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EDITORIALS

Doppler ultrasound in obstetrics obstetrics, doppler ultrasound is unique in allowing repeated access to the circulations on both sides of the placenta and, moreover, it is the first technique to be subjected to strict scientific testing before clinical applications were mooted. By contrast, biochemical tests of the feto-placental unit, fetal heart rate monitoring, and real-time ultrasound were widely adopted into practice without such detailed In

evaluation. The first

doppler waveforms in studiously ignored by obstetricians. pregnancy vascular Although surgeons began studying such report

of

was

waveforms from vessels in the 1960s, obstetricians’ resistance prevented the flow of research until 1980, when attempts were made to measure fetal cardiac output.2°3 Despite technical difficulties, changes in waveforms were seen in complicated pregnancies. Simple indices representing the outline of the waveform showed distinct abnormalities in small babies who ultimately died or were severely ill perinatally.4 We now know that fetuses shown to be small by real-time ultrasound measurements are not at risk if umbilical artery waveforms remain normal.5 However, if end-diastolic frequencies are absent, the fetus is likely to be hypoxic and acidotic6 and, without therapy, has a high risk of deathand morbidity. Doppler waveforms from the umbilical artery are of no value in screening for small-for-gestational-age fetuses or unexplained stillbirths.88 Another

important breakthrough

came

in 1983,

when waveforms were obtained from the maternal side of the placenta.9 In pregnancy-induced hypertension, such waveforms are better prognostic indicators than existing methods of evaluation and many researchers believe that results of doppler analysis should form part, if not all, of the classification of these hypertensive disorders. Severe pre-eclampsia is associated with failure of the second wave of trophoblastic invasion of the maternal spiral arterioles," which leads to retention of about 200 cm of small arteriolar peripheral resistance vessels. These resistance vessels are sensitive to circulating or local vasoactive agents, and arteriolar

damage is followed by platelet deposition and acute arteriosclerosis. Doppler waveforms from the uteroplacental circulation seem to reflect the depth of trophoblastic invasion.12 Inadequate invasion leads to intervillous space ischaemia and spasm or occlusion of the resistance vessels on the fetal side of the placentathe tertiary stem arterioles. The doppler correlate is loss of end-diastolic frequencies in the umbilical artery. Detailed studies on the fetal circulation by use of colour flow and pulsed doppler waveforms have shown that intervillous ischaemia (the placental lesion) leads to centralisation of the fetal circulation so that blood returning from the placenta is shunted to the fetal brain, coronary arteries, and adrenals,13 a sequence of events long recognised in sheep. studies and Efficacy pathophysiological investigations into waveform changes were followed by randomised controlled trials. The results of giving doppler information to clinicians in charge of patients have now been reported in four such trials, all on high-risk populations. Trudinger and his group14 showed that knowledge of doppler waveforms from the umbilical artery identified those fetuses that would not tolerate labour, thereby reducing the need for caesarean section for fetal distress in labour. Tyrell et ap5 compared routine versus highly selective doppler waveform and biophysical assessment and found no increase in antenatal intervention and a decrease in neonatal morbidity. From their study on waveforms from both sides of the placenta, Newnham et a116 showed no effect on neonatal morbidity but their interventions reduced the amount of fetal distress in labour. These three studies all recruited patients from a general high-risk population whereas Pearce17 studied only patients with hypertension and/or a small baby. He found a significant decrease in the length of antenatal stay and a reduction in the number of perinatal deaths when the doppler waveform results were known. Results of intervention studies based on doppler waveforms are now emerging. Trudinger et all8 found that small babies with abnormal umbilical waveforms were a mean of 500 g heavier when their mothers received low-dose aspirin rather than placebo from the time of diagnosis. In another randomised placebocontrolled study, McParland et ap9 found that lowdose aspirin given to primigravidae with abnormal uteroplacental waveforms delayed the onset of hypertension and reduce its severity. Although the study was small (48 patients vs 52 controls), there were no perinatal deaths from early delivery of small babies in women treated with aspirin vs 3 in the placebo group.

What of the future? Colour flow and pulsed doppler ultrasound evaluation of the fetal response to placental lesion are now being used to monitor therapies aimed at modifying the disease process. Initial transvaginal doppler studies suggest that placental changes may be detected before 10 weeks’ gestation, which may pave the way for earlier and more effective interventions.

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1.

Fitzgerald DE, Drumm JE. Non-invasive measurement of human fetal circulation using ultrasound: a new technique. Br Med J 1977; ii:

1450-51. 2. Eik-Nes SH, Brubakk AO, Ulstein MK. Measurement of human fetal blood flow. Br Med J 1980; i: 283-84. 3. Griffin D, Cohen-Overbeek T, Campbell S. Fetal and utero-placental blood flow. Clin Obstet Gynaecol 1983; 10: 565-602. 4. Ng A, Trudinger BJ. The application of umbilical artery studies to complicated pregnancies. In: Pearce JMF, eds. Doppler ultrasound in perinatal medicine. Oxford: Oxford University Press, 1992: 143-58. 5. Burke G, Stuart B, Crowley P, Scanaill SN, Drumm JE. Is intrauterine growth retardation with normal umbilical artery blood flow a benign condition? Br Med J 1990; 300: 1044-45. 6. Nicolaides KH, Bilardo CM, Soothill PW, Campbell S. Absence of end-diastolic frequencies in the umbilical artery: a sign of fetal hypoxia and acidosis. Br Med J 1988; 297: 1026-27. 7. McParland P, Steel SA, Pearce JMF. The clinical implications of absent or reversed end-diastolic frequencies in umbilical artery flow velocity waveforms. Eur J Obstet Gynecol Repro Biol 1990 37: 15-23. 8. Dornan J, Beattie B. Umbilical artery doppler ultrasonography as a screening tool. In: Pearce JMF, ed. Doppler ultrasound in perinatal medicine. Oxford: Oxford University Press, 1992: 95-111. 9. Campbell S, Diaz-Recasens J, Griffin DR, et al. New doppler technique for assessing uteroplacental blood flow. Lancet 1983; i: 675-77. 10. Ducey J, Schulman H, Farmakides G. A classification of hypertension based on doppler velocimetry. Am J Obstet Gynecol 1987; 157: 680-85. 11. Robertson WB, Brosens I, Dixon HG. The pathological response of the vessels of the placenta to hypertensive pregnancies. J Pathol Bacteriol 1967; 93: 581-92. 12. Morrow R, Adamson L, Ritchie K, Pearce JMF. The pathophysiological basis of Doppler waveforms. In: Pearce JMF, ed. Doppler ultrasound in perinatal medicine. Oxford: Oxford University Press, 1992: 196-220. 13. Vyas S, Campbell S. Doppler studies of the cerebral and renal circulations in small-for gestational age fetuses. In: Pearce JMF, ed. Doppler ultrasound in perinatal medicine. Oxford: Oxford University Press, 1992: 268-78. 14. Trudinger BJ, Cook CM, Giles WB, Connelly A, Thompson RS. Umbilical artery flow velocity waveforms in high-risk pregnancy. Lancet 1987; i: 188-90. 15. Tyrell SN, Lilford RJ, MacDonald HN, Nelson EJ, Porter J, Gupta JK. Randomised comparison of routine versus highly selective use of Doppler ultrasound and biophysical scoring to investigate high risk pregnancies. Br J Obstet Gynaecol 1990; 97: 909-16. 16. Newnham JP, O’Dea MR-A, Reid KP, Diepeveen DA. Doppler flow velocity waveform analysis in high risk pregnancies: a randomised controlled trial. Br J Obstet Gynaecol 1991; 98: 956-63. 17. Pearce JMF. The application of uteroplacental waveforms to complicated pregnancies. In: Pearce JMF, ed. Doppler ultrasound in pennatal medicine. Oxford: Oxford University Press, 1992: 159-77. 18. Trudinger BJ, Cook CM, Thompson RS, Giles WB, Connelly A. Low dose aspirin therapy improves fetal weight in umbilical placental insufficiency. Am J Obstet Gynecol 1988; 159: 681-85. 19. McParland P, Pearce JM, Chamberlain GVP. Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension. Lancet 1990; 335: 1552-55.

Lymphoma classification—where now? Management of patients with malignant lymphoma is largely determined by interpretation of histological features and, especially for non-Hodgkin lymphomas, by an allocation of subtype and grade. Most lymphomas represent a clonal expansion of B or T lymphocytes whose normal maturation has been arrested or disregulated. The histological appearance represents, to a variable degree, infiltration of normal structures with these malignant cells, the host (immune) response to the tumour, and reactive changes that may result from secretion of cytokines. These appearances may vary within and between tumour sites and from host to host and tumour to tumour.

Pathologists commonly examine lymphoma tissue (haematoxylin and eosin, Giemsa, periodic-acid-Schiff) and with immunohistochemical techniques, for which they use antibodies directed against leucocyte-specific, lineage-specific, and activation antigens. In difficult cases, cytogenetic analysis can help (eg, by revealing the 11;14 translocation of mantle cell lymphomas or the 14;18 translocation of follicle centre cell lymphomaS2) , as can analysis of DNA for clonal rearrangement of the T-cell receptor or immunoglobulin genes. Sometimes these studies produce conflicting results. Thus, cases with morphological and immunophenotypic characteristics of a T-cell lymphoma may not show clonal T-cell receptor gene rearrangements,3 which suggests that they may be reactive rather than malignant processes. Clinical classification of the lymphomas has been debated for decades. A major advance in the classification of the non-Hodgkin lymphomas was Rappaport’s appreciation in the 1950s that the presence of a follicular growth pattern was a feature associated with a more indolent natural history, and that large lymphocytes (then incorrectly described as histiocytes) were associated with a rapidly progressive 4 course and poor outcome. Rappaport’s classification4 proved clinically more relevant than earlier attempts, and its widespread acceptance coincided with the first descriptions of long-term remission for advanced diffuse large cell (histiocytic) lymphomas by combination chemotherapy.5 During the late 1970s this classification became outdated as the biology of lymphocyte maturation became better defmed, and the B-cell and T-cell lymphomas were recognised as separate entities. Classifications such as those described by the Kiel group in Europe6or Lukes and Collins in the USA’ were devised, leading to nosological chaos with multiple classifications in use around the world. A temporary respite, for clinicians at least, was provided by the introduction of the Working Formulation sponsored by National Cancer Institute.8 This compromise categorisation was based on the clinical behaviour (updated in 19889) of over a thousand well-documented cases of non-Hodgkin lymphoma from the USA and Europe. Only routine, stained sections were used in the study, and the non-Hodgkin lymphomas were divided into low, intermediate, and high grade types. For most cases of non-Hodgkin lymphoma, especially low-grade and high-grade varieties, this classification achieved international acceptance and served clinicians well. However, the Working Formulation has now become outdated, partly because of increased recognition of the peripheral T-cell lymphomas, but also because newer diagnostic techniques have led to characterisation of many new entities within the lymphoma spectrum. Peripheral T-cell lymphomas are difficult to classify, differ widely in their clinical presentation, and behave unpredictably. 11 Attempts to grade and with routine stains