539
ischaemic stroke. Haemodilution should be avoided. Data on all other agents are inconclusive. However, the trials (and overviews) in progress show every promise of identifying effective treatments in the near future.
REFERENCES 1. Bamford JM, Sandercock PAG, Dennis MS, Burn JPS, Warlow CP. A
prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project 1981-1986. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage. J Neural Neurosurg Psychiatry 1990; 53: 16-22.
WB, Oxbury JM, Grainger KM, Greenhall RC. A blind controlled trial of dextran 40 in the treatment of ischaemic stroke. Brain
6. Matthews
1976; 99: 193-206. 7. Peto R. Why do we need systematic overviews of randomized trials? Stat Med 1987; 6: 233-40. 8. Antiplatelet Trialists’ Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320-31. 9. Asplund K. Hemodilution in acute stroke. Cerebrovasc Dis 1991; 1 (suppl 1): 129-38. 10. Ciuffetti G, Aisa G, Mercuri M, et al. Effects of ticlopidine on the neurologic outcome and the hemorheologic pattern in the postacute phase of ischemic stroke: a pilot study. Angiology 1990; 41: 505-11. 11. ISIS-2
Collaborative
Group.
Randomised
trial
of intravenous
2. TRUST
Study Group. Randomised, double-blind, placebo-controlled trial of nimodipine in acute stroke. Lancet 1990; 336: 1205-09. 3. Yusuf S, Collins RC, Peto R. Why do we need some large, simple randomised trials? Stat Med 1984; 3: 409-20. 4. Italian Acute Stroke Study Group. Haemodilution in acute stroke: results
streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349-60. 12. Editorial. Treatment for stroke? Lancet 1991; 337: 1129-30. 13. Gelmers HJ, Hennerici M. Effect of nimodipine on acute ischemic stroke: pooled results from five randomised trials. Stroke 1990; 21 (suppl IV):
of the Italian Haemodilution Trial. Lancet 1988; i: 318-21. 5. Gelmers HJ, Goner K, de Weerdt CJ, Wiezer HJ. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med 1988; 318: 203-07.
IV-81-84. 14. Anderson DC, Bottini AG, Jagiella WM, et al. A pilot study of hyperbaric oxygen in the treatment of human stroke. Stroke 1991; 22: 1137-42.
HYPOTHESIS
Immune surveillance, organophosphorus exposure, and lymphomagenesis DAVID S. NEWCOMBE
Prevalence of lymphoproliferative disorders is increased in populations with various chemical exposures,
including
organophosphorus
compounds. Lymphomas are also more common in individuals with a substantially decreased monocyte esterase activity. Organophosphorus compounds inhibit esterases associated with monocytes, natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and cytotoxic T lymphocytes, and these inhibitory effects impair immune surveillance and cytotoxic functions mediated by such cells. Lymphoma development is also associated with Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6) infections, which are regulated by cytotoxic immune responses mediated by monocytes, T cells, and NK cells. My hypothesis is that lymphomagenesis is a multistep process, and the absence or inhibition of monocyte esterase and perhaps other immune cell esterases alters esterasedependent detoxification of a factor critical for the early steps of oncogenesis. Also, such an enzyme deficit might impair the processes that regulate the dissemination and limit the total burden of pathogens such as the lymphoma-associated herpesviruses. An added risk to any viralmediated lymphoproliferation might be an
organophosphorus-induced change.
oncogenic
genetic
Lympnoma epidemiology and organophosphorus exposure Certain population groups that have or are likely to have been exposed to organophosphorus agents are at increased
risk of lymphoma.l-4 According to some studies, mortality from lymphoma in farm workers is high;1,3 such workers are exposed to various fertilisers and pest-control substances, including organophosphorus compounds. Grain mill workers also have an excess of lymphatic and haemopoietic tumours, including lymphomas.s These workers are exposed to malathion and presumably its
contaminant, O,O,S-trimethyl immunosuppressive a Furthermore, phosphorothioate.6,7 statistically significant increase in non-Hodgkin lymphoma has been recorded in blue-collar white men employed in motor vehicle and resin product manufacturing processes;2 these men may have been exposed to organophosphorus flame retardants and plasticisers from resins and resin use in moulding automobile parts.
Esterases, immune functions, and organophosphorus agents Cytotoxic T lymphocytes and natural killer (NK) cells are essential for cell-mediated immunity in man. These cell types and monocyte cytotoxic activities are responsible for the elimination of virus-infected cells and provide immune surveillance for premalignant cells. Both functions have an important role in the regulation oflymphoproliferation and lymphoma development. Serine esterases, a ubiquitous family of enzymes found in cytotoxic T cells, monocytes, and NK cells, seem to be an integral component of the cytolytic mechanisms of these cells. Since some of these serine esterases are inhibited by organophosphorus compounds, organophosphorus agents that enter a person’s bloodstream might impair critical cell-mediated ADDRESS: Department of Environmental Health Sciences, 615 North Wolfe Street, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205, USA (Prof D. S. Newcombe, MD).
540
immune functions and might place the host at an increased risk of specific diseases.8.9 In fact, molecular epidemiological studies have shown an increased frequency of the complete absence of or substantial reductions in monocyte esterase activity in the peripheral blood of patients with lymphoproliferative disorders. 10 A deficiency of this enzyme
significantly less common in healthy populations than in patients with lymphomas (0-8% vs 3-9%).10 Additionally, monocyte cytotoxicity. responses are suppressed in individuals with esterase-negative monocytesll and in monocytes whose esterase activity has been inhibited by organophosphorus compounds.8,12 Furthermore, various organophosphorus agents have been shown to inhibit monocyte esterase activity in exposed populations and in monocytes treated with such compounds in vitro.13-16 Other immune cells, such as NK and cytotoxic T cells, also have esterase-dependent killing mechanisms,9,17 and these functions are inhibited by organophosphorus agents.6,17 These studies point to an association between organophosphorus exposure, esterase deficiency, and lymphoma. is
Virus infection, lymphoma, and immune surveillance virus
is associated with both
Epstein-Barr (EBV) malignant and non-malignant lymphoid proliferations. Human herpesvirus-6 (HHV-6) has also been detected in lymphoma tissues.18 EBV was first isolated from African Burkitt’s lymphoma and subsequently shown in other types of Hodgkin’s and non-Hodgkin lymphoma. Immunosuppressed patients are also prone to clonal Blymphocyte expansions and malignant lymphomas consisting of EBV-infected cells. Immune surveillance by NK cells, cytotoxic T cells, and cytotoxic monocytes can recognise virus-altered cells and destroy them. NK-celldeficient and immunocompromised patients are especially prone to repeated viral infections, including infections with
EBV.19 NK-cell-deficient mice with the bg + /bg + mutation have an increased frequency of lymphoma, as do people with congenital immune deficiencies. 20 The cells from such patients almost always contain EBV genomes.21 Acquired immune dysfunctions also are associated with lymphoma development.22 There is a lot of experimental data to support the role of NK and LAK cells in the destruction of autologous tumours and the suppression of tumour metastases-2324 with NK-cell deficiencies, this activity seems to be lost. These studies establish the association of deficient immune surveillance systems with virus infections and the detection and subsequent lysis of transformed cells.
Chromosomal
changes, organophosphorus exposure, and lymphomagenesis
Lymphomagenesis is also closely associated with oncogenic chromosomal (genetic) changes.21 Several mechanisms may be responsible for such oncogenic changes. Without immunological constraints, virus-altered lymphoid proliferation may lead to malignant transformation by increasing the chance of oncogenic genetic changes.2’ Reactivation of a latent EBV or HHV-6 infection may cause unregulated immune-cell proliferation, which would increase the chance of oncogenic mutation. A deficiency of immunological constraints could be mediated by organophosphorus-induced esterase deficiencies. Additionally, cytogenetic effects have been recorded in
peripheral blood lymphocytes exposed in vitro to organophosphorus insecticides, and human lymphoid cell lines of B-cell origin exposed to organophosphorus compounds have an increased frequency of sister chromatid exchanges.25 Structural chromosomal abnormalities have been seen in pesticide (organophosphorus) sprayers during high spraying seasons.26 Increased chromatid breaks and aberrations stable including chromosomal-type translocations have en recorded in patients with acute organop orus intoxications ’27 28 and floriculturists (cultiv tors of ornamental flowers) have a frequency of chro osome-exchange-type aberrations four times that of nonfiexposed control subjects.29 Additionally, workers producing organophosphate insecticides have chromosomal aberrations.3O.31 Thus, virus-altered lymphoid proliferation in the presence of impaired cytotoxic responses may have the additional burden of organophosphorus-induced chromosomal aberrations in exposed populations and such chemically-induced chromosomal changes could be oncogenic. These data suggest that the excess of lymphomas in certain populations may be related to organophosphorus exposure, which impairs esterase-dependent immune surveillance systems active against virus-infected and human
transformed cells. To establish absolute causal associations and between organophosphorus exposure lymphoproliferative malignant diseases requires additional fundamental studies of the molecular basis of lymphoproliferative or other carcinogenic processes. Casecontrol studies can establish whether there is an association between specific organophosphorus exposures in patients with lymphoproliferative diseases. Prospective cohort studies of individuals (exposed and not exposed to organophosphorus) to define immune-cell esterase status, chromosomal patterns, and herpesvirus antigen expression would identify those at increased risk of lymphoproliferative disorders and could establish the frequency of the ultimate expression of tumours in such groups. Retrospective cohort studies of non-exposed and exposed individuals could define the incidence of lymphoproliferative disorders in organophosphorus-exposed subjects. Such studies should separate HIV-positive and HIV-negative individuals since non-Hodgkin lymphoma is a prominent feature of the acquired immunodeficiency syndrome.31 Either a randomised removal of subjects from organophosphorus exposure or the maintenance in a randomised exposure group of organophosphorus concentrations at or below levels that cause esterase deficiencies in immune surveillance cells could provide evidence for a decrease in lymphoproliferative malignant diseases in such nonexposed or controlled exposure groups, respectively. An Ames test can be used to compare the effect of carcinogens on esterase-deficient monocytes and/or other immune surveillance, esterase-negative cells with that in control cells with fully active esterases. In-situ hybridisation and ploymerase chain reaction methods can be used to assess the prevalence of EBV and HHV-6 nucleic acids in esterasepositive and esterase-negative patients with lymphomas.32.33 Since virus-associated malignant diseases may have a prolonged latency, as does hepatitis B virus infection and liver cancer,34 long-term epidemiological studies may have to be done. Such prolonged latent periods may be related to the increasing prevalence of lymphomas in patients over sixty-five.35The results of these studies should provide additional evidence towards the notion that immune-cell esterases serve as lymphoma susceptibility biomarkers.
.
541
REFERENCES A, Malker H, Cantor KP, Burmeister L, Wiklund K. Cancer among farmers: a review. Scand J Work Environ Health 1985; 11: 397-407. 2. Hall NE, Rosenman KD. Cancer by industry: analyses of a populationbased cancer registry with emphasis on blue-collar workers. Am J Ind Med 1991; 19: 145-59. 3. La Vecchia C, Negri E, D’Avanzo B, Franceschi S. Occupation and lymphoid neoplasms. Br J Cancer 1989; 60: 385-88. 4. Alavanja MCR, Blair A, Masters MN. Cancer mortality in the US flour industry. J Natl Cancer Inst 1990; 82: 840-48. 5. Alavanja MCR, Rush GA, Stewart P, Blair A. Proportionate mortality study of workers in the grain industry. J Natl Cancer Inst 1987; 78: 1. Blair
247-52. 6. Rogers KE, Inamura
T, Devens BH. Organophosphorus pesticide immunotoxicity: effects of O,O,S-trimethyl phosphorothioate on cellular and humoral immune response systems. Immunopharmacology 1986; 12: 193-202.
KE, Grayson MH, Ware CF. Inhibition of cytotoxic T lymphocyte and natural killer cell-mediated lysis by O,O,S-trimethyl phosphorodithioate is at an early prerecognition step. J Immunol 1988;
7. Rogers
30.
Kiraly J, Szentesi I, Ruzicska M, Czeizel A. Chromosome studies in workers producing organophosphate insecticides. Arch Environ
Contam Toxicol 1979; 8: 309-19. 31. Gaill MH, Pluda JM, Rabkin CS, et al. Projections of the incidence of non-Hodgkin’s lymphoma related to acquired immunodeficiency syndrome. J Natl Cancer Inst 1991; 83: 695-701. 32. Ambinder RF, Laube BC, Mann RB, et al. Oligonucleotides for polymerase chain reaction amplification and hybridization of EpsteinBarr virus DNA in clinical specimens. Mol Cell Probes 1990; 4: 397-407. 33. Wu T-C, Mann RB, Epstein J, et al. Abundant expression of EBR1 small nuclear RNA in nasopharyngeal carcinoma: a morphologically distinctive target for detection of Epstein-Barr virus in formalin-fixed paraffin-embedded carcinoma specimens. Am J Pathol 1991; 138: 1461-69. 34. Steiner PE. Cancer of the liver and cirrhosis in trans-Saharan Africa and the United States of America. Cancer 1960; 13: 1085-1166. 35. Reynolds T. Non-Hodgkin’s lymphoma rate climbed rapidly. J Natl Cancer Inst 1991; 83: 232-33.
140: 564-70. 8. Emmett EA, Lewis
PG, Tanaka F, et al. Industrial exposure to organophosphorus compounds. J Occup Med 1985; 27: 904-14. 9. Newcombe DS, Esa AH. Immunotoxicity of organophosphorus compounds. In: Newcombe DS, Rose NR, Blood JC, eds. Clinical immunotoxicology. New York: Raven Press, 1992: 349-63. 10. Markey GM, McCormick JA, Morris TCM, et al. Monocyte esterase deficiency in malignant neoplasia. J Clin Pathol 1990; 43: 282-86. 11. McCormick JA, Markey GM, Morris TCM, Auld PW, Alexander HD. Lactoferrin inducible monocyte cytotoxicity defective in esterase deficient monocytes. Br J Haematol 1991; 77: 287-90. 12. Oertel J, Hagner G, Kastner M, Huhn D. The relevance of alphanaphthyl acetate esterases to various monocyte functions. Br J Haematol 1985; 61: 717-26. 13. Oehmichen M, Pedal M, Besserer K, Gencic M. Inhibition of
non-specific leukocyte esterase. Absence of monocyte esterase activity due to phosphoric and thiophosphoric acid ester intoxication. Forensic Sci Int 1984; 25: 181-89. 14. Mandel JS, Berlinger NJ,
Kay N, Connett J, Reape M III. Organophosphorus exposure inhibits non-specific esterase staining in human blood monocytes. Am J Ind Med 1989; 15: 207-12. 15. Lee MJ, Waters HC, III. Inhibition of monocyte esterase activity by organophosphate insecticides. Blood 1977; 50: 947-51. 16. Talcott RE, Mallipudi NM, Umetsu N, Fukuto TR. Inactivation of esterases by impurities isolated from technical malathion. Toxicol Appl Pharmacol 1979; 49: 107-12. 17. Pastemack MS, Eisen HN. A novel serine esterase expressed by cytotoxic T lymphocytes. Nature 1985; 314: 744-45. 18. Torelli G, Marasca R, Luppi M, et al. Human herpes virus-6 in human lymphomas: identification of specific sequences in Hodgkin’s lymphoma by polymerase chain reaction. Blood 1991; 77: 2251-58. 19. Biron CA, Byron KS, Sullivan JL. Severe herpes virus infections in an adolescent without natural killer cells. N Engl J Med 1989; 320: 1731-35. 20. Biemer JJ. Malignant lymphomas associated with immunodeficiency states. Ann Clin Lab Sci 1990; 20: 175-91. 21. Ambinder RF. Human lymphotropic viruses associated with lymphoid malignancy: Epstein-Barr and HTLV-1. Hematol Oncol Clin North Am 1990; 4: 821-33. 22. Subar M, Neri A, Inghirami G, Knowles D, Della-Favera R. Frequent c-myc oncogene activation and infrequent presence of Epstein-Barr virus genome in AIDS-associated lymphoma. Blood 1988; 72: 667-71. 23. Trinchieri G. Biology of natural killer cells. Adv Immunol 1989; 47: 187-376. 24. Mule JJ, Shu S, Rosenberg SA. The antitumor efficacy of lymphokineactivated killer cells and recombinant interleukin 2 in vivo. J Immunol 1985; 135: 646-52. 25. Sobti RC, Krishan A, Pfaffenberger CD. Cytokinetic and cytogenetic effects of some agricultural chemicals on human lymphoid cells in vitro: organophosphates. Mutat Res 1982; 102: 89-102. 26. Yoder J, Watson W, Benson WW. Lymphocyte chromosome analysis of agricultural workers during extensive occupational exposure to pesticides. Mutat Res 1973; 21: 335-40. 27. van Bao T, Szabo I, Ruzicska P, Czeizel A. Chromosome aberrations in patients suffering acute organic phosphate insecticide intoxications. Hum Genet 1974; 24: 33-57. 28. Ruzicska P, Czeizel A, van Bao T, Szabo I. Human chromosome aberrations in acute organic phosphorus acid ester (pesticide) intoxication. Mutat Res 1973; 21: 187-88. 29. Dulout FN, Pastori MC, Olivero DA, et al. Sister-chromatid exchanges and chromosomal aberrations in a population exposed to pesticides. Mutat Res 1985; 143: 237-44.
BOOKSHELF Histology for Pathologists Edited
by Stephen S. Sternberg. New York:
991.$244/130.
Raven. 1991.
Pp
ISBN 0-881676217.
Practising histopathologists need to keep up to date with advances in understanding of the structure and organisation of normal tissues and organs, but it is surprisingly difficult to do so. Standard textbooks of histology, most of which are directed to the needs of undergraduates, usually fail to resolve questions with even a modest clinical connotation. These needs have been recognised, and are very largely satisfied, in this outstanding book edited by Stephen Sternberg, from the Memorial Sloan-Kettering Cancer Center in New York. 80 authors provide 48 chapters in nearly a thousand pages, organised mainly on a conventional, system-oriented basis. The scope is clearly vast, and it is difficult for any one reviewer to encompass the entire text in a uniformly informed and critical manner. The individual contributions vary in their emphasis (for example, in the space devoted to embryological development, ultrastructure, or immunohistochemical profiles), but a rigid format is unnecessary. Most chapters fulfil their brief and deal exclusively with normal structure, but some contributions have a strong clinical bias. Issues such as age-related changes, artifacts in biopsy and necropsy tissues, and "border-line normality" are extensively discussed and illustrated. Pictures are plentiful, most of them reproduced in colour of good or outstanding quality, and detailed bibliographies are provided for each chapter. It is almost obligatory for a reviewer to identify some shortcomings, and a few minor points are worth noting. Contributions on the head and neck are curiously organised, with a chapter on periodontium, minor salivary glands, and the maxillary sinus but no section on the oral cavity itself; similarly, joints do not receive their own chapter but nails do. A personal list of topics which merit more attention includes oncocytes, marrow stroma, transformation of germinal centres, and the effects of oral contraceptives on endometrial histology. A few photomicrographs are substandard, usually because of inadequate or unequal illumination, and magnifications for electronmicrographs should be included consistently. Histology for Pathologists is beautifully produced, erudite, interesting, and practical. The high price-although
ischaemic stroke. Haemodilution should be avoided. Data on all other agents are inconclusive. However, the trials (and overviews) in progress show every promise of identifying effective treatments in the near future.
REFERENCES 1. Bamford JM, Sandercock PAG, Dennis MS, Burn JPS, Warlow CP. A
prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project 1981-1986. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage. J Neural Neurosurg Psychiatry 1990; 53: 16-22.
WB, Oxbury JM, Grainger KM, Greenhall RC. A blind controlled trial of dextran 40 in the treatment of ischaemic stroke. Brain
6. Matthews
1976; 99: 193-206. 7. Peto R. Why do we need systematic overviews of randomized trials? Stat Med 1987; 6: 233-40. 8. Antiplatelet Trialists’ Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 320-31. 9. Asplund K. Hemodilution in acute stroke. Cerebrovasc Dis 1991; 1 (suppl 1): 129-38. 10. Ciuffetti G, Aisa G, Mercuri M, et al. Effects of ticlopidine on the neurologic outcome and the hemorheologic pattern in the postacute phase of ischemic stroke: a pilot study. Angiology 1990; 41: 505-11. 11. ISIS-2
Collaborative
Group.
Randomised
trial
of intravenous
2. TRUST
Study Group. Randomised, double-blind, placebo-controlled trial of nimodipine in acute stroke. Lancet 1990; 336: 1205-09. 3. Yusuf S, Collins RC, Peto R. Why do we need some large, simple randomised trials? Stat Med 1984; 3: 409-20. 4. Italian Acute Stroke Study Group. Haemodilution in acute stroke: results
streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349-60. 12. Editorial. Treatment for stroke? Lancet 1991; 337: 1129-30. 13. Gelmers HJ, Hennerici M. Effect of nimodipine on acute ischemic stroke: pooled results from five randomised trials. Stroke 1990; 21 (suppl IV):
of the Italian Haemodilution Trial. Lancet 1988; i: 318-21. 5. Gelmers HJ, Goner K, de Weerdt CJ, Wiezer HJ. A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med 1988; 318: 203-07.
IV-81-84. 14. Anderson DC, Bottini AG, Jagiella WM, et al. A pilot study of hyperbaric oxygen in the treatment of human stroke. Stroke 1991; 22: 1137-42.
HYPOTHESIS
Immune surveillance, organophosphorus exposure, and lymphomagenesis DAVID S. NEWCOMBE
Prevalence of lymphoproliferative disorders is increased in populations with various chemical exposures,
including
organophosphorus
compounds. Lymphomas are also more common in individuals with a substantially decreased monocyte esterase activity. Organophosphorus compounds inhibit esterases associated with monocytes, natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and cytotoxic T lymphocytes, and these inhibitory effects impair immune surveillance and cytotoxic functions mediated by such cells. Lymphoma development is also associated with Epstein-Barr virus (EBV) and human herpesvirus-6 (HHV-6) infections, which are regulated by cytotoxic immune responses mediated by monocytes, T cells, and NK cells. My hypothesis is that lymphomagenesis is a multistep process, and the absence or inhibition of monocyte esterase and perhaps other immune cell esterases alters esterasedependent detoxification of a factor critical for the early steps of oncogenesis. Also, such an enzyme deficit might impair the processes that regulate the dissemination and limit the total burden of pathogens such as the lymphoma-associated herpesviruses. An added risk to any viralmediated lymphoproliferation might be an
organophosphorus-induced change.
oncogenic
genetic
Lympnoma epidemiology and organophosphorus exposure Certain population groups that have or are likely to have been exposed to organophosphorus agents are at increased
risk of lymphoma.l-4 According to some studies, mortality from lymphoma in farm workers is high;1,3 such workers are exposed to various fertilisers and pest-control substances, including organophosphorus compounds. Grain mill workers also have an excess of lymphatic and haemopoietic tumours, including lymphomas.s These workers are exposed to malathion and presumably its
contaminant, O,O,S-trimethyl immunosuppressive a Furthermore, phosphorothioate.6,7 statistically significant increase in non-Hodgkin lymphoma has been recorded in blue-collar white men employed in motor vehicle and resin product manufacturing processes;2 these men may have been exposed to organophosphorus flame retardants and plasticisers from resins and resin use in moulding automobile parts.
Esterases, immune functions, and organophosphorus agents Cytotoxic T lymphocytes and natural killer (NK) cells are essential for cell-mediated immunity in man. These cell types and monocyte cytotoxic activities are responsible for the elimination of virus-infected cells and provide immune surveillance for premalignant cells. Both functions have an important role in the regulation oflymphoproliferation and lymphoma development. Serine esterases, a ubiquitous family of enzymes found in cytotoxic T cells, monocytes, and NK cells, seem to be an integral component of the cytolytic mechanisms of these cells. Since some of these serine esterases are inhibited by organophosphorus compounds, organophosphorus agents that enter a person’s bloodstream might impair critical cell-mediated ADDRESS: Department of Environmental Health Sciences, 615 North Wolfe Street, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205, USA (Prof D. S. Newcombe, MD).
540
immune functions and might place the host at an increased risk of specific diseases.8.9 In fact, molecular epidemiological studies have shown an increased frequency of the complete absence of or substantial reductions in monocyte esterase activity in the peripheral blood of patients with lymphoproliferative disorders. 10 A deficiency of this enzyme
significantly less common in healthy populations than in patients with lymphomas (0-8% vs 3-9%).10 Additionally, monocyte cytotoxicity. responses are suppressed in individuals with esterase-negative monocytesll and in monocytes whose esterase activity has been inhibited by organophosphorus compounds.8,12 Furthermore, various organophosphorus agents have been shown to inhibit monocyte esterase activity in exposed populations and in monocytes treated with such compounds in vitro.13-16 Other immune cells, such as NK and cytotoxic T cells, also have esterase-dependent killing mechanisms,9,17 and these functions are inhibited by organophosphorus agents.6,17 These studies point to an association between organophosphorus exposure, esterase deficiency, and lymphoma. is
Virus infection, lymphoma, and immune surveillance virus
is associated with both
Epstein-Barr (EBV) malignant and non-malignant lymphoid proliferations. Human herpesvirus-6 (HHV-6) has also been detected in lymphoma tissues.18 EBV was first isolated from African Burkitt’s lymphoma and subsequently shown in other types of Hodgkin’s and non-Hodgkin lymphoma. Immunosuppressed patients are also prone to clonal Blymphocyte expansions and malignant lymphomas consisting of EBV-infected cells. Immune surveillance by NK cells, cytotoxic T cells, and cytotoxic monocytes can recognise virus-altered cells and destroy them. NK-celldeficient and immunocompromised patients are especially prone to repeated viral infections, including infections with
EBV.19 NK-cell-deficient mice with the bg + /bg + mutation have an increased frequency of lymphoma, as do people with congenital immune deficiencies. 20 The cells from such patients almost always contain EBV genomes.21 Acquired immune dysfunctions also are associated with lymphoma development.22 There is a lot of experimental data to support the role of NK and LAK cells in the destruction of autologous tumours and the suppression of tumour metastases-2324 with NK-cell deficiencies, this activity seems to be lost. These studies establish the association of deficient immune surveillance systems with virus infections and the detection and subsequent lysis of transformed cells.
Chromosomal
changes, organophosphorus exposure, and lymphomagenesis
Lymphomagenesis is also closely associated with oncogenic chromosomal (genetic) changes.21 Several mechanisms may be responsible for such oncogenic changes. Without immunological constraints, virus-altered lymphoid proliferation may lead to malignant transformation by increasing the chance of oncogenic genetic changes.2’ Reactivation of a latent EBV or HHV-6 infection may cause unregulated immune-cell proliferation, which would increase the chance of oncogenic mutation. A deficiency of immunological constraints could be mediated by organophosphorus-induced esterase deficiencies. Additionally, cytogenetic effects have been recorded in
peripheral blood lymphocytes exposed in vitro to organophosphorus insecticides, and human lymphoid cell lines of B-cell origin exposed to organophosphorus compounds have an increased frequency of sister chromatid exchanges.25 Structural chromosomal abnormalities have been seen in pesticide (organophosphorus) sprayers during high spraying seasons.26 Increased chromatid breaks and aberrations stable including chromosomal-type translocations have en recorded in patients with acute organop orus intoxications ’27 28 and floriculturists (cultiv tors of ornamental flowers) have a frequency of chro osome-exchange-type aberrations four times that of nonfiexposed control subjects.29 Additionally, workers producing organophosphate insecticides have chromosomal aberrations.3O.31 Thus, virus-altered lymphoid proliferation in the presence of impaired cytotoxic responses may have the additional burden of organophosphorus-induced chromosomal aberrations in exposed populations and such chemically-induced chromosomal changes could be oncogenic. These data suggest that the excess of lymphomas in certain populations may be related to organophosphorus exposure, which impairs esterase-dependent immune surveillance systems active against virus-infected and human
transformed cells. To establish absolute causal associations and between organophosphorus exposure lymphoproliferative malignant diseases requires additional fundamental studies of the molecular basis of lymphoproliferative or other carcinogenic processes. Casecontrol studies can establish whether there is an association between specific organophosphorus exposures in patients with lymphoproliferative diseases. Prospective cohort studies of individuals (exposed and not exposed to organophosphorus) to define immune-cell esterase status, chromosomal patterns, and herpesvirus antigen expression would identify those at increased risk of lymphoproliferative disorders and could establish the frequency of the ultimate expression of tumours in such groups. Retrospective cohort studies of non-exposed and exposed individuals could define the incidence of lymphoproliferative disorders in organophosphorus-exposed subjects. Such studies should separate HIV-positive and HIV-negative individuals since non-Hodgkin lymphoma is a prominent feature of the acquired immunodeficiency syndrome.31 Either a randomised removal of subjects from organophosphorus exposure or the maintenance in a randomised exposure group of organophosphorus concentrations at or below levels that cause esterase deficiencies in immune surveillance cells could provide evidence for a decrease in lymphoproliferative malignant diseases in such nonexposed or controlled exposure groups, respectively. An Ames test can be used to compare the effect of carcinogens on esterase-deficient monocytes and/or other immune surveillance, esterase-negative cells with that in control cells with fully active esterases. In-situ hybridisation and ploymerase chain reaction methods can be used to assess the prevalence of EBV and HHV-6 nucleic acids in esterasepositive and esterase-negative patients with lymphomas.32.33 Since virus-associated malignant diseases may have a prolonged latency, as does hepatitis B virus infection and liver cancer,34 long-term epidemiological studies may have to be done. Such prolonged latent periods may be related to the increasing prevalence of lymphomas in patients over sixty-five.35The results of these studies should provide additional evidence towards the notion that immune-cell esterases serve as lymphoma susceptibility biomarkers.
.
541
REFERENCES A, Malker H, Cantor KP, Burmeister L, Wiklund K. Cancer among farmers: a review. Scand J Work Environ Health 1985; 11: 397-407. 2. Hall NE, Rosenman KD. Cancer by industry: analyses of a populationbased cancer registry with emphasis on blue-collar workers. Am J Ind Med 1991; 19: 145-59. 3. La Vecchia C, Negri E, D’Avanzo B, Franceschi S. Occupation and lymphoid neoplasms. Br J Cancer 1989; 60: 385-88. 4. Alavanja MCR, Blair A, Masters MN. Cancer mortality in the US flour industry. J Natl Cancer Inst 1990; 82: 840-48. 5. Alavanja MCR, Rush GA, Stewart P, Blair A. Proportionate mortality study of workers in the grain industry. J Natl Cancer Inst 1987; 78: 1. Blair
247-52. 6. Rogers KE, Inamura
T, Devens BH. Organophosphorus pesticide immunotoxicity: effects of O,O,S-trimethyl phosphorothioate on cellular and humoral immune response systems. Immunopharmacology 1986; 12: 193-202.
KE, Grayson MH, Ware CF. Inhibition of cytotoxic T lymphocyte and natural killer cell-mediated lysis by O,O,S-trimethyl phosphorodithioate is at an early prerecognition step. J Immunol 1988;
7. Rogers
30.
Kiraly J, Szentesi I, Ruzicska M, Czeizel A. Chromosome studies in workers producing organophosphate insecticides. Arch Environ
Contam Toxicol 1979; 8: 309-19. 31. Gaill MH, Pluda JM, Rabkin CS, et al. Projections of the incidence of non-Hodgkin’s lymphoma related to acquired immunodeficiency syndrome. J Natl Cancer Inst 1991; 83: 695-701. 32. Ambinder RF, Laube BC, Mann RB, et al. Oligonucleotides for polymerase chain reaction amplification and hybridization of EpsteinBarr virus DNA in clinical specimens. Mol Cell Probes 1990; 4: 397-407. 33. Wu T-C, Mann RB, Epstein J, et al. Abundant expression of EBR1 small nuclear RNA in nasopharyngeal carcinoma: a morphologically distinctive target for detection of Epstein-Barr virus in formalin-fixed paraffin-embedded carcinoma specimens. Am J Pathol 1991; 138: 1461-69. 34. Steiner PE. Cancer of the liver and cirrhosis in trans-Saharan Africa and the United States of America. Cancer 1960; 13: 1085-1166. 35. Reynolds T. Non-Hodgkin’s lymphoma rate climbed rapidly. J Natl Cancer Inst 1991; 83: 232-33.
140: 564-70. 8. Emmett EA, Lewis
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BOOKSHELF Histology for Pathologists Edited
by Stephen S. Sternberg. New York:
991.$244/130.
Raven. 1991.
Pp
ISBN 0-881676217.
Practising histopathologists need to keep up to date with advances in understanding of the structure and organisation of normal tissues and organs, but it is surprisingly difficult to do so. Standard textbooks of histology, most of which are directed to the needs of undergraduates, usually fail to resolve questions with even a modest clinical connotation. These needs have been recognised, and are very largely satisfied, in this outstanding book edited by Stephen Sternberg, from the Memorial Sloan-Kettering Cancer Center in New York. 80 authors provide 48 chapters in nearly a thousand pages, organised mainly on a conventional, system-oriented basis. The scope is clearly vast, and it is difficult for any one reviewer to encompass the entire text in a uniformly informed and critical manner. The individual contributions vary in their emphasis (for example, in the space devoted to embryological development, ultrastructure, or immunohistochemical profiles), but a rigid format is unnecessary. Most chapters fulfil their brief and deal exclusively with normal structure, but some contributions have a strong clinical bias. Issues such as age-related changes, artifacts in biopsy and necropsy tissues, and "border-line normality" are extensively discussed and illustrated. Pictures are plentiful, most of them reproduced in colour of good or outstanding quality, and detailed bibliographies are provided for each chapter. It is almost obligatory for a reviewer to identify some shortcomings, and a few minor points are worth noting. Contributions on the head and neck are curiously organised, with a chapter on periodontium, minor salivary glands, and the maxillary sinus but no section on the oral cavity itself; similarly, joints do not receive their own chapter but nails do. A personal list of topics which merit more attention includes oncocytes, marrow stroma, transformation of germinal centres, and the effects of oral contraceptives on endometrial histology. A few photomicrographs are substandard, usually because of inadequate or unequal illumination, and magnifications for electronmicrographs should be included consistently. Histology for Pathologists is beautifully produced, erudite, interesting, and practical. The high price-although
