an enigma. Perhaps a fat-soluble antigen initially attracts the lymphocytes. We were impressed by the histologic wreathlike appearance of T lymphocytes surrounding normal-appearing adipocytes within the lobules of fat. The relative lack of fat necrosis was also surprising. We found almost exclusively T lymphocytes within the adipose tissue. This was a consistent pattern adjacent to multiple organs. The lymphocytes present within hematopoietic tissue did not stain consistently with T- or B-cell stains. We were unable to explain why the megakaryocytes
Journal of the American Academy of Dermatology Volume 31, Number 5, Part 2
within the bone marrow stained with CD3, a relatively specific pan-T-cell marker. Itis conceivable that reactive T lymphocytes are stimulated to release lymphokines, which recruit histiocytes. These histiocytes phag~ize not only lymphocytes but also erythrocytes and platelets, and this process explains the pancytopenia. Ultimately, the bone marrow cannot produce cellular elements as fast as they are consumed and destroyed by the histiocytes, and death by hemorrhage ensues. CHP is a reactive histologic process in which histiocytes and T lymphocytes preferentially infiltrate adipose tissue. CHP may occur in a spectrum of disorders from viral infections to lymphomas. REFERENCES
I. Winkelmann RK, Bowie EJW. Hemorrhagic diathesis as-
2.
3.
4. 5.
sociated with benign histiocytic, cytophagic panniculitis and systemic histiocytosis. Arch Intern Med 1980;140: 1460-3. Crotty CP, Winkelmann RK. Cytophagic histiocytic panniculitis with fever, cytopenia, liver failure, and terminal hemorrhagicdiathesis. JAMAcADDERMATOLI981;4:1 8194. Gonzalez CL, Medeiros LJ, Braziel RM, et a1. T-cell1ymphoma involving subcutaneous tissue: a clinicopathologic entity commonly associated with hemophagocytic syndrome. Am J Surg PathoI1991;15:17-27. Perniciaro C, Zalla MJ, White JW Jr, et a1. Subcutaneous T cell lymphoma: report of two additional cases and further observations. Arch DermatoI1993;129:1171-6. Smith KJ, Skelton HG III, Giblin WL, et a1. Cutaneous lesions ofhemophagocytic syndrome in a patientwith T-cell lymphoma and active Epstein-Barr infection. JAM ACAD DERMATOL 1991;25:919-24.
Perniciaro et al. 905 6. White JW Jr, Winkelmann RK. Cytophagic histiocytic panniculitis is not always fatal. J CutanPatholI989;16:l37-
44.
7. Peters MS, Winkelmann RK. Cytophagic panniculitis and B cell lymphoma. JAM ACAD DERMATOL 1985;13:882-5. 8. Kurtin P J, Roche PC. Immunoperoxidase staining of nonHodgkin's lymphomas for T-cell lineage associated antigens in paraffin sections: comparison of the performance characteristics of four commercially available antibody preparations. Am J Surg Patho1 1993;17:898-904. 9. March LM, Webb J, Eckstein RP. Cytophagic panniculitis. Aust N Z J Med 1986;16:397-401. 10. Barron DR, Davis BR, Pomeranz JR, et a1. Cytophagic histiocytic panniculitis: a variant of malignant histiocytosis. Cancer 1985;55:2538-42. 11. Delsol G, Al Saati T, Gatter KC, et a1. Coexpression of epithelial membrane antigen (EMA), Ki-l, and interleukin-2 receptor by anaplastic large cell lymphomas: diagnostic value in so-called malignant histiocytosis. Am J Patho1 1988;130:59-70. 12. Arai E, Su WPD, Roche PC, et a1. Cutaneous histiocytic malignancy: immunohistochemical re-examination ofcases previously diagnosed as cutaneous "histiocytic lymphoma" and "malignanthistiocytosis." JCutanPathoI1993;20:1l520. 13. Wilson MS, Weiss LM, Gatter KC, et a1. Malignant histiocytosis: a reassessment of cases previously reported in 1975 based on paraffin section immunophenotyping studies. Cancer 1990;66:530-6. 14. Reiner AP, Spivak JL. Hematophagic histiocytosis: a report of 23 new patients and a review of the literature. Medicine (Baltimore) 1988;67:369-88. 15. Mostofi FK, Engleman E. Fatal relapsing febrile nonsuppurative panniculitis. Arch PathoI1947;43:4l7-26. 16. Aronson IK, WestDP, Variakojis D, et a1. Fatal panniculitis. JAM ACAD DERMATOL 1985;12:535-51. 17. Gutierrez-Rave Pecero VM, Marquez RL, Lerchundi MAA, et al. Phenytoin-induced hemocytophagic histiocytosis indistinguishable from malignant histiocytosis. South Med J 1991;84:649-50.
Copyright © 1994 by the American Academy of Dermatology, Inc.
0190-9622/94 $3.00 + 0 16/4/54673
CASE REPORT
A previously healthy 20-year-old Hawaiian man slipped and bruised his left leg. Two days later swelling occurred in the left thigh and chills and fever to 39° C developed. The patient was hospitalized and treated with intravenous clindamycin for presumed cellulitis. On admission findings included diffuse swelling with ecchymosis of the left thigh and mild hypogastric tenderness. No lymphadenopathy was present. During hospitalization intermittent fever persisted to 40° C, and a progressive, severe, generalized myalgia developed. The creatine phosphokinase concentration (all skeletal muscle fraction) increased to 10,967 IU/L (normal, 24 to 195 IU/L). A muscle biopsy specimen showed a few scattered degenerating fibers undergoing phagocytosis, but no significant inflammation, vasculitis, or atrophy was found. Although initial blood counts were normal, pancytopenia developed. The hemoglobin value decreased from 17.6 gm/dl on admission to 8.9 gm/dI23 days later, and there was a corresponding decrease in the leukocyte count from 6700/mm 3 to 3200/mm3 and a decrease in the platelet count from 169,Ooo/mm3 to 104,OOO/mm3• A peripheral blood smear on admission showed a few atypical lymphocytes. The differential cell count was normal. Prothrombin time was increased to 15.7 seconds (control, II to 13.5 seconds), partial thromboplastin time was elevated to 38 seconds (control, 20 to 32 seconds), and fibrinogen was decreased to 26 mg/dl (normal, 153 to 389 mg/dI). D-Dimerwasincreased to 2.0 to 4.0 jLg/rnl of serum (normal, <0.5 J.Lg/ml). The percentage of factor IX was decreased to 28% (normal, 50% to 150%). A bone marrow biopsy specimen showed markedly decreased cellularity but no evidence of lym-
901
Journal of the American Academy of Dermatology November 1994
902 Perniciaro et al.
Fig. 1. Characteristic "beanbag" cells of cytophagic histiocytic panniculitis. These cells represent histiocytes that have phagocytized lymphoid cells, erythrocytes, or cellular debris. (Hematoxylin-eosin stain; X53.)
phoma or infection. Cultures were negative for bacteria, fungi, and acid-fast organisms. 'Liver function values increased during the illness: aspartate aminotransferasewas 150 U jL (normal, 7 to 35 U /L) on admission and peaked at 654 U /L on the fourteenth hospital day. Similar to this increase were those of alkaline phosphatase (peak, 426 U IL; normal, 50 to 130 U/L), total bilirubin (peak, 1.6mg/dl;normal, 0.1 to 1.0 mg/dl), and i'-glutamyltransferase (peak, 346 lUlL; normal, 15 to 85 lUlL). The serum calcium concentration was decreased slightly on admission to 8.5 mg/dl (nonnal, 8;8 to 10.5 mg/dl) and decreased to 7.1 mg/dl by the second hospital day. A computed tomographic scan of the abdomen showed hepatosplenomegaly without focal masses or lymphadenopathy. The following values were negative or normal: erythrocyte sedimentation rate, glucose, creatinine, urea nitrogen, a11:JUmin, uric acid, phosphorus, amylase, neutrophil cytoplasmic antibody, antinuclear antibody, rheumatoid factor, thyroid-stimulating hormone, antistreptolysin titer, 'Monospot test (1gM heterophile), hepatitis B surface antigen, H1V antibody, leptospirosis titer, febrile agglutinIns to typhoid antigens (0 and H), parathyroid antigens (A and B), Brucella abortus, Proteus Ox-19, and thyroid-stimulating hormone. Results were also normal for the following studies: urinalysis, radiograph of the left femur, chest radiograph, gallium scan, electromyelogram, electrocardiogram, and bacterial cultures from urine, blood (aerobic and anaerobic), and left thigh. On the eighteenth hospital day, therapy with prednisone, 60 mg daily, was started. During the subsequent
°
13 days, febrile episodes decreased and the patient was discharged; at that time the dosage of prednisone was 30 mg daily. Ten days later generalized ecchymoses developed and thepatient collapsed at home. Resuscitation was unsuccessful. METHODS We reviewed hematoxylin-eosin-stained material prepared from tissue obtained at autopsy from the following sites: skin and subcutaneous tissue, spleen, stomach, heart, hilar lymph nodes, muscle, bone marrow, liver, and adrenal gland. Except for the liver and adrenal gland, additional sections were recut from the original paraffin blocks and were stained with a standard streptavidin-biotin technique with the following antibodies: Leu-22 (CD43, Dako, Carpenteria, Calif.), UCHL-I (CD45RO, Dako) , L26 (CD20, Dako), Ber-H2 (CD30, Dako), Leu-Ml (CD IS, Becton-Dickinson, Mountain' yiew, Calif.), KP-1 (CD68, Dako), and lysozyme (Biogenex, San Ramon, Calif.). A modified streptavidin-biotin techniqueS was used to stain the sections with polyclonal CD3 (Dako).
RESULTS The adipose tissue in the skin and adjacent to multiple organs (adrenal gland, stomach, heart, and muscle) displayed similar histopathologic findings: an infiltrate of large histiocytes with medium-sized, benign-appearing lymphoid cells. Within the skin biopsy specimen, no abnormalities were detected in the epidermis and dermis. Lymphoid cells formed rings around intact adipocytes.
Journal of the American Academy of Dermatology Volume 31, Number 5, Part 2
Perniciaro et al. 903
Fig. 2. Numerous cytophagic histiocytes within hilar lymph node. (Hematoxylin-eosin stain; X53.)
Most of the lymphoid cells stained positive with T-cell stains (UCHL-I, Leu-22, CD3) and negative with the B-cell stain (L26). However, up to 20% of the lymphoid cells in adipose tissue did not stain with any of the lymphocyte stains. The histiocytes were cytologically benign and contained abundant eosinophilic cytoplasm with small, eccentrically placed nuclei. Histiocytes stained prominently with the macrophage stain KP-I and weakly with UCHL-l. These cells did not stain with lysozyme. Some sections showed distinct cytophagocytosis by histiocytes of lymphoid cells and karyorrhectic debris (Fig. 1). Erythrophagocytosis was prominent in some areas. In histiocytes that had ingested lymphocytes, debris from these cells caused the cytoplasm of the histiocytes to stain positive with T-cell stains. Nonphagocytizing histiocytes did not stain with T- or B-Iymphocyte stains. Cytophagic changes were limited to the skin and adnexal adipose tissue. Except for the spleen and lymph nodes, the parenchyma of all organs examined was not involved. Sections from the liver indicated severe fatty change and focal hepatocellular necrosis with a minimal lymphoid infiltrate, primarily around central lobular veins. The portal areas did not show any abnormalities. The spleen showed an expansion of red pulp, and the sinusoids were stuffed with erythrocytes, lymphoid cells, histiocytes, and cytophagic cells. The lymphoid cells within these sinusoids did not stain with T- or B-cell stains. Cytophagia, particularly erythrophagia, was prominent in the spleen. Specimens taken from the hilar lymph nodes had sinus histiocytosis with almost total effacement of normal nodal architecture by large histiocytes with abun-
dant eosinophilic cytoplasm and small nuclei (Fig. 2). As in the adipose tissue, these histiocytes stained positive with KP-I and negative with the lymphocyte stains. The few lymphoid follicles remaining within the node contained small, benign-appearing lymphoid cells that stained positive with L26 in the germinal centers and positive with T-cell stains around the mantle. Cytophagia was present within the node, but the ingested lymphocytes did not stain with T- or B-cell stains. There was no evidence of lymphoma. The bone marrow specimen taken at autopsy was 75% cellular and contained abundant histiocytes (KP-l positive). Cytophagia was also prominent in the marrow. The cytoplasm of some histiocytes contained multiple lymphocytes, erythrocytes, or both (Fig. 3). Although lymphoid cens within the marrow did not stain with T- or B-cell stains, the megakaryocytes stained weakly positive with the T-cell stain CD3. Staining with Ber-H2 was negative in all sections except for rare isolated lymphoid cells. Some phagocytized debris within histiocytes stained positive with Leu-MI, but no positive Reed-Sternberg-like cells were identified.
DISCUSSION
CHP was originally described in 1980 as a disorder 'of morphologically benign histiocytes that invaded adipose tissue and phagocytized lymphocytes and other cells. 1 Additional patients were subsequently reported with the clinical course and histologic features of CHP.2, 7 These patients had an ill-
904 Perniciaro et al.
Journal of the American Academy of Dermatology November 1994
Fig. 3. Bone marrow biopsy specimen with prominent cytophagia by large histiocytes (arrows) of lymphoid cells and erythrocytes. (Hematoxylin-eosin stain; X84.)
ness characterized by a hemophagocytic syndrome (fever, hepatosplenomegaly, liver function abnormalities, and death from a hemorrhagic diathesis). None of these patients had lymphoma at the time of death, with the exception of one patient with a B-cell malignancy. Electron microscopy performed in one patient showed no evidence of viral inclusions. Several authors presumed CHP to be a form of malignant histiocytosis. 9, 10 We now recognize that true histiocytic malignancies (malignancies of macrophage lineage) are rare. I I, 12 Many disorders previously classified as histiocytic lymphomas are actually T-cell lymphomas. 13 Recently a subcutaneous variant of T-cell lymphoma has been identified. 3, 4 One characteristic feature of subcutaneous T-cell lymphoma is the presence of reactive phagocytic histiocytes within adipose tissue, resembling CHP. Patients frequently die of hemorrhagic complications. A hemophagocytic syndrome has also been identified as a sequela of infections with at least 18 different organisms. 14 Viral infections have been most commonly described, particularly with Epstein-Barr virus, cytomegalovirus, and HIV-l. The clinical course in some patients was rapidly fatal; others fully recovered. Patients with documented evidence of Epstein-Barr virus have been reported with CHP.5 Our patient had screening tests for Epstein-Barr virus, HIV-1, and other infectious agents. No definite
infections were found. Nonetheless, the rapidly fatal clinical course in our previously healthy patient suggests the possibility of an infection. Studies for molecular genetics analysis were not performed, but the cytologic characteristics of the histiocytes and lymphocytes we observed did not allow us to make a diagnosis of malignancy. Fatal cases of generalized CHP have been described by others as "fatal Weber-Christian disease,,15 and "fatal panniculitis."16 These cases are similar to the case we describe and may represent a reaction to infection or subcutaneous T-cell lymphoma. CHP has also been reported in one patient with a B-celllymphoma. 7 In rare patients, CHP has an apparent benign clinical course. 9 Reversible phenytoin-induced hemophagocytic histiocytosis was reported by Gutierrez-Rave Pecero et al. 17 The lipotropic predilection of CHP remains an enigma. Perhaps a fat-soluble antigen initially attracts the lymphocytes. We were impressed by the histologic wreathlike appearance of T lymphocytes surrounding normal-appearing adipocytes within the lobules of fat. The relative lack of fat necrosis was also surprising. We found almost exclusively T lymphocytes within the adipose tissue. This was a consistent pattern adjacent to multiple organs. The lymphocytes present within hematopoietic tissue did not stain consistently with T- or B-cell stains. We were unable to explain why the megakaryocytes
Journal of the American Academy of Dermatology Volume 31, Number 5, Part 2
within the bone marrow stained with CD3, a relatively specific pan-T-cell marker. Itis conceivable that reactive T lymphocytes are stimulated to release lymphokines, which recruit histiocytes. These histiocytes phag~ize not only lymphocytes but also erythrocytes and platelets, and this process explains the pancytopenia. Ultimately, the bone marrow cannot produce cellular elements as fast as they are consumed and destroyed by the histiocytes, and death by hemorrhage ensues. CHP is a reactive histologic process in which histiocytes and T lymphocytes preferentially infiltrate adipose tissue. CHP may occur in a spectrum of disorders from viral infections to lymphomas. REFERENCES
I. Winkelmann RK, Bowie EJW. Hemorrhagic diathesis as-
2.
3.
4. 5.
sociated with benign histiocytic, cytophagic panniculitis and systemic histiocytosis. Arch Intern Med 1980;140: 1460-3. Crotty CP, Winkelmann RK. Cytophagic histiocytic panniculitis with fever, cytopenia, liver failure, and terminal hemorrhagicdiathesis. JAMAcADDERMATOLI981;4:1 8194. Gonzalez CL, Medeiros LJ, Braziel RM, et a1. T-cell1ymphoma involving subcutaneous tissue: a clinicopathologic entity commonly associated with hemophagocytic syndrome. Am J Surg PathoI1991;15:17-27. Perniciaro C, Zalla MJ, White JW Jr, et a1. Subcutaneous T cell lymphoma: report of two additional cases and further observations. Arch DermatoI1993;129:1171-6. Smith KJ, Skelton HG III, Giblin WL, et a1. Cutaneous lesions ofhemophagocytic syndrome in a patientwith T-cell lymphoma and active Epstein-Barr infection. JAM ACAD DERMATOL 1991;25:919-24.
Perniciaro et al. 905 6. White JW Jr, Winkelmann RK. Cytophagic histiocytic panniculitis is not always fatal. J CutanPatholI989;16:l37-
44.
7. Peters MS, Winkelmann RK. Cytophagic panniculitis and B cell lymphoma. JAM ACAD DERMATOL 1985;13:882-5. 8. Kurtin P J, Roche PC. Immunoperoxidase staining of nonHodgkin's lymphomas for T-cell lineage associated antigens in paraffin sections: comparison of the performance characteristics of four commercially available antibody preparations. Am J Surg Patho1 1993;17:898-904. 9. March LM, Webb J, Eckstein RP. Cytophagic panniculitis. Aust N Z J Med 1986;16:397-401. 10. Barron DR, Davis BR, Pomeranz JR, et a1. Cytophagic histiocytic panniculitis: a variant of malignant histiocytosis. Cancer 1985;55:2538-42. 11. Delsol G, Al Saati T, Gatter KC, et a1. Coexpression of epithelial membrane antigen (EMA), Ki-l, and interleukin-2 receptor by anaplastic large cell lymphomas: diagnostic value in so-called malignant histiocytosis. Am J Patho1 1988;130:59-70. 12. Arai E, Su WPD, Roche PC, et a1. Cutaneous histiocytic malignancy: immunohistochemical re-examination ofcases previously diagnosed as cutaneous "histiocytic lymphoma" and "malignanthistiocytosis." JCutanPathoI1993;20:1l520. 13. Wilson MS, Weiss LM, Gatter KC, et a1. Malignant histiocytosis: a reassessment of cases previously reported in 1975 based on paraffin section immunophenotyping studies. Cancer 1990;66:530-6. 14. Reiner AP, Spivak JL. Hematophagic histiocytosis: a report of 23 new patients and a review of the literature. Medicine (Baltimore) 1988;67:369-88. 15. Mostofi FK, Engleman E. Fatal relapsing febrile nonsuppurative panniculitis. Arch PathoI1947;43:4l7-26. 16. Aronson IK, WestDP, Variakojis D, et a1. Fatal panniculitis. JAM ACAD DERMATOL 1985;12:535-51. 17. Gutierrez-Rave Pecero VM, Marquez RL, Lerchundi MAA, et al. Phenytoin-induced hemocytophagic histiocytosis indistinguishable from malignant histiocytosis. South Med J 1991;84:649-50.