of the forthcoming 10th revision of the International Classification of Diseases contains a list of reactions to severe stress and adjustment disorders. 3 Two examples provide sufficient illustration. Acute stress reaction comprises exposure to an exceptional medical or physical stress followed by the onset, within one hour, of generalised anxiety or any two of the following: social withdrawal, narrowing of attention, apparent disorientation, anger or verbal aggression, despair or hopelessness, inappropriate or purposeless overactivity, and uncontrollable and excessive grief. Treatment is supportive and non-specific and the prognosis is favourable. Post-traumatic stress disorder includes brief or prolonged exposure to an exceptional mental or physical stress followed within six months by persistent remembering or reliving of the stress; by intrusive flashbacks, vivid memories, recurring dreams; or by distress when exposed to (or avoiding) circumstances associated with the stressor. These features are accompanied by either psychogenic amnesia or persistent increased psychological sensitivity and arousal with at least two of the following: difficulty in falling or staying asleep, irritability, difficulty concentrating, distractibility or increased restlessness and apprehension. Again, treatment is supportive and non-specific, though the long term outlook is uncertain. Thus at a popular level stress is a vigorous concept that has engendered a prosperous industry dedicated to its relief, while in scientific and medical contexts the concept languishes

with dubious reliability and validity. Fifty years ago the stress hypothesis began displacing obscure focuses of infection as an antecedent of a variety of life's ills. As Susser has remarked: "Many excellent sets of teeth and many pairs of tonsils were sacrificed to that hypothesis. We can count ourselves fortunate that the stress hypothesis does not require surgical intervention. "'14 GREG WILKINSON Reader in Psychological Medicine, University of Wales College of Medicine, North Wales Hospital, Denbigh, Clwyd LL16 5SS 1 Firth-Cozens J. Emotional distress in junior house officers. BMJf 1987;295:533-6. 2 McCall TB. The impact of long working hours on resident physicians. N Engl J Med 1988;381:

775-8. 3 Cooper CL, Rout U, Faragher B. Mental health, job satisfaction, and job stress among general practitioners. BMJ 1989;298:366-70. 4 Consumers' Association. Living with stress. London: Consumers' Association, 1982. 5 Whitmore B. Living with stress and anxiety. Manchester: Manchester University Press, 1987. 6 Wilkinson G. Coping'with stress. London: Family Doctor Publications, British Medical Association, 1987. 7 Cooper CL, Cooper RD, Eaker LH. Living with stress. London: Penguin Books, 1988. 8 Weiner H. The concept of stress and its role in disease onset. In: Lolas F, Mayer H, eds. Perspectives on stress and stress-related topics. Berlin: Springer Verlag, 1987:%-107. 9 Dorian B, Garfinkel PE. Stress, immunity and illness-a review. Psychol Med 1987;17:393-407. 10 Edwards JR, Cooper CL. Research in stress, coping, and health: theoretical and methodological issues. PsycholMed 1988;18:15-20. 11 Glaser R, Kennedy S, Lafuse WP, et al. Psychological stress-induced modulation of interleukin 2 receptor gene expression and interleukin 2 production in peripheral blood leukocytes. Arch Gen

Psychiatry 1990;47:707-12. 12 World Health Organisation. Lexicon of psychiatric and mental health terms. Vol 1. Geneva: World Health Organisation, 1989: 65. 13 World Health Organisation. Extractfrom clinical descriptions and diagnostic guidelines to chapter V(F) of ICD-1O mental behavioural and developmental disorders. List of categories (April 1988 draft). Geneva: World Health Organisation, 1988. 14 Susser M. The epidemiology of life stress. PsycholMed 1981;11:1-8.

Hepatic and portal vein thrombosis Closely associated with chronic myeloproliferative disorders Until recently most cases of hepatic vein thrombosis were considered to be idiopathic-although occasional cases were linked to underlying diseases such as myeloproliferative disorders, systemic lupus erythematosus, paroxysmal nocturnal haemoglobinuria, and antithrombin III deficiency. As a result of advances in the early diagnosis of chronic myeloproliferative disorders,' recent evidence now suggests that most patients who develop hepatic vein thrombosis have an associated, occult chronic myeloproliferative disorder.2 3 The chronic myeloproliferative disorders are distinguishable clinical entities that have a common origin from a single malignant haemopoietic stem cell. These disorders have long been known to be associated with thrombosis, particularly in untreated polycythaemia vera and myelofibrosis, in which the incidence of postoperative thrombosis can rise to 75%.4 The risk is less in essential thrombocythaemia and chronic granulocytic leukaemia.56 Thromboses commonly affect the cerebral and coronary arteries, but there is also a high incidence of intra-abdominal thrombosis in the inferior vena cava or in the splenic, hepatic, portal, mesenteric, and renal vessels.' The diagnosis in polycythaemia vera is confirmed by an increased red cell mass, the presence of splenomegaly, a normal arterial oxygen saturation, and high white cell and platelet counts, leucocyte alkaline phosphatase activities, and serum concentrations of vitamin B-12. Treatment with phlebotomy and myelosuppressive drugs is effective and symptom free survival for 10-20 years common. In myelofibrosis there is leucoerythroblastosis and the bone marrow shows typical collagen-reticulin fibrosis. In some patients with myelofibrosis the disease does not progress and they may 192

survive many years, but most need chemotherapy to control splenomegaly and blood transfusions for anaemia. There are several different causes of polycythaemia, and in some cases the aetiology is initially unclear. Over a period of years, however, two fifths of patients develop recognisable polycythaemia vera.8 More recently cytogenetic analysis and in vitro haemopoietic stem cell cultures have identified clonal bone marrow characteristics and colony culture growth patterns that have made it possible to identify chronic myeloproliferative disorders at an even earlier stage."'3 In these occult cases the usual clinical or haematological features of chronic myeloproliferative disorders may develop later. Recent reports showing that up to three quarters of patients with hepatic vein thrombosis have associated occult forms of myeloproliferative disorder23 may also explain why hepatic vein thrombosis can recur after successful liver transplantation.9 Patients with thromboses associated with myeloproliferative disorders should be treated with anticoagulant drugs, initially heparin and in the longer term warfarin or low dose aspirin.'0 If thrombosis recurs-and there are no contraindications such as oesophageal varices, thrombocytopenia, or severe liver dysfunction-lifelong treatment with anticoagulants should be considered. The cause of thrombosis in chronic myeloproliferative disorders has been the subject of a longstanding debate. Infiltration of the hepatic portal tracts with extramedullary haemopoietic tissue might predispose to thrombosis in the hepatic or portal vein. In polycythaemia vera there is a prethrombotic state in which the raised packed cell volume and increased blood viscosity lead to a low grade disseminated intravascular coagulation and activated fibrinolysis.'II These BMJ

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abnormalities and the risk of thrombosis are reversed in polycythaemic patients by therapeutic phlebotomy. The liver is the main site for clearing plasminogen activator,'4 and in the absence of antiplasmin this may account for the localisation of thrombus formation in the hepatic outflow. Thrombocytosis is a common feature in myeloproliferative disorders, and platelet IgG Fc receptors may be activated in vivo by the high concentrations of circulating immune complexes found in these disorders.'5 16 The raised concentrations of plasma D thromboglobulin and'the high incidence of clinical thromboses are both reduced by prophylaxis with aspirin.'0 15 There is also a high incidence of thrombosis in systemic lupus erythematosus and an associated reduction in endothelial cell synthesis of prostacyclin'7 and vasculitis. DNA antibodies are found in about a tenth of patients with myelofibrosis,'0 and a vasculitis affecting small vessels has also been described.'9 It remains to be established, however, whether these observations are important in the aetiology of thrombosis in chronic myeloproliferative disorders. Another feature that has been seen in a few patients with myelofibrosis is the paroxysmal nocturnal haemoglobinuria syndrome.20 This is another clonal haemopoietic stem cell disorder, which is more often associated with aplastic anaemia and acute leukaemia. Patients with paroxysmal nocturnal haemoglobinuria have a high incidence of intra-abdominal thrombosis, which is probably caused by complement induced platelet activation.2 22 Paroxysmal nocturnal haemoglobinuria-like abnormalities found by the sucrose and cold antibody lysis tests20 and activation of complement23 are also common in myelofibrosis, and thrombosis in chronic myeloproliferative disorders may therefore be linked to these abnormalities. There are, therefore, several different explanations for the hepatic vein thrombosis seen in chronic myeloproliferative disorders. The development of thromboses in patients with occult disorders suggests that previously overlooked mechanisms may be important. Different mechanisms may

be at work in different patients, and each may require different treatment strategies. B J BOUGHTON Senior Lecturer in Haematology, University of Birmingham, Birmingham B15 2TT 1 Reid Cl), Chanarin I, Lewis J. Formes frustes in mveloproliferative disorders. Identification by the growth of an endogenous erythroid clone in patients with arterial vascular disease. Luncet 1982;i: 14-6. 2 Valla D, Casadevall N, Lacomb C. Primary mveloproliferative disorder and hepatic vein thrombosis. A prospective study of ervthroid colonv formation in 20 patients with Btudd Chiari syndrome. Ann Intern Med 1985;103:329-34. 3 Pagliuca A, Mufti GJ, Tahernia JMI, et al. In vitro colony culture and chromosomal studies in hepatic and portal vein thrombosis-possible evidence of an occult myeloproliferative state. QJ Med 1990;76:981-9. 4 Wasserman LR, Gilbert HS. Surgery in polycythemia vera. N Engi]f Med 1963;269:1226. 5 Kessler CM, Klein HG, Havlik RJ. Uncontrolled thrombocvtosis in chronic myeloproliferative diseases. Br] Haematol 1982;50: 157-67. 6 Mason JE, De Vita VT, Canello GP. Thrombocvtosis in chronic granulocytic leukemia. Incidence and clinical significance. Blood 1974;44:483. 7 Gilbert HS. Definition, clinical features and diagnosis of polycvthaemia vera. Clinics in Haematologo 1975;4:263-90. 8 Pearson TC, Wetherley-Mein G. The course and complications of idiopathic erythrocytosis. Clin Lab Haematol 1979;1:189-96. 9 MacDougall BR, McMaster P, Calne RY, Williams R. Survival and rehabilitation after orthotopic liver transplantation. Lancet 1980;i: 1326-8. 10 Gilbert HS, Hanna MM. Low dose aspirin/low hematocrit regime: a safe and effective treatment for polycythemia vera [Abstract]. Blood 1986;68 (suppl 1):770. 11 Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polvcythaemia. Lancet 1978;ii: 1220-2. 12 Boughton BJ, Dallinger KJ. "I fibrinogen turnover in polycythaemia; the effect of phlebotomy. Br7 Haematol 1983;53:97. 13 Bjorkman SE, Laurel CB. Serum proteins and fibrinolysis in polycythaemia vera. Scand]7 Clin Lab Invest 1956;8:304. 14 Brozovic M. Acquired disorders of coagulation. In: Bloom AL, Thomas DP, eds. Haemostasis and thrombosis. Edinburgh: Churchill Lis-ingstone, 1987:519-34. 15 Boughton BJ, Allington MJ, King A. Platelet and plasma l-thromboglobulin in myeloproliferative syndromes and secondary thrombocytosis. Br] Haematol 1978;40:125. 16 Baglin TP, Price SM, Boughton BJ. Circulating high molecular weight IgG complexes in myeloproliferative disorders. ] Clin Pathol 1990;43:102-5. 17 Carreras LO, Defryn G, Machin SJ. Arterial thrombosis, intrauterinedeathand lupusanticoagulant. Detection of immunoglobulin interfering with prostacyclin formation. Lancet 1981 ;i:244-6. 18 Rondeau E, Seligny SS, Dhermy D, et al. Immune disorders in agnogenic myeloid metaplasia: relations to myelofibrosis. Br]7 Haematol 1983;53:467-75. 19 Singh AK, Wetherley-Mein G. Microvascular occlusive lesions in thrombocvtopenia. Br J7 Haematol 1977;36:553. 20 Catovsky D, Lewis SM, Sherman D. Erythrocyte sensitivitv to in vitro lysis in leukaemia. Br3 Haematol 1971;21:451. 21 Rosse WE. Paroxysmal nocturnal haemoglobinuria. In: Clinical immunohaematology. Oxford: Blackwell Scientific, 1990:593-648. 22 Shrieber AD. Paroxysmal nocturnal hemoglobinuria revisited. N EnglJ Med 1983;109:723-5. 23 Gordon BR, Coleman Mi, Parirorkhe K, Norbibi KD. Immunologic abnormalities in myelofibrosis with activation of complement. Blood 1981;58:904-10.

Second malignant tumours in head and neck cancer Commoner than elsewhere Although advances in surgical repair, radiotherapy, and chemotherapy have improved control of cancer of the head and neck,' 2 these improvements have hardly influenced survival.395 One of the main reasons for this failure is the development of second malignant tumours, which occur more commonly in the head and neck than in any other site.68 Among patients with head and neck cancer more are alleged to die from second tumours than from their original disease.36 Despite recent interest in second tumours little is known about risk factors and in particular about the influence of treatment of the first primary tumour on development of a second. Several workers have tried to assess the influence of TNM stage, sex, site, and behavioural characteristics on the development of second malignant tumours. The risk of a second primary tumour is thought to be independent of the stage of the first79 and seems to be no greater in men than in women,'0 but whether it is influenced by the site of the primary tumour remains controversial.79 The greatest risk, however, seems to be continued use of alcohol and tobacco, though opinion varies about which is more influential. Wynder et al found tobacco but not alcohol to be associated BMJ

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with an increased risk." They also found, however, that stopping both smoking and drinking did not prevent further tumours from developing, although Moore showed a decreased incidence when smoking ceased. 12 Moore also noted a greater risk of second malignant tumours with continued smoking,'3 although Castigliano did not.'4 Others have found that smoking and drinking together seem to increase the risk of second malignant tumours.7 9 II I6 Thus, although smoking and drinking may increase the risk, stopping smoking and drinking do not seem to remove it. The increased interest in second malignant tumours has not been matched by an equally critical appraisal of the effect of treatment on the primary lesion. Most squamous carcinomas of the head and neck region are managed with surgery, radiotherapy, or a combination of both. Most studies have not clearly distinguished between the numbers of second tumours arising after surgical treatment of the primary tumour and after radiotherapy.689' 723 Those that have recorded them separately have made little or no attempt to correlate this with the extent of disease at the time of initial treatment,7 101124-28 although one study found that the risk of second malignant tumours was independent of the stage of the disease.9 193

Hepatic and portal vein-thrombosis.

of the forthcoming 10th revision of the International Classification of Diseases contains a list of reactions to severe stress and adjustment disorder...
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