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predetermined and arbitrary number of tissue blocks in the hope that they will be sufficient to detect microscopic lesions with a reasonable degree of probability. The first method can be time-consuming and expensive, and the second raises questions about the optimum number of blocks that should provide an adequate sample. Schnitt and Wang in Boston1 have now examined this important and curiously neglected topic. These workers reviewed material from 384 women with palpable breast lumps that were subsequently described macroscopically as unremarkable fibrofatty tissue and submitted in toto for histopathological examination. Excluded from the investigation were specimens from women having mammoplasties, and those taken for mammographic abnormalities. Other exclusions were needle biopsy specimens of any kind, and those from patients with recurrent cancer or who had received radiotherapy. Three

histopathological categories

were

investigated-infiltrating

carcinoma, carcinoma in situ, and atypical hyperplasia of ducts or lobules. (Schnitt and Wang note that the distinction between carcinoma in situ and some examples of atypical hyperplasia is debatable.) The patients, aged between 20 and 88 years (median 45), provided 3342 tissue blocks, with a range of 1 to 77 blocks per case. About 75% of specimens were completely processed in 10 tissue blocks or less, but about 39 specimens required 30 blocks or more; the median number of tissue blocks per case was 6. Features of carcinoma or atypical hyperplasia were found in specimens from 26 patients (6°8%), distributed as follows: lobular carcinoma in situ 12; atypical lobular hyperplasia 4; ductal carcinoma in situ 4; atypical ductal hyperplasia 3. The 3 remaining patients had tubular carcinoma and in-situ lobular carcinoma, in-situ and infiltrating lobular carcinoma, and a focus of carcinoma in lymphatic spaces unaccompanied by invasive or in-situ cancer anywhere else in the specimen. The proportion of blocks from these 26 patients that contained carcinoma or atypical hyperplasia ranged from 37 to 100%: 18 of the 19 carcinomas (95%) were present in more than 10% of the blocks while 6 of the 7 examples of atypical hyperplasia (86%) were identified in less than 10% of the blocks. In 25 of the 26 cases, some or all of the focal abnormalities were found in blocks containing macroscopic fibrous parenchyma, the sole exception being a focus of atypical lobular hyperplasia buried in fat. Zones of cancer or atypical hyperplasia were more likely to be detected in the larger specimens, presumably because they constituted bigger samples of the breast as a whole. Nevertheless the number of blocks required to detect a lesion initially was small (1-11 blocks per case). Schnitt and Wang calculated the likelihood of detecting cancer and atypical hyperplasia with different numbers of tissue blocks. Under these hypothetical conditions, the use of 2 blocks from each patient would have resulted in 13 (50%) of the lesions being missed and 6 blocks would have missed 6 (23%) of the lesions. By contrast, 10 blocks would have missed only 1 lesion-a single focus of in-situ lobular carcinoma. Further calculations indicated that the probability of detecting microscopic foci of cancer or atypical hyperplasia was determined primarily by the percentage of tissue blocks containing the lesions and the numbers of blocks submitted, although the Boston workers clearly show that the probability of detection falls off beyond

certain number of blocks. By comparison, the total size of the biopsy specimen was found to be relatively unimportant. This work leads to two principal conclusions. Foci of atypical hyperplasia and cancer were almost always associated with macroscopic fibrous parenchyma-ie, their distribution was not entirely random. Secondly, submission of a predetermined number of tissue blocks (irrespective of the size of the biopsy specimen) is theoretically sound. Schnitt and Wang propose that if the fibrous component of a biopsy specimen can be submitted in 10 blocks or less, all the parenchyma should be processed. For larger specimens, a maximum of 10 blocks of fibrous parenchyma should be submitted as a first step. If no carcinoma or atypical hyperplasia is identified, the likelihood of finding such changes in more blocks is small. By contrast, if lesions are encountered among the first 10 blocks, the rest of the specimen should be processed to determine their extent, to identify any other changes, and to evaluate excision margins. a

The probability of detecting cancer or atypical hyperplasia in specimens that appear to consist solely of fat has been shown to be low, but the Boston researchers adopt a cautious approach and again recommend that sections from up to 10 tissue blocks should be examined. Biopsy specimens from women with mammographically detected lesions were excluded from the Boston series but the findings are clearly relevant to this group of patients as well. The numbers of such specimens are increasing as a result of screening programmes, and the Boston results raise a question about pathologists’ precise role. Are they required simply to diagnose mammographic abnormalities or do they have a secondary screening function in detecting

occult malignancy and borderline changes in specimens from patients with benign radiological abnormalities? In the UK, the Department of Health/Royal College of

Pathologists Advisory Group has lately prepared guidelines on reporting biopsy specimens from women in screening programmes,2.3 but is not yet able to state firmly the precise number of blocks that should be taken. The usefulness and cost effectiveness of extensive sampling of specimens generated by mammographic screening must be established before a standardised procedure can be recommended.

SUPERSTRING THEORY OVER the past five years there has been widespread excitement among theoretical physicists that a key has been found to the basic principle underlying the seemingly haphazard collection of "fundamental" particles and physical forces. Superstring theory is a radically new kind of theory, in which the constituents of matter are unified with the structure of space and time at a very basic level. The experimental classification of the fundamental particles-particles such as the electron, the neutrinos, and the quarks (which are the constituents of the proton and neutron)--is based on research at the largest accelerator 2. Guidelines 3. 4. 5. 6.

for pathologists (NHS breast screening programme). London: Department of Health and Royal College of Pathologists (in press) Pathology reporting in breast cancer screening (NHS breast screening programme) London: Department of Health and Royal College of Pathologists (in press). Taubes G. Everything’s now tied to strings. Discover November, 1986: 34-56. Green MB. Superstring theory. Sci Am 1986; 254: 48-60. Green MB. Unification of forces and particles in superstring theory. Nature 1985, 314: 409-14.

PCW, Brown J, eds. interviews with eminent 1988.

7. Davies 1. Schnitt

SJ, Wang HH. Histologic sampling of grossly benign

Surg Pathol 1989;

13: 505-12

breast

biopsies. Am J

Superstrings. A theory of everything? A compilation of physicists Cambndge: Cambridge University Press,

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laboratories such as those at CERN in Geneva. By the mid-1970s, these experiments had led to the so-called "standard model", a kind of periodic table of the particles, analogous to Mendeleev’s periodic table of the elements in 19th century chemistry. Just as the understanding of atomic structure explained the properties of the chemical elements and their forces, theoretical physicists hope that a simple underlying principle can be found that will predict the existence of the numerous fundamental particles and the physical forces that occur in nature. Another, and more pressing, problem facing theoretical

physics has been the mutual inconsistency of two of its most triumphant successes this century. The framework of quantum theory is crucial in the explanation of all phenomena on atomic and sub-atomic scales, whereas Einstein’s theory of general relativity, which unifies the force of gravity with the geometry of space and time, is well tested on astronomical scales. However, attempts to unite quantum theory and general relativity have led to major theoretical difficulties. Thus the laws of physics must be substantially modified at incredibly short distancesdistances of about 10-33 cm. Recall that the size of an atom is about 10 cm, so this distance-known as the Planck distance-is less than a millionth of a millionth of a millionth of a millionth of the size of an atom. The search for such a consistent quantum theory of gravity has been an important endeavour for the past sixty years. Since 1984, there has been an explosion of enthusiasm for superstring theory, motivated by indications that this theory will not only lead to a consistent understanding of quantum gravity but also necessarily unify all the fundamental particles and the physical forces. The basic principle is that the fundamental particles (eg, the electron, the quarks, and the other particles) are extended, string-like, objects rather than the structureless point-like objects that appear in all previous quantum theories (eg, those based on Maxwell’s electromagnetism or Einstein’s gravity). The length of these strings has to be about the Planck length, precisely the size at which the conventional theories have to be substantially changed due to inconsistencies with quantum theory. Although this size is far too small ever to be directly measurable, the consequences of particles having extension are radical. Unlike point-like particles, strings can vibrate (rather like a violin string). Roughly speaking, different modes of vibration correspond to the different kinds of fundamental particles seen in experiments. The conventional laws of physics, such as Maxwell’s laws of electromagnetism and Einstein’s theory of gravity, are unified in superstring theory. In this view these familiar laws are seen to arise as approximations that are valid at distance scales very much greater than the Planck distance. The solutions of the equations of superstring theory are not yet well enough understood to make precise predictions of the spectrum of particles or their forces, but the general structure of the theory and the nature of its predictions goes well beyond any previous attempt at a unification of the laws of

physics. For example, although the structure of the equations is very restrictive, it has been understood that the particular species of particles seen in experiments would arise from certain solutions of the superstring equations. The real challenge facing this kind of theory involves an even deeper issue. In its present formulation, superstring theory describes the quantum theory of the fundamental particles as strings, rather than points, moving through an inert space and time. For general reasons, in a complete quantum theory that includes gravity along with the other

forces, this familiar notion of space-time must be altered-at around the Planck distance scale quantum theory affects the structure of space-time itself. At these incredibly small distances space-time can no longer be considered as a smooth collection of points but is continuously fluctuating in a manner that depends on the forces exerted by the particles that move through it. Our familiar notions of distances in space and the passage of time are then meaningless. Just as the theory should predict the dynamics of the particles it should also predict the dynamics of space and time. In a yet-to-be-discovered reformulation of superstring theory, the structure of space and time should be unified with the particles and forces. Such a reformulation is now the subject of intensive research. Resolution of this problem will require a generalisation of the geometric notions that underly Einstein’s theory of general relativity to a kind of "stringy" geometry. The close relation of these ideas to many interesting developments in modern mathematics has led to a most unusual scale of interaction between theoretical physicists and pure mathematicians in this area. Although superstring theory has yet to make any precise experimental predictions concerning fundamental particle physics, the structure of the theory is so different from any earlier theory that it has totally altered the approach to understanding the unification of the physical forces. Its links with other areas of physics and pure mathematics have already produced a wealth of interesting results which indicate that the excitement of the past few years will continue for some time to come.

FISH OIL REVISITED WE discussed the therapeutic potential of fish oil in an editorial last year.1 A commercially available preparation (’Maxepa’, Duncan Flockhart) is currently promoted for the reduction of plasma triglycerides in patients with severe hypertriglyceridaemia who are judged to be at special risk of ischaemic heart disease and pancreatitis and in whom diet alone has proved inadequate. In addition to effects on eicosanoids and plasma lipids, several new biochemical actions have been described, including inhibition of endothelial cell production of platelet-derived growthfactor-like proteinsuppression of plasma fibrinogen,3,4 and inhibition of cytokine synthesis (interleukin 1 and tumour necrosis factor) by macrophages.5 A well-controlled study of polyunsaturated fatty acid supplements over a four-week period in patients with essential hypertension has now shown that high doses of fish oil (50 ml/day) reduce blood pressure and thromboxane A2 production but have only a transient effect on total prostacyclin synthesis.6 In patients with atopic asthma, dietary supplementation with maxepa (18 capsules/day for 10 weeks) attenuated the late (but not the immediate) antigen-induced asthmatic response.7 1. Editorial. Fish oil. Lancet 1988; i: 1081-83. 2. Fox PL, DiCorleto PE. Fish oils inhibit endothelial cell production of platelet-derived growth factor-like protein. Scioence 1988; 241: 453-56. 3. Høstmark AT, Bjerkedal T, Kierulf P, Flaten H, Ulshagen K. Fish oil and plasma fibrinogen. Br Med J 1988; 297: 180-81. 4. Saynor R, Gillott T. Fish oil and plasma fibrinogen. Br Med J 1988; 297: 1196. 5. Endres S, Ghorbani R, Kelley VE, et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989; 320: 265-71. 6. Knapp HR, FitzGerald GA. The antihypertensive effects of fish oil N Engl J Med 1989; 320: 1037-43 7. Arm JP, Horton CE, Spur BW, Mencia-Huerta J-M, Lee TH. The effects of dietary supplementation with fish oil lipids on the airways response to inhaled allergen in bronchial asthma. Am Rev Respir Dis 1989; 139: 1395-400.