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Histiocytic cytophagic panniculitis: Molecular evidence for a clonal T-cell disorder
Volume 27 Number 2, Part 2 August 1992 angiolipoleiomyoma. J AM ACAD DERMATOL1990;23: 1093-8. 3. ArgenyiZB, Piette WW, Goeken JA. Cutaneous angiomyolipoma: a light microscopic, immunohistoehemical, and electron-microscopic study. Am J Dermatopathol 1991;13:497-502. 4. MacDonald DM, Sanderson KV. Angioleiomyomaof the skin. Br J Dermatol 1974;91:161-8. 5. Hachisuga T, Hashimoto H, Enjoji M. Angioleiomyoma: a clinieopathologic reprisal of 562 cases. Cancer 1984; 54:126-30. 6. Chen KTK. Angiomyolipomaof the vagina. GynecolOncol 1990;37:302-4. 7. Peh SC, Sivanesaratnam V. Angiomyolipomaof the vagi-
Angiomyolipoma 333 ha--an uncommontumor, case report. Br J Obstet Gynaecol 1988;95:820-3. 8. Fri J, Hjortrup A. Extrarenal angiomyolipoma:diagnosis and management. J Urol 1982;127:528-9. 9. Sant GR, Ueci AA, Measures EM Jr. Multicentrie angiomyolipoma,renal and lymph node involvement.Urology 1986;28:111-3. 10. Pounder DJ. Hepatic angiomyolipoma.Am J Surg Patho[ 1982;6:677-81. 11. Dawlatty EE, Anita JT, E1-Hassan AY. Angiomyolipoma of the nasal cavity. J Laryngoi Otol t988;102:1 t56-8. 12. Gutman J, Cifuentes C, Vicuna R, et al. Intraoral angiomyolipoma.Oral Surg 1975;39:945-8.
Histiocytic cytophagic panniculitis" Molecular evidence for a clonal T-cell disorder Prodromos Hytiroglou, MD, a Robert G. Phelps, M D , a' e Debra J. Wattenberg, M D , c and James A. Strauchen, MD, a, b New York, New York Histiocytic cytophagic panniculitis is a systemic disease of unknown etiopathogenesis that invariably involves the subcutaneous fat and is histologically characterized by phagocytosis of blood elements by histiocytes that appear to be benign. Immunophenotypic and genotypic studies of biopsy specimens of the lesions of a 58-year-old woman showed that the lymphocytic infiltrates accompanying the histiocytes in the subcutis were eomlx3sed of clonal T-cells with rearrangement of the surface receptor gene. Our findings suggest that the primary abnormality in histiocytic cytophagic panniculitis may be a clonal T-cell proliferation. (J AM ACAD DERMATOL 1992;27:333-6.) Histiocytic cytophagic panniculitis (HCP) was described in 1980 as a chronic histiocytic disease of the subcutaneous fat associated with systemic manifestations such as fever, serositis, and hepatosplenomegaly.t, 2 The histologic hallmark of this condition is phagocytosis of erythrocytes, leukocytes (particularly lymphocytes), and platelets by histiocytes that appear to be benign in the subcutis and other involved organs. 3 The histiocytes in the panniculus are accompanied by lymphocytic infiltrates composed of mature T cells. 3 In most cases the disease follows a long-term course leading to death, which often occurs as a result of coagulation abnormalities.2, 3 We report a case of H C P and proFrom the Departmentsof Pathology,a NeoplasticDiseases,uand Dermatology,e MountSinai Schoolof Medicine, Reprint requests:RobertG. Phelps,MD, DermatopathologyDivision, MountSinaiSchoolofMedicine,1GustavcL. LevyPlace,Box1194, New York, NY 10029. 16/4/33969
vide results of immunophenotypic and genotypic studies, which demonstrate that a clonal T-cell proliferation may be the primary abnormality in this condition. CASE REPORT A previously healthy 58-year-old white woman had a 5-week history of fever up to 102 ~ F, diffuse myatgia, arthra[gia, night sweats, and a 10-pound weight loss. She was admitted to the hospital for evaluation. Her initial examination revealed a positive tuberculin test; anemia (hemoglobin, 106 gm/L); lymphopenia (615 lymphocytes//A, normal T4/T8 ratio); mildly elevated transaminases (SOOT, 76 U/L; SGPT, 68 U/L); an erythmcyte sedimentation rate of 54 mm in the first hour; and a positive titer for rheumatoid factor (1:80). Serum protein electrophoresis showed a polyclonal hypergammaglobulinemia. Results of a bone marrow biopsy specimen showed a mildly hyperce|lular marrow with granulocytic hyperplasia. Hemophagocytosis was not identified. Bone marrow cultures were negative.
334
Journal of the American Academy of Dermatology
Hytiroglou et aL
Molecular genetics. Genotypic studies were performed with the Southern blot technique. DNA was extracted from frozen biopsy material, and the purified genomic DNA samples were aliquoted and digested to completion with restriction endonucleases BamHI, EcoRI and HindIII. Each digest contained 25/Lg of DNA. Approximately 5 #g of each sample were size fractionated on 0.7% agarose gels and transferred under alkaline conditions to activated nylon membranes by the method of Southern. 4 Membranes were hybridized with DNA probe fragments radiolabeled with phosphorus 32 by the random hexamer priming method of Feinberg and Vogelstein: The DNA probes used in the assay included the following: Fig. 1. Macroscopic appearance of lesion in right gluteal region. On repeat physical examination a 3 • 5 cm, erythematous, indurated, nonblanching plaque with mild tenderness was noted in the right gluteal region (Fig. 1). In addition, a 1 • 1 Cln, erythematous, indurated plaque on the right cheek, multiple erythematous, indurated plaques with surrounding violaceous mottled discoloration on the inner thighs, and multiple erythematous papules on the fingertips and palms were noted. A punch biopsy specimen of the gluteal lesion was obtained. Cultures for bacteria and fungi were negative. In several days the erythema progressed to involve both thighs. An incisional biopsy specimen was obtained for additional studies. After the histologic diagnosis was made, prednisone (50 mg/day) was begun and was later reduced to a maintenance dose of 20 rag/day. No new skin lesions developed, but the patient continued to have low-grade fevers and persistent myalgias and arthralgias.
Methods Histopathology. Tissues were fixed in 10% buffered neutral formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin, Giemsa, and toluidine blue. Immunohistochemlstry.Tissues were snap-frozen at -70 ~ C and 5 #m thick, acetone-fixed, fresh-frozen sections were reacted with a battery of antibodies to lymphocyte surface antigens (CD1, CD2, CD3, CD4, CD5, CD7, CD8, CDI0, CD14, CDI5, CD20, CD22, CD25, CD30, CD45, and ~, X, and # chains) by the avidin-biotin peroxidase technique. Antibodies were obtained from Becton Dickinson, Mountainview, Calif., except for CD2 and CD20, which were obtained from Coulter Electron its, Hialeah, Fla. Immunohistochemical studies were also performed on formalin-fixed, para ffin-embedded tissue for eq-antitrypsin and lysozyme by the avidin-biotin peroxidase method. The antibodies were obtained from DAKO Corp.,Carpenteria, Calif., by Dennis M.Todd, PhD (GenCare Biomedical Research Corp., Mountainside, N J).
1. The/3 chain T-cell receptor eDNA clone, which is a 1.1 ldlobase (kb) Bgl II genomic fragment containing almost the entire T-cell receptor C2 constant region; this fragment has greater than 90% homology with the T-cell receptor C~ constant region. 2. The JH probe, which is a 5.6 kb BamHI-HindIII fragment recognizing the entire/z heavy-chain joining region. 3. A 2.5 kb EcoRI fragment containing the entire K gene constant region (C probe). 4. A 0.8 kb BamHI-HindIII fragment recognizing the constant region of the X 1 gene (C probe). After hybridization the nylon membranes were washed, air dried, and photographed. Genomic DNA samples obtained from placental tissue and normal lymphocytes were used as controls.
Results Histopathology. Histologic examination of the skin biopsy specimens revealed a chronic inflammatoryinfiltrate in the reticular dermis, which was composed mainly of small lymphocytes and occasional histiocytes with a distinct perivascular and perieccrine distribution. The infiltrate extended into the subcutaneous fat and involved both septa and lobules. The infiltrate in the fat was predominantly lymphocytic; however, histiocytes, plasma cells, and rare neutrophils were also present. Many histiocytes contained red blood cells, lymphocytes, or karyorrhectic debris in their cytoplasm; an occasional "beanbag" cell was seen (Fig. 2). The fat showed evidence of cytolysiswith focal dissolution of cytoplasmic membranes and the presence of lipophages. Immunohistochemistry. The lymphocytes predominantly showed a T-helper cell profile (CD2, CD3, CD4, CD5, CD7:+, CD8, CD20, CD22, CD30:-, and immunoglobulin negative). Clonal antigen deletion was not observed. Occasional lymphocytes were positive for CD8, whereas rare lymphocytes were positive for B-cell markers. The histiocytes were positive for CD 14, CD 15, a-iantitrypsin, and lysozyme. Molecular genetics. Rearrangement of the t-chain surface receptor gene was detected in two of three digests.
Volume 27 Number 2, Part 2 August 1992
Histiocytic cytophagic pannieulitis
335
I
.Y ,
.
~,~.,~,,~.
......i'.;. ~~~.:"
gg
, ,,@
!~,
2r
.
Fig. 2. High-power photomicrograph of inflammatory infiltrate in panniculus. Arrows indicate histiocytes containing erythrocytes in their cytoplasm. (Hematoxylin-eosin stain; X400.)
Rearranged bands were found in the EcoRI and the BamHI digests (Fig. 3). No rearrangements were identiffed with the other three probes.
A
B
DISCUSSION H C P is a systemic disease characterized histologically by histiocytosis and cytophagocytosis in the reticuloendothelial system and skin. A recent article has summarized the clinical and histologic features of 19 cases. 3 Thirteen patients died as a result of the disease, whereas four had a more long-term course, as in our patient. Irnmunohistochemical studies of the lymphocytic infiltrates were performed in five cases with a T-cell (UCHL-1) and a B-cell (4KBS) marker on paraffin-embedded tissues. 3 As in oar case the lymphocytes were of T-cell lineage. In the present study immunophenotyping was performed on frozen sections and demonstrated a proliferation of helper T cells. Antigen deletions, as sometimes seen in T-cell lymphomas, were not identified. Genotypic studies demonstrated a clonal T-cell population. Our findings indicate that the primary abnormality in H C P may be a T-cell disorder and suggest that the histiocytic phagocytosis, which is the predominant histologic feature, may result from lymphokine production by the helper T-cell population. H C P is one of a number of disorders associated with prominent hemophagocytosis. Infection-associated systemic hemophagocytosis may be seen in
.........
.....
....
11
kb
4.2 kb
Fig. 3. Photograph of autoradiogram obtained with DNA extracted from biopsy (A) and control (B) specimens and hybridized with DNA fragment probes specific for/3 chain of T-cell surface receptor gene after digestion with restriction endonuclease EeoRI. Germline configuration is represented by bands at 4.2 and 11 kb; rearranged band is indicated by arrow. Additional rearranged band was seen in the BamHI digest (not shown). the reticuloendothelial system in a variety of viral, bacterial, myeobacterial, and parasitic infections (the pertinent literature is summarized by Alegre and Winkelman3). Although an exanthem is occa-
336
Hytiroglou et al.
sionally seen in these conditions, hemophagocytosis predominantly in the subcutis is not a feature. Malignant histiocytosis often involves the skin and subcutis, in addition to the reticuloendothelial system, and m a y show prominent phagocytosis. 6 However, the infiltrates are composed of pleomorphic cells with malignant cytologic features, in contrast to the cytologically benign infiltrates of HCP. With recent advances in immunophenotypic and genotypic techniques m a n y cases of malignant histiocytosis have been recognized as non-Hodgkin's lymphomas, which are often positive for Ki- 1 (CD30) antigen. 7, 8 Hemophagocytic syndromes may also be the sequelae of a variety of lymphoproliferative disorders, including angiocentric immunoproliferative lesions v, lo acute and chronic lymphocytic leukemia, 11,I2 lymphoblastic lymphoma, 13 Lennert's lymphoma, 14and other T-cell lymphomas of mature phenotype.9, is Malignant T-cell lymphoma primarily involving the subcutaneous tissue m a y mimic H C P both clinically and histologically. A recent study has summarized the clinical, histologic, immunophenotypic, and genotypic features of eight cases and has suggested that such lymphomas m a y represent the late stage or the malignant counterpart of HCP. s REFERENCES
l. Winkelrnann RK. Cytophagic panniculitis. G Ital Dermatol Venereo11980;115:175-7. 2. Crotty CP, Winkelmann RK. Cytophagie histiocyticpanniculitis with fever, cytopenia, liver failure, and terminal hemorrhagic diathesis. J AMACADDERMATOL1981;4:18194.
Journal of the American Academy of Dermatology 3. Alegre VA, Winkelman RK. Histiocytic cytophagiepanniculitis. J AM ACADDERMATOL1989;20:177-85. 4. SouthernEM. DetectionofspecificsequencesamongDNA fragments separated by gel electrophoresis. J Mol Biol 1975;98:503-17. 5. FeinbergAP, Vogelstein B. A technique for radiolabeling DNA restriction endonucleasefragments to high specific activity. Anal Biochem 1983;132:6-13. 6. Jaffe ES, ed. Surgical pathology of the lymph nodes and related organs. Philadelphia: WB Saunders, 1985:397-403. 7. Wilson MS, Weiss LM, Gatter KC, et al. Malignant histiocytosis: a reassessment of cases previouslyreported in 1975basedon paraffinsectionimmunophenotypingstudies. Cancer 1990;66:530-6. 8. GonzalezCL, MedeirosLJ, Braziel RM, et al. T-cell lyrephoton involving subcutaneous tissue: a clinicopathologic entity commonly associated with hemophagocytic syndrome. Am J Surg Pathol 1991;15:17-27. 9. Jaffe ES, Costa J, Fauci AS, et al. Malignant lymphoma and erythrophagocytosissimulating malignant histiocytosis. Am J Med 1983;75:741-9. 10. Aronson IK, West DP, Variakojis D, et al. Panniculitis associated with cutaneous T-cell lymphoma and cytophagocytic histiocytosis.Br J Dermatol 1985;112:87-96. 11. Karcher DS, Head DR~Mullins JD. Malignant hist~ocytosis occurring in patients with acute lymphocyticleukemia. Cancer 1978;41:1967-73. 12. Manoharan A, CatovskyD, Lampert IA, et al. Histiocytic medullary reticulosis complicating chronic lymphocytic leukaemia: malignant or reactive? Stand J Haematol 1981;26:5-13. 13. WoodruffRD, Nolting SF. Malignant histiocytosisas a sequel to lymphoblastic lymphoma. Arch Pathol Lab Meal 1981;105:336-7. 14. EconomopoulosTC, Stathakis N, Stathopoulos E, et al. "Lennert's lymphoma" terminating as malignant histiocytosis. Scand J Haematol 1979;23:427-32. 15. Ng C-S, Chan JKC, Cheng PNM, et al. Nasal T-cell lymphoma associatedwith hemophagocyticsyndrome. Cancer 1986;58:67-71.
Angiomyolipoma 333 ha--an uncommontumor, case report. Br J Obstet Gynaecol 1988;95:820-3. 8. Fri J, Hjortrup A. Extrarenal angiomyolipoma:diagnosis and management. J Urol 1982;127:528-9. 9. Sant GR, Ueci AA, Measures EM Jr. Multicentrie angiomyolipoma,renal and lymph node involvement.Urology 1986;28:111-3. 10. Pounder DJ. Hepatic angiomyolipoma.Am J Surg Patho[ 1982;6:677-81. 11. Dawlatty EE, Anita JT, E1-Hassan AY. Angiomyolipoma of the nasal cavity. J Laryngoi Otol t988;102:1 t56-8. 12. Gutman J, Cifuentes C, Vicuna R, et al. Intraoral angiomyolipoma.Oral Surg 1975;39:945-8.
Histiocytic cytophagic panniculitis" Molecular evidence for a clonal T-cell disorder Prodromos Hytiroglou, MD, a Robert G. Phelps, M D , a' e Debra J. Wattenberg, M D , c and James A. Strauchen, MD, a, b New York, New York Histiocytic cytophagic panniculitis is a systemic disease of unknown etiopathogenesis that invariably involves the subcutaneous fat and is histologically characterized by phagocytosis of blood elements by histiocytes that appear to be benign. Immunophenotypic and genotypic studies of biopsy specimens of the lesions of a 58-year-old woman showed that the lymphocytic infiltrates accompanying the histiocytes in the subcutis were eomlx3sed of clonal T-cells with rearrangement of the surface receptor gene. Our findings suggest that the primary abnormality in histiocytic cytophagic panniculitis may be a clonal T-cell proliferation. (J AM ACAD DERMATOL 1992;27:333-6.) Histiocytic cytophagic panniculitis (HCP) was described in 1980 as a chronic histiocytic disease of the subcutaneous fat associated with systemic manifestations such as fever, serositis, and hepatosplenomegaly.t, 2 The histologic hallmark of this condition is phagocytosis of erythrocytes, leukocytes (particularly lymphocytes), and platelets by histiocytes that appear to be benign in the subcutis and other involved organs. 3 The histiocytes in the panniculus are accompanied by lymphocytic infiltrates composed of mature T cells. 3 In most cases the disease follows a long-term course leading to death, which often occurs as a result of coagulation abnormalities.2, 3 We report a case of H C P and proFrom the Departmentsof Pathology,a NeoplasticDiseases,uand Dermatology,e MountSinai Schoolof Medicine, Reprint requests:RobertG. Phelps,MD, DermatopathologyDivision, MountSinaiSchoolofMedicine,1GustavcL. LevyPlace,Box1194, New York, NY 10029. 16/4/33969
vide results of immunophenotypic and genotypic studies, which demonstrate that a clonal T-cell proliferation may be the primary abnormality in this condition. CASE REPORT A previously healthy 58-year-old white woman had a 5-week history of fever up to 102 ~ F, diffuse myatgia, arthra[gia, night sweats, and a 10-pound weight loss. She was admitted to the hospital for evaluation. Her initial examination revealed a positive tuberculin test; anemia (hemoglobin, 106 gm/L); lymphopenia (615 lymphocytes//A, normal T4/T8 ratio); mildly elevated transaminases (SOOT, 76 U/L; SGPT, 68 U/L); an erythmcyte sedimentation rate of 54 mm in the first hour; and a positive titer for rheumatoid factor (1:80). Serum protein electrophoresis showed a polyclonal hypergammaglobulinemia. Results of a bone marrow biopsy specimen showed a mildly hyperce|lular marrow with granulocytic hyperplasia. Hemophagocytosis was not identified. Bone marrow cultures were negative.
334
Journal of the American Academy of Dermatology
Hytiroglou et aL
Molecular genetics. Genotypic studies were performed with the Southern blot technique. DNA was extracted from frozen biopsy material, and the purified genomic DNA samples were aliquoted and digested to completion with restriction endonucleases BamHI, EcoRI and HindIII. Each digest contained 25/Lg of DNA. Approximately 5 #g of each sample were size fractionated on 0.7% agarose gels and transferred under alkaline conditions to activated nylon membranes by the method of Southern. 4 Membranes were hybridized with DNA probe fragments radiolabeled with phosphorus 32 by the random hexamer priming method of Feinberg and Vogelstein: The DNA probes used in the assay included the following: Fig. 1. Macroscopic appearance of lesion in right gluteal region. On repeat physical examination a 3 • 5 cm, erythematous, indurated, nonblanching plaque with mild tenderness was noted in the right gluteal region (Fig. 1). In addition, a 1 • 1 Cln, erythematous, indurated plaque on the right cheek, multiple erythematous, indurated plaques with surrounding violaceous mottled discoloration on the inner thighs, and multiple erythematous papules on the fingertips and palms were noted. A punch biopsy specimen of the gluteal lesion was obtained. Cultures for bacteria and fungi were negative. In several days the erythema progressed to involve both thighs. An incisional biopsy specimen was obtained for additional studies. After the histologic diagnosis was made, prednisone (50 mg/day) was begun and was later reduced to a maintenance dose of 20 rag/day. No new skin lesions developed, but the patient continued to have low-grade fevers and persistent myalgias and arthralgias.
Methods Histopathology. Tissues were fixed in 10% buffered neutral formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin, Giemsa, and toluidine blue. Immunohistochemlstry.Tissues were snap-frozen at -70 ~ C and 5 #m thick, acetone-fixed, fresh-frozen sections were reacted with a battery of antibodies to lymphocyte surface antigens (CD1, CD2, CD3, CD4, CD5, CD7, CD8, CDI0, CD14, CDI5, CD20, CD22, CD25, CD30, CD45, and ~, X, and # chains) by the avidin-biotin peroxidase technique. Antibodies were obtained from Becton Dickinson, Mountainview, Calif., except for CD2 and CD20, which were obtained from Coulter Electron its, Hialeah, Fla. Immunohistochemical studies were also performed on formalin-fixed, para ffin-embedded tissue for eq-antitrypsin and lysozyme by the avidin-biotin peroxidase method. The antibodies were obtained from DAKO Corp.,Carpenteria, Calif., by Dennis M.Todd, PhD (GenCare Biomedical Research Corp., Mountainside, N J).
1. The/3 chain T-cell receptor eDNA clone, which is a 1.1 ldlobase (kb) Bgl II genomic fragment containing almost the entire T-cell receptor C2 constant region; this fragment has greater than 90% homology with the T-cell receptor C~ constant region. 2. The JH probe, which is a 5.6 kb BamHI-HindIII fragment recognizing the entire/z heavy-chain joining region. 3. A 2.5 kb EcoRI fragment containing the entire K gene constant region (C probe). 4. A 0.8 kb BamHI-HindIII fragment recognizing the constant region of the X 1 gene (C probe). After hybridization the nylon membranes were washed, air dried, and photographed. Genomic DNA samples obtained from placental tissue and normal lymphocytes were used as controls.
Results Histopathology. Histologic examination of the skin biopsy specimens revealed a chronic inflammatoryinfiltrate in the reticular dermis, which was composed mainly of small lymphocytes and occasional histiocytes with a distinct perivascular and perieccrine distribution. The infiltrate extended into the subcutaneous fat and involved both septa and lobules. The infiltrate in the fat was predominantly lymphocytic; however, histiocytes, plasma cells, and rare neutrophils were also present. Many histiocytes contained red blood cells, lymphocytes, or karyorrhectic debris in their cytoplasm; an occasional "beanbag" cell was seen (Fig. 2). The fat showed evidence of cytolysiswith focal dissolution of cytoplasmic membranes and the presence of lipophages. Immunohistochemistry. The lymphocytes predominantly showed a T-helper cell profile (CD2, CD3, CD4, CD5, CD7:+, CD8, CD20, CD22, CD30:-, and immunoglobulin negative). Clonal antigen deletion was not observed. Occasional lymphocytes were positive for CD8, whereas rare lymphocytes were positive for B-cell markers. The histiocytes were positive for CD 14, CD 15, a-iantitrypsin, and lysozyme. Molecular genetics. Rearrangement of the t-chain surface receptor gene was detected in two of three digests.
Volume 27 Number 2, Part 2 August 1992
Histiocytic cytophagic pannieulitis
335
I
.Y ,
.
~,~.,~,,~.
......i'.;. ~~~.:"
gg
, ,,@
!~,
2r
.
Fig. 2. High-power photomicrograph of inflammatory infiltrate in panniculus. Arrows indicate histiocytes containing erythrocytes in their cytoplasm. (Hematoxylin-eosin stain; X400.)
Rearranged bands were found in the EcoRI and the BamHI digests (Fig. 3). No rearrangements were identiffed with the other three probes.
A
B
DISCUSSION H C P is a systemic disease characterized histologically by histiocytosis and cytophagocytosis in the reticuloendothelial system and skin. A recent article has summarized the clinical and histologic features of 19 cases. 3 Thirteen patients died as a result of the disease, whereas four had a more long-term course, as in our patient. Irnmunohistochemical studies of the lymphocytic infiltrates were performed in five cases with a T-cell (UCHL-1) and a B-cell (4KBS) marker on paraffin-embedded tissues. 3 As in oar case the lymphocytes were of T-cell lineage. In the present study immunophenotyping was performed on frozen sections and demonstrated a proliferation of helper T cells. Antigen deletions, as sometimes seen in T-cell lymphomas, were not identified. Genotypic studies demonstrated a clonal T-cell population. Our findings indicate that the primary abnormality in H C P may be a T-cell disorder and suggest that the histiocytic phagocytosis, which is the predominant histologic feature, may result from lymphokine production by the helper T-cell population. H C P is one of a number of disorders associated with prominent hemophagocytosis. Infection-associated systemic hemophagocytosis may be seen in
.........
.....
....
11
kb
4.2 kb
Fig. 3. Photograph of autoradiogram obtained with DNA extracted from biopsy (A) and control (B) specimens and hybridized with DNA fragment probes specific for/3 chain of T-cell surface receptor gene after digestion with restriction endonuclease EeoRI. Germline configuration is represented by bands at 4.2 and 11 kb; rearranged band is indicated by arrow. Additional rearranged band was seen in the BamHI digest (not shown). the reticuloendothelial system in a variety of viral, bacterial, myeobacterial, and parasitic infections (the pertinent literature is summarized by Alegre and Winkelman3). Although an exanthem is occa-
336
Hytiroglou et al.
sionally seen in these conditions, hemophagocytosis predominantly in the subcutis is not a feature. Malignant histiocytosis often involves the skin and subcutis, in addition to the reticuloendothelial system, and m a y show prominent phagocytosis. 6 However, the infiltrates are composed of pleomorphic cells with malignant cytologic features, in contrast to the cytologically benign infiltrates of HCP. With recent advances in immunophenotypic and genotypic techniques m a n y cases of malignant histiocytosis have been recognized as non-Hodgkin's lymphomas, which are often positive for Ki- 1 (CD30) antigen. 7, 8 Hemophagocytic syndromes may also be the sequelae of a variety of lymphoproliferative disorders, including angiocentric immunoproliferative lesions v, lo acute and chronic lymphocytic leukemia, 11,I2 lymphoblastic lymphoma, 13 Lennert's lymphoma, 14and other T-cell lymphomas of mature phenotype.9, is Malignant T-cell lymphoma primarily involving the subcutaneous tissue m a y mimic H C P both clinically and histologically. A recent study has summarized the clinical, histologic, immunophenotypic, and genotypic features of eight cases and has suggested that such lymphomas m a y represent the late stage or the malignant counterpart of HCP. s REFERENCES
l. Winkelrnann RK. Cytophagic panniculitis. G Ital Dermatol Venereo11980;115:175-7. 2. Crotty CP, Winkelmann RK. Cytophagie histiocyticpanniculitis with fever, cytopenia, liver failure, and terminal hemorrhagic diathesis. J AMACADDERMATOL1981;4:18194.
Journal of the American Academy of Dermatology 3. Alegre VA, Winkelman RK. Histiocytic cytophagiepanniculitis. J AM ACADDERMATOL1989;20:177-85. 4. SouthernEM. DetectionofspecificsequencesamongDNA fragments separated by gel electrophoresis. J Mol Biol 1975;98:503-17. 5. FeinbergAP, Vogelstein B. A technique for radiolabeling DNA restriction endonucleasefragments to high specific activity. Anal Biochem 1983;132:6-13. 6. Jaffe ES, ed. Surgical pathology of the lymph nodes and related organs. Philadelphia: WB Saunders, 1985:397-403. 7. Wilson MS, Weiss LM, Gatter KC, et al. Malignant histiocytosis: a reassessment of cases previouslyreported in 1975basedon paraffinsectionimmunophenotypingstudies. Cancer 1990;66:530-6. 8. GonzalezCL, MedeirosLJ, Braziel RM, et al. T-cell lyrephoton involving subcutaneous tissue: a clinicopathologic entity commonly associated with hemophagocytic syndrome. Am J Surg Pathol 1991;15:17-27. 9. Jaffe ES, Costa J, Fauci AS, et al. Malignant lymphoma and erythrophagocytosissimulating malignant histiocytosis. Am J Med 1983;75:741-9. 10. Aronson IK, West DP, Variakojis D, et al. Panniculitis associated with cutaneous T-cell lymphoma and cytophagocytic histiocytosis.Br J Dermatol 1985;112:87-96. 11. Karcher DS, Head DR~Mullins JD. Malignant hist~ocytosis occurring in patients with acute lymphocyticleukemia. Cancer 1978;41:1967-73. 12. Manoharan A, CatovskyD, Lampert IA, et al. Histiocytic medullary reticulosis complicating chronic lymphocytic leukaemia: malignant or reactive? Stand J Haematol 1981;26:5-13. 13. WoodruffRD, Nolting SF. Malignant histiocytosisas a sequel to lymphoblastic lymphoma. Arch Pathol Lab Meal 1981;105:336-7. 14. EconomopoulosTC, Stathakis N, Stathopoulos E, et al. "Lennert's lymphoma" terminating as malignant histiocytosis. Scand J Haematol 1979;23:427-32. 15. Ng C-S, Chan JKC, Cheng PNM, et al. Nasal T-cell lymphoma associatedwith hemophagocyticsyndrome. Cancer 1986;58:67-71.