Reactive hemophagocytic syndrome: A study of 7 fatal cases

Pathology (1987), 19, pp. 43-50

REACTIVE HEMOPHAGOCYTIC SYNDROME: A STUDY OF 7 FATAL CASES JOHNK. C. CHAN,*C. S. N G , C. ~ K. LAW,§W.F. NG* AND K. F. WONG* *Institute of Pathology, and $Institute of Radiology and Oncology, Queen Elizabeth Hospital; IDepartment of Morbid Anatomy, Prince of Wales Hospital, Hong Kong

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Summary Reactive hemophagocytic syndrome is a clinico-pathologicentity characterized by systemic proliferation of non-neoplastic histiocytes showing phagocytosis of hemopoietic cells, resulting in blood cytopenia. It is best known to be associated with virus infection, but other associated diseases have also been implicated. The clinical and pathological findings of 7 fatal cases are described. The syndrome affected both sexes of a wide age range, and all patients had fever. Significant laboratory findings were blood cytopenia, abrupt drop in the blood cell counts, deranged liver function tests and abnormal coagulation profile. The associated diseases were diverse: two patients had bacterial infection; two had peripheral T-cell lymphoma; one had disseminated undifferentiated carcinoma of the ovary; one had both tuberculosis and disseminated nasopharyngeal carcinoma, and one had no obvious underlying disease. It is postulated that lymphokines secreted by lymphoid cells or tumor cells may be responsible for the systemic activation of histiocytes. The differential diagnosis from malignant histiocytosis is discussed. Key words: Reactive hemophagocytic syndrome, hemophagocytosis,

malignant histiocytosis, histiocytic medullary reticulosis. Accepted July 4, 1986

INTRODUCTION Histiocytic medullary reticulosis (HMR), first described by Scott and Robb-Smith in 1939,’ is a clinicopathologic entity characterized by acute onset of fever, wasting, generalized lymphadenopathy and hepatosplenomegaly , and in the final stages jaundice, purpura and profound pancytopenia. There is systemic proliferation of histiocytes actively engaged in phagocytosis of erythrocytes. Rappaport in 1966’ coined the term “malignant histiocytosis” (MH) for the neoplastic disease characterized by a systemic, progressive and invasive proliferation of morphologically atypical histiocytes and of their precursors. Though HMR and MH are generally considered to be ~ y n o n y m o u s ,the ~ ’ ~latter is a broader collective term to embrace a whole range of conditions involving abnormal histiocytes, while the former is the name proposed for a clinicopathological entity with a characteristic natural history and histopathology.s,6 However, some cases reported in the literature under the designation “HMR” or “MH” were not truly neoplastic disorders but represented reactive proliferation of histiocytes associated with e r y t h r o p h a g o c y t o s i ~ The .~~~ article on “virus associated hemophagocytic syndrome”

(VAHS) by Risdall et al.,9 which appeared in 1979, was a milestone paper emphasizing that reactive histiocytic proliferation might clinically and morphologically mimic malignant histiocytosis, though there had been prior reports of isolated cases in the This syndrome occurs particularly in immunosuppressed subjects such as patients with acute lymphoblastic leukemia after chemotherapygs1’ or renal transplant recipients.’ However, this syndrome may also develop in association with diseases other than viral infection. We report on the findings of seven patients dying with hemophagocytic syndrome associated with a variety of diseases, to emphasize the broad clinical spectrum of this entity and the histological changes in the reticuloendothelial system. MATERIALS AND METHODS Eight patients dying with reactive hemophagocytic syndrome (RHS) and with postmortem materials available were collected from the Institute of Pathology, Queen Elizabeth Hospital, and Department of Morbid Anatomy, Prince of Wales Hospital, Hong Kong, over the period January 1984 to October 1985. One case has been previously r ep~ r t e d, ’ ~ and the other seven cases constitute the subject of the present report. The clinical and autopsy records were reviewed. The antemortem blood smears, marrow aspirate and other biopsies if performed, and the postmortem materials were available for study. The aspirate smears were stained with the Romanowsky method. The biopsies and postmortem tissues were processed in the usual way for paraffin embedding. Four micron sections were cut and stained with haematoxylin-eosin (H & E). For the 2 cases of malignant lymphoma, cryostat sections were studied for acid phosphatase, non-specific esterase and immunological markers.13 The following monoclonal antibodies were used: from Coulter Immunology - T11 (pan-T), T8 (Tsuppressor/cytotoxic), T6 (thymocyte), T4 (T-helper), T3 (mature thymocyte and peripheral T-lymphocyte), B1 (pan-B), B4 (pan-B), I2 (HLA-DR), M 0 1 (monocyte/granulocyte/null cell), M 0 2 (monocyte/macrophage); from Becton-Dickinson - Leu3a (T-helper), Leu2a (T-cytotoxic/suppressor), Leu4 (mature thymocyte and peripheral T-lymphocyte), Leu5 (pan-T), LeuM1 (monocyte/granulocyte); and from Dakopatt - Pan-B (pan-B). Immunostaining for lysozyme and alpha-I-antitrypsin was performed on paraffin sections, the antisera (Dakopatt) being used at a dilution of 1:lOO.

RESULTS Clinical features The clinical features are summarized in Table 1. Swinging fever was a prominent feature, and the temperature peaked above 40°C in 5 patients. The liver and spleen were palpable in 6 and 3 patients respectively. The

Case

Associated diseases

Pneumococcal pneumonia and septicemia

Tuberculosis; disseminated nasopharyngeal carcinoma

Peripheral T-cell lymphoma

Nil

Peripheral T-cell lymphoma and pelvic abscess

Typhoid fever

Disseminated undifferentiatec carcinoma of ovary

Sex/Age

MI38

F/69

M/73

M/t3

M/49

M/11

F/23

TABLE1 Clinical features and postmortem findings

~

~

Alcoholic. Fever and confusion for 2 days. Found to have pneumonia and septicemia. Rapid deterioration and died. Nasopharyngeal carcinoma, presenting with cervical lymph node enlargement, on radiotherapy. Developed fever, delirium and later coma. (History of craniotomy for traumatic subdural hematoma 4 months before.) General malaise and cough. Found to have fever, hepatosplenomegaly, ascites and pancytopenia. Rapid deterioration. No chemotherapy given. Swinging fever and hepatosplenomegaly with no response to antibiotics. Died from bleeding gastric ulcer and post-liver biopsy hemoperitoneum (despite prior clotting facto and platelet replacement). Recurrent rectal bleeding and fever. Bilateral pleural effusion, hepatomegaly and right lower quadrant mass. At laparotomy, resection of perforated ileum performed. Complicated by pelvic abscess. No chemotherapy given. Fever, diarrhoea and abdominal pain for 4 days. Delirium, severe abdominal guarding. Died despite administration of antibiotics. Lower abdominal mass. Laparotomy showed disseminated ovarian tumor. Persistent fever after operation. Also hepatomegaly. Abrupt drop in blood cell counts terminally. No chemotherapy given.

~

Presentation and clinical course

3 weeks

1 week

6 weeks

6 weeks

1 week

5 weeks

3 days

Duration of fever before death

Enlarged Peyer’s patches, 2 mm to 4 cm in longest diameter, involving ileum and colon. Generalized enlargement of lymph nodes. Enlarged liver (1210 grams) and spleen (290 grams). Disseminated undifferentiated carcinoma (tumor cells cytokeratinpositive) involving ovaries, myometrium, pelvic and para-aortic lymph nodes, omentum, liver and lung.

No autopsy. Ileum showed full-thickness involvement by lymphoma, with ulceration and perforation; no evidence of coeliac disease. Postmortem marrow biopsy showed reactive hemophagocytic cells, and liver biopsy did not show lymphoma infiltration.

Enlarged liver (2360 grams), spleen (1285 grams) and visceral lymph nodes. Histology showed reactive hemophagocytosis and extramedullary hematopoiesis. Gastrointestinal bleeding from gastric ulcer, and hemoperitoneum. No evidence of infection or malignancy.

Enlarged liver (1890 grams), spleen (1060 grams) and abdominal lymph nodes, all showing involvement by lymphoma.

Right upper lobar pneumonia and bilateral pulmonary edema. Bilateral adrenal hemorrhage. Enlarged fatty liver 2300 grams. Spleen 170 grams. Enlarged pulmonary hilar lymph nodes. Undifferentiated carcinoma involving nasopharynx, liver (1 300 grams), lungs, vertebral bones. Tuberculosis involving cervical lymph nodes and lungs. Midbrain infarction. Cortical atrophy beneath site of previous subdural hematoma.

~

Relevant postmortem findings

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LI

W

I-

v

-4

m

W

h e

E Y oa

P

P

REACTIVE HEMOPHAGOCYTIC SYNDROME

45

TABLE2 Results of laboratory investigations Nadir blood counts

6 7

7.8 9.6 9.4 7.9

WBC

Pit

1.79 12.1 2.88 6.52 3.37 3.21 24.9

62 70 21 39 29 45 70

14 92

SCOT

ALP

2350 75 144 71

51 449 457 586 45 97 212

-

125 41

16/22 21/20 25/27 35/20

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Abbreviations: H b = Hemoglobin g/dl; WBC =White cell count x lo9& TON=Percentage neutrophils; % L =Percentage lymphocytes; Plt = Platelet count x 109/l; BCR = British corrected ratio for prothrombin time; APTT = Activated partial thromboplastin time (Control 30 seconds); SCOT = Aspartate transaminase W/I; SGPT = Alanine transaminase ILJ/l; GGTP =Gamma glutamyl transpeptidase IUA; ALP =Alkaline phosphatase I U A ; Bil = Bilirubin mmol/l; A/G = Albumin/Globulin g/l.

associated diseases were diverse. However, there was no apparent underlying disease in Case 4; blood cultures were negative, and the antibody titres to the various viruses (cytomegalovirus, Epstein-Barr virus, rubella, herpes simplex, enterovirus, mumps), Chlamydia, Toxoplasma and Coxiella were not raised.

The blood counts showed thrombocytopenia with or without anemia or leucopenia (Table 2). In Case 2, hemoglobin level dropped from 10.7 g/dl to 7.0 g/dl over 4 weeks and further to 5.0 g/dl over another week; there was no source of blood loss. In Case 7, the hemoglobin level fell from 9.6 g/dl to 7.9 g/dl and platelet count from

Fig. 1 (A-F) Composite figure showing the varied morphology of the histiocytes as seen in the marrow aspirate smear of Case 4. Note that the nuclei vary little in size but the amount of cytoplasm varies greatly from cell to cell. Phagocytes of red cells is seen in A, C, D, white cell in E, and platelets in B, F. (Romanowsky x 1500).

46

Pathology (1987), 19, January

CHAN el a/.

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Fig. 2 (A-B) Lymphoma cells in marrow smear of Case 3 photographed at the same magnification as in Fig. 1, for comparison. Note the large nuclei and prominent nucleoli. (Romanowsky x 1500).

188 x 109/1 to 70 x 109/1 over 2 days. The prothrombin time and activated partial thromboplastin time were prolonged. The liver function tests showed elevation of the various enzymes.

Pathological features The antemortem biopsies and significant postmortem findings pertaining to those of the reticuloendothelial system of the 7 cases are presented.

Bone marrow. Antemortem marrow aspirate smears were available in 3 cases. The hypercellular marrow showed active hemopoiesis. Histiocytes were scattered individually among the hemopoietic cells, usually accounting for 5-10070 of the nucleated elements. They were most striking on medium-magnification examination, by reason of their abundant pale grey-blue cytoplasm, which was in striking contrast to the surrounding cells. The cytoplasmic borders were fluffy or drawn into long processes. Some showed vacuolation and many showed phagocytosis of red cells, normoblasts, white cells, platelets, nuclear debris or partially digested materials (Fig. 1). The eccentric nuclei were oval to indented, with moderately condensed chromatin and indistinct nucleoli. Though there was marked variation in the size of the histiocytes, the nuclei were fairly constant in size, approximately the size of the band form (Fig. 1B). In Case 3, there were in addition isolated large cells with nuclear diameter measuring over 20 pm and multiple large nucleoli. The cytoplasm was basophilic and vacuolated (Fig. 2). These cells were initially interpreted as malignant histiocytes, and a diagnosis of MH rendered. The patient was subsequently found to have T-cell lymphoma at autopsy, and these cells therefore represented lymphoma cells. The histiocytes were not as easy to identify in the bone marrow sections because of lack of the color contrast of the cytoplasm* a search SXttered PhagocYtic histiocytes among the hemopoietic cells.

Lymph nodes. The lymph nodes appeared pale on low power examination due to lymphocytic depletion, with few small residual lymphoid follicles. Histiocytes, isolated or in small aggregates, were increased in the sinusoids and paracortex, particularly the case of typhoid fever (Fig. 3). The histiocytes had oval, indented to elongated nuclei with evenly distributed fine chromatin; nucleoli were

Fig. 3 Case 2. The sinusoids of the lymph node are filled with histiocytes. (H & E x 300). The histiocytes show prominent erythrophagocytosis. (Inset x 600).

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REACTIVE HEMOPHAGOCYTIC SYNDROME

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Fig. 4 Case 3 . The lymph node is infiltrated by large pleomorphic lymphoma cells and reactive histiocytes. (H & E x 300) The reactive erythrophagocytic cells are shown in the inset. (H & E x 600).

Fig. 5 Case 3 . Several erythrophagocytic histiocytes (arrows) are seen lying in the sinusoids of the liver. (H & E x600).

absent or indistinct. The cytoplasm was abundant and palely eosinophilic in H & E sections; a proportion showed phagocytosis of red cells, white cells, lymphocytes or nuclear debris (Fig. 3 Inset). In Case 4,large numbers of normoblasts and megakaryocytes were found in the lymph nodes. In Cases 3 and 5, large atypical mononuclear cells with round, convoluted to lobulated nuclei, coarse chromatin and prominent nucleoli effaced the architecture of the involved lymph nodes (Fig. 4).There were many admixed phagocytic cells. On frozen section, the large blastic cells in both cases were shown to stain for Tll/LeuS, T4/Leu3a and 12, but not T6, T8/Leu2a, pan-B, B1 and B4. The lymphoma cells in Case 3, but not Case 5, also stained for T3/Leu4. Unlike the reactive histiocytes, they were negative for acid phosphatase, non-specific esterase, lysozyme, alpha-1-antitrypsin, M01, M 0 2 and LeuMl. There were small numbers of small lymphoid cells staining for B, T-helper and T-suppressor cell markers. The immunological profile and morphological features were consistent with those of peripheral T-cell lymphoma.

Aggregates of histiocytes (“typhoid nodules”) were present in Case 6 .

Liver. Bland-looking histiocytes, with or without phagocytosis, were increased in the sinusoids (Fig. 5 ) .

Spleen. The spleens were of normal size to massively enlarged. Histologically, there was lymphocytic depletion in the white pulp. The pulp cords were filled with red cells and phagocytic histiocytes. The spleen in Case 3 was involved by lymphoma, but that in Case 5 was not available for examination. DISCUSSION Hemophagocytic syndrome is a heterogeneous entity encompassing both neoplastic and non-neoplastic systemic proliferation of histiocytes associated with phagocytosis of hemopoietic elements (Table 3). The term “virus associated hemophagocytic syndrome” (VAHS) was coined by Risdall et al.9,’4 for a benign histiocytic proliferation distinct from malignant histiocytosis (MH), which is a neoplastic and often fatal disease. The clinical features simulated those of MH but there was also evidence of active viral infection. The histiocytes were highly phagocytic but lacked cytologic atypia. Though there was a mortality of 32%, many patients recovered

48

CHAN e/

Pathology (1987), 19, January

01.

TABLE 3 Classification of hemophagocytic syndrome Hemophagocytic syndrome

Reactive hemophagocytic syndrome (RHS)

Malignant histiocytosis/ Histiocytic medullary reticulosis

Infection-associated

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Virus

Bacteria

I I

\

\ \ \

\

\

Lymphoma

Other causes,

Idiopathic

Other cancers

/

I

I

Others, e.g. fungi, parasite

Tumor-associated

!

/

/ /

I

$7

Hodgkin’s disease

non-Hodgkin’s lymphoma

? Including familial erythrophagocytic lymphohistiocytosis

with supportive treatment. Recognition of this syndrome is therefore important, because immunosuppressive and cytotoxic drugs are contraindicated. These authors subsequently broadened the syndrome t o include bacteria-associated cases (BAHS)” and coined the term “infection-associated hemophagocytic syndrome”. However, in addition to viruses10*16-1*and b a ~ t e r i a , ’ ~ * ’fungi,” ~ - ~ ~ Leishmania,22 Hodgkin’s disease,24 malignant lymphoma’2425and carcinoma26 have also been associated from hemophagocytic syndrome. There were also a few patients with no obvious associated diseases.’ Since more than one associated disease may be found in an individual patient, and some patients have no apparent associated diseases, we prefer using the non-committal term “reactive hemophagocytic syndrome” (RHS). We define it as a reactive condition in which there is systemic proliferation of non-neoplastic histiocytes engaged in phagocytosis of hemopoietic cells, associated with otherwise unexplained blood cytopenia, and fever. Further qualifications such as “probably lymphoma-associated” may be added after the diagnostic label according to the clinical circumstances. Familial erythrophagocytic lymphohistiocytosis is probably the same entity occurring in patients with familial immunodefi~iency.~~~’-~~ The seven cases in the present report illustrate well the diverse clinical circumstances in which RHS may occur. Occurrence of the syndrome in patients with tuberculosis,’l pneumococcal infection,” typhoid fever21 and malignant l y m p h ~ r n a as , ~ found ~ in 5 of our cases, has also been previously reported. Thorough work-up to entirely exclude concomitant viral infection was not possible in all our cases except Case 4 because some died

shortly after admission to hospital and some developed the syndrome only terminally. However, even if there were co-existing viral infection, it would not have been possible to prove that the virus did play an etiological role, especially in the presence of other known associated factors. The disease occurred in both sexes with a wide age range. Fever, hepatosplenomegaly, cytopenia, impaired liver function and coagulation parameters were common findings, as has been reported in the literature.’ An unexplained abrupt drop in the blood cell counts was particularly characteristic in some patients. Unlike Risdall’s series, most of our patients were not apparently immunosuppressed before the onset of d i ~ e a s eRHS . ~ is not invariably fatal as suggested from this report; we choose to report these fatal cases because adequate histological materials are available for study. The pathogenesis of RHS is still unknown, though the blood cytopenia can probably be attributed to phagocytosis of hemopoietic cells by the activated histiocytes. It is unproven whether the histiocytes or the hemopoietic cells are at fault, though the former is the more likely explanation. In peripheral T-cell lymphoma, a lymphokine, “phagocytosis inducing factor”, harvested from supernatants of lymphoma cell cultures has been implicated to stimulate phagocytic f~nction.~’ It appears highly likely that similar lymphokines that can cause systemic activation of histiocytes may be involved as the “final common pathway” in the pathogenesis of RHS. Carcinoma or lymphoma cells may secrete the lymphokines directly, or activate lymphocytes to secrete the lymphokines. Viruses, bacteria, fungi, parasites, drugs and other antigenic stimuli probably act indirectly

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REACTIVE HEMOPHAGOCYTIC SYNDROME

49

ACKNOWLEDGEMENTS The authors thank the by activating lymphocytes to secrete the lymphokines. Histopathology Panel of the Royal College of Surgeons However, since only few individuals with the various of England for confirming the diagnosis of Case 4, and associated diseases develop RHS, genetic susceptibility Coulter Electronics (H.K.) Ltd. for kind support. and the immunological status of the host probably play an important r0le.I4 That is, the disease may be viewed Address for correspondence: J. C., Institute of Pathology, Queen Elizabeth as the result of an inappropriately or excessively mounted Hospital, Wylie Road, Kowloon, Hong Kong immunological response. The demonstration of histiocytes with phagocytosis of References hemopoietic cells in the marrow or lymph node per se 1. Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis. is not pathognomonic of RHS. We require the presence Lancet 1939; 2: 194-8. of otherwise unexplained cytopenia, preferably with 2. Rappaport H. Tumors of the hematopoietic system. Atlas of tumor fever, before accepting the diagnosis. Small numbers of pathology. Section 111, Fascicle 8. Washington DC: AFIP, 1966; hemophagocytoic histiocytes may be found in the marrow 49-63. in hemolytic anemia,j’ drug and even normal Lampert IA, Catovsky D, Bergier N. Malignant histiocytosis: a 3. individual^.^ We have also not uncommonly observed clinico-pathological study of 12 cases. Br J Hematol 1978; 40: 65-77. erythrophagocytosis in reactive abdominal and inguinal 4. Warnke RA, Kim H, Dorfman RF. Malignant histiocytosis lymph nodes. (histiocytic medullary reticulosis): clinicopathologic study of 29 RHS must be differentiated from MH, because the cases. Cancer 1975; 35: 215-30. former requires only supportive treatment while the latter 5. Byrne GE, Rappaport H. Malignant histiocytosis. Gann Monograph requires aggressive chemotherapy. Bland-looking on Cancer Research, 1973; 15: 145-62. histiocytes with low nuclear-cytoplasmic ratio and fine 6. Robb-Smith AHT, Taylor CR. Lymph node biopsy. London: Miller chromatin pattern may be found in both RHS and MH. Heyden 1981; 137-40. Atypical “malignant histiocytes” are found in addition 7. Natelson EA, Lynch EC, Hettig RA, Alfrey CP. Histiocytic only in MH - they are classically described as having medulllary reticulosis, the role of phagocytosis in pancytopenia. distinct and thick nuclear membranes, irregular nuclear Arch Intern Med 1968; 122: 223-9. chromatin and prominent n ~ c l e o l i .To ~ this however, 8. Jaffe ES. Malignant histiocytosis and true histiocytic lymphomas. should be added “with histiocytic markers demonstrable In: Jaffe ES, ed. Surgical pathology of the lymph nodes and related on these cells”. We add this last criterion because what organs. Philadelphia: WB Saunders, 1985; 381-41 1. has been described as “malignant histiocytes” or 9. Risdall RJ, McKenna RW, Nesbit ME et al. Virus-associated hemophagocyticsyndrome, a benign histiocytic proliferation distinct “prohistiocytes” are indistinguishable morphologically from malignant histiocytosis. Cancer 1979; 44: 993-1002. from immunoblasts. No doubt some cases reported as “HMR” or “MH” represented examples of malignant 10. Zinkham WH, Medearis DN, Osborn JE. Blood and bone marrow lymphoma with a reactive histiocytic ~ o m p o n e n t . ~ ~ - ~ ~findings in congenital rubella. J Pediatr 1967; 71: 512-24. This problem is well illustrated by Case 3, in which 1 1 . Chandra P, Chaudhery SA, Rosner F, Kagen M. Transient histiocytosis with striking phagocytosis of platelets, leukocytes and malignant cells seen in the marrow aspirate were erythrocytes. Arch Intern Med 1975; 135: 989-91. mistakenly considered to be histiocytic in nature in view 12. Yin JAL, Kimaran TO, Marsh GW et al. Complete recovery of of the cytoplasmic vacuolation and the associated histiocytic medullary reticulosis-likesyndrome in a child with acute proliferation of phagocytic cells. The best markers for lymphoblastic leukemia. Cancer 1983; 51: 200-2. histiocytes are still unsettled.37 The time-honoured 13. Ng CS, Chan JKC, Cheng PNM, Szeto SC. Nasal T cell lymphoma markers lysozyme and alpha-1-antitrypsin have recently associated with hemophagocytic syndrome. Cancer 1986; 58: been reported in non-histiocytic lymphomas as ell.^^.^' 67-7 1 . Perhaps a combination of lysozyme, alpha-1-antitrypsin, 14. McKenna RW, Risdall RJ, Brunning RD. Virus associated alpha-1-antichymotrypsin, acid phosphatase, non-specific hemophagocytic syndrome. Hum Pathol 1981; 12: 395-8. esterase and monoclonal antibodies such as M 0 1 , M02, 15. Risdall RJ, Brunning RD, Hernandez JI, Gordon DH. BacteriaOKM1, KiMl may be h e l p f ~ 1 . j ~ associated hemophagocytic syndrome. Cancer 1984; 54: 2968-72. Failure to demonstrate cytological atypia in the 16. Reisman RP, Greco MA. Virus associated hemophagocytic histiocytes in a biopsy specimen cannot exclude the possisyndrome due to Epstein-Barr virus. Hum Pathol 1984; 15: 290-3. bility of MH entirely, because the histiocytes in MH may 17. Mills MJ. Post-viral haemophagocytic syndrome. J R SOCMed 1982; demonstrate varying degrees of atypia in different sites.2s4 75: 555-7. Further biopsies from other sites should be performed 18. Wilson ER, Malluh A, Stagno S, Crist WM. Fatal EBV-associated if clinically indicated. Since the peripheral lymph nodes hernophagocytic syndrome. J Pediatr 1981; 98: 260-2. are not always enlarged, one may need to resort to liver 19. Manoharan A, Painter D. Histiocytic medullary reticulosis. Lancet bi0psy.j The dilemma, however, is that the biopsy 1982; 2: 881. procedure is not without risk because of the bleeding 20. Zuazu JP, Duran JW, Julia AF. Haemophagocytosis in acute tendency. brucellosis. Lancet 1979; 2: 1185-6. In conclusion, RHS is not a very rare entity. Some 21. Fernandes-Costa F, Eintracht I. Histiocytic medullary reticulosis. patients may develop the full-blown syndrome mimicking Lancet 1979; 2: 204-5. MH, while others may have a milder form of the disease 22. Matzner Y, Behar A, Beeri E et al. Systemic leishmaniasis mimicking with mainly fever and blood cytopenia. It may occur in malignant histiocytosis. Cancer 1979; 43: 398-402. association with a variety of diseases, but some cases 23. Tsan MF, Mehlman DJ, Green RS, Bell WR. Dilantin, appear to be “idiopathic”. Its recognition is important agranulocytosisand phagocytic marrow histiocytes. Ann Intern Med 1976; 84: 710-1. because chemotherapy is contraindicated.

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24. Korman LY, Smith JR, Landaw SA, Davey FR. Hodgkin’s disease: intramedullary phagocytosis with pancytopenia. Ann Intern Med 1979; 91: 60-1. 25. Jaffe ES, Costa J , Fauci AS et al. Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis. Am J Med 1983; 75: 741-9. 26. James LP, Stass SA, Peterson V, Schumacher HR. Abnormalities of bone marrow simulating histiocytic medullary reticulosis in a patient with gastric carcinoma. Am J Clin Pathol 1979; 71: 600-2. 27. Ladisch S, Poplack DG, Holman B, Blease RM. Immunodeficiency in familial erythrophagocytic lymphohistiocytosis. Lancet 1978; 1: 581-3. 28. Perry MC, Harrison EG, Burgert 0, Gilchrist GS. Familial erythrophagocyticlymphohistiocytosis,report of 2 cases and clinicopathologic review. Cancer 1976; 38: 209-18.

Pathology Downloaded from informahealthcare.com by Nyu Medical Center on 06/11/15 For personal use only.

29. Fullerton P, Ekert H, Hosking C, Tauro GP. Hemophagocytic reticulosis, a case report with investigations of immune and white cell function. Cancer 1975; 36: 441-5. 30. Simrell CR, Crabtree GR, Cossman J et al. Stimulation of phagocytosis by a T-cell lymphoma-derivedlymphokine. In: Vitetta ES, ed. B and T cell tumors. New York: Academic Press, 1982; 247 -5 2.

Pathology (1987). 19, January 31. Wilcox DRC. Hemolytic anemia and reticulosis. Br Med J 1952; 1: 1322-5.

32. Frisch B, Lewis SM, Burkhardt R, Bart1 R. Biopsy pathology of bone and bone marrow. London: Chapman and Hall, 1985; 36-7. 33. Weiss LM, Trela MJ, Cleary ML et al. Frequent immunoglobulin and T-cell receptor gene rearrangement in “histiocytic” neoplasms. Am J Pathol 1985; 121: 369-73. 34. Risdall RJ, Sibley RK, McKenna RW et al. Malignant histiocytosis, a light and electron-microscopic and histochemical study. Am J Surg Pathol 1980; 4: 439-50.

35. Economopoulos TC, Stathakis N, Stathopoulos E, Alexopoulos C. Lennert lymphoma terminating as malignant histiocytosis. Scand J Hematol 1979; 23: 427-32. 36. Isaacson PG, O’Connor NTJ, Spencer J et al. Malignant histiocytosis of the intestine: a T-cell lymphoma. Lancet 1985; 2: 688-91. 37. Isaacson PG. Histiocytic malignancy (commentary). Histopathol 1985; 9: 1007-11. 38. Stein H, Lennert K , Feller AC, Mason DY. Immunohistological analysis of human lymphoma: correlation of histological and immunological categories. Adv Cancer Res 1984; 42: 67-73.

ANGINA. 1773 I was attacked suddenly with a pain nearly about the pylorus; it was a pain peculiar to those parts, and became so violent that I tried every position to relieve myself, but could get no ease. I then took a teaspoonful of tincture of rhubarb, with thirty drops of laudanum, but still found no relief. As I was walking about the room, I cast my eyes on a looking-glass, and observed my countenance pale, my lips white, and I had the appearance of a dead man looking at himself. This alarmed me. I could feel no pulse in either arm. The pain still continuing, I began to think it very serious. I found myself at times not breathing; and being afraid of death soon taking place if I did not breathe, I produced a voluntary action of breathing, working my lungs by the power of my will. I continued in this state, three quarters of an hour, when the pain lessened, the pulse was felt, and involuntary breathing began to take place. John Hunter. Quoted by Stephen Paget in John Hunter. T. Fisher Unwin. 1897. p. 101.