- Email: [email protected]
INTRAVENOUS HYDROCHLORIC ACID
1296 WORKING CLASSIFICATION OF
NON-HODGKIN’S
LYMPHOMAS
(DORFMAN, 1974)
institutional clinicopathological investigations, are impressed by its applicability. The terminology would appear to be
self-explanatory. Department of Pathology, Stanford University School of Medicine,
Stanford, California 94305, U.S.A.
*
Composite lymphomas, comprising two well-defined and apparently different types of lymphoma within the same tissue and lymphomas associated with sclerosis, are suitably designated. "
RONALD F. DORFMAN.
LONG-ARM DELETION WITH FEATURES OF TURNER’S SYNDROME SIR,-We read with interest the letter by Mr Wright and Dr Scanlon (May 11, p. 933). The partial karyotypes of 3 pairs of G-banded X chromosomes presented appear open to a different interpretation to that given in the letter. When compared to the standard G-banding pattern,l the X chromosome on the right side of each pair, designated as a partially deleted X chromosome, is more likely a normal X chromosome placed upside down. The X chromosome on the left side of each pair appears to us to be an isochromosome of the long arm of X,i(Xq); this was interpreted as a normal chromosome by the authors. Since it is known that patients with an isochromosome of the long arm of X have classical Turner’s syndrome, the correlation with the clinical findings is not surprising.
cells in many lymphomas heretofore designated as histiocytic " or " reticulum cell". In-vitro incubation of mature ", " well differentiated lymphocytes with phytohsemagglutinin and other mitogens has shown that these cells are capable of transformation to " large lymphoid cells ". There is increasing evidence to suggest that a similar phenomenon occurs in vivo with the production of large lymphoid cells or so-called immunoblasts. Uncells in the past have erroneously been doubtedly, these " interpreted as reticulum cells ". Like those of Jaffe et al., our studies provide convincing evidence of the origin of nodular lymphomas from follicular B lymphocytes, thus substantiating the term follicular lymphoma. Our reported studies at Stanford University Medical Center 5,6 have emphasised the imperative need to identify lymphomas with a follicular pattern, by virtue of their favourable prognosis, despite their tendency for early widespread dissemination. Clinicopathological observations have further stressed the need for precise cytological identification. Proposed alternative terminology and classifications must therefore make provision for these behavioural differences in order to provide the clinician with adequate information so that appropriate therapy may be instituted. While the emergence of concepts based on a presumed functional capacity of the component cells is clearly recognised, it is questionable whether sufficient information is available to clearly subdivide the malignant lymphomas into B-cell or T-cell types. In order to reach a compromise between the concepts of Rappaport,4 which have been so usefully applied to our collaborative studies, those recently propounded by Lukes,7 and those of Farrer-Brown, Bennett, and Henry8 in England, I presented at the recent meeting of the International Academy of Pathology in San Francisco a new classification of the non-Hodgkin’s lymphomas (see accompanying table). This classification hopefully eliminates controversial terminology, introduces new designations based to some extent on the functional capacity of the component cells, and yet employs terms which will be acceptable to the pathologist in his everyday diagnostic work and to the hsmatologist and oncologist burdened with the choice of therapy for patients affected by the non-Hodgkin’s lymphomas. We are in the process of applying this terminology retrospectively to the series of cases previously reported by us 5,6 and will similarly attempt to do so in a prospective fashion. Until this terminology proves to be valid, we will continue to utilise the classification of Rappaport4 in our routine pathology reports. It will be of great interest to me to determine whether pathologists, in private practice or involved in
to draw attention to a biochemical in our letter (May 25, p. 1055) in the last sentence of the third paragraph. What we meant to write was that the osmolality of 150 ml. of 1 N hydrochloric acid made up to a litre with sterile water is 300 milliosmols per litre, not that " the osmolality of 1 N hydrochloric acid is 300 milliosmols per litre ". We apologise for this oversight. We should like to comment on the letter by Dr Whelton (May 25, p. 1055) who believes this form of therapy to be potentially dangerous. He refers to acute hxmolysis in dogs after " slow intravenous infusions of more dilute hydrochloric acid solutions (0-1 N and 0,3 N HCI) than described in the editorial " (April 20, p. 720). In actual fact the normality of the hydrochloric acid finally infused by Abouna et al.2, on whose article your editorial is based, is 0-15 N-i.e., after allowing for dilution by the vehicle. Thus the 0-3 N HCI used by Dr Whelton is in fact a more concentrated solution of HCI than that described in your editorial. In terms of a variable perhaps more relevant to hoemolysis, the osmolality of the infused solution described in the editorial is 300 milliosmols per litre, which is only slightly hyperosmolar with respect to plasma (285-295 mosmol. per litre) whilst that of the 0-3 N HCI used by Dr Whelton is at least 600 milliosmols per litre, depending on the nature of the vehicle, and is therefore distinctly hyperosmolar. There is no mention of whether a central or a peripheral venous catheter was used, or of the vehicle employed (with its own osmolality), or of the actual rate of infusion in the dogs. These aspects are of importance in seeking for a cause of the hxmolysis in the dogs. The osmotic fragility of canine erythrocytes is apparently similar to that of their human counterparts. In the patient described in our previous letter (May 25, p. 1055) haemolysis did not occur
Lukes, R. J. Monograph, International Academy of Pathology (edited by J. W. Rebuck and C. W. Berard) (in the press). 8. Berard, C. W., Dorfman, R. F. Clin. Hemat. 1974, 3, 39.
1. Paris Conference on Standardization in Human Genetics. National Foundation, New York, 1972. 2. Abouna, G. M., Veazay, P. R., Terry, D. B. Surgery, 1974, 75, 194.
"
7.
"
Division of Medical Genetics, Department of Pediatrics, Mount Sinai School of Medicine, New York, N.Y. 10029, U.S.A.
HYON J. KIM LILLIAN Y. HSU KURT HIRSCHHORN.
INTRAVENOUS HYDROCHLORIC ACID
SIR,—We hasten
error
1297
with infusion of 0-16 N HCl in 5% dextrose (598 mosmol. per litre.) via a central venous catheter. Of course there is one basic difference between Dr Whelton’s research observations and the results of therapy referred to in the editorial. The infusion of HCl in the former situation is to purposely induce an acidosis in dogs which start off with a normal pH, whilst in the editorial reference is made to HCl being infused therapeutically to restore an alkalosis in patients back to a normal pH. Increased haemolysis has been described in the presence of acidosis, but not alkalosis due to red-cell-enzyme inhibition.2,3 We would disagree with Dr Whelton concerning the safety of NH4Cl solutions in patients with gross metabolic alkalosis plus hepatic insufficiency (such as referred to in the editorial) or of NaCl solutions in patients with metabolic alkalosis plus sodium-retaining states. In both these situations we believe that HCl would be contrariwise safe. Division of Clinical Chemistry, Institute of Medical and
Veterinary Science, Adelaide, South Australia. Intensive Care Unit, Anaesthetics Department, Royal Adelaide Hospital, Adelaide, South Australia.
ROY W. PAIN.
L. WORTHLEY.
PATHOGENS IN THE URINARY TRACT SIR,—May I comment on Dr Maskell’s Occasional Survey (June 8, p. 1155) ? First, she rightly draws attention to the importance of quantitative colony-counts in determining if organisms cultured after catheterisation or suprapubic aspiration (S.P.A.) are contaminants. But of the three references cited for S.P.A., one 4 mentions colony-counts and S.P.A. but does not mention the use of one with the other. A second 5 mentions the use of colonycounts on urine obtained from S.P.A. but gives no results. Indeed these authors state later that " because the urine was obtained by S.P.A. colony-counts are unnecessary". The possibility of contamination of urine cultures obtained by S.P.A. with common skin commensals, such as coagulasenegative staphylococci, remains very real. Second, in ideal conditions when so-called midstream urines (M.S.U.) are obtained from women, cultures yielding a pure growth of more than 100,000 organisms per ml. will give about 5% false-positive results. In her survey, the specimens were obtained in the less than ideal conditions of domiciliary practice and she chose to select as " positive " or " showing definite infection " those specimens which gave pure growths of greater than 10,000 organisms per ml. The two factors together will undoubtedly increase the proportion of false positives to an extent that cannot be quantified, but must, I submit, seriously detract from the validity of her conclusions. Third, most of the 10,065 M.s.u. specimens will have come from women who might have been menstruating. With the average menstrual cycle there is a 1-in-5 (20%) chance that microscopic hasmaturia (which she does not define) will occur by simple contamination without any red cells being derived from the urinary tract. Unless it is possible to exclude all specimens obtained from women during or for 2-3 days after menstruation, it is not justifiable to conclude that microscopic hasmaturia and " gross " pyuria indicate acute inflammation of the urinary tract. North Ormesby Hospital, North Ormesby,
Middlesbrough, Teesside TS3 6HJ. 2. 3. 4.
** * This letter
was
shown
to
Dr
Maskell, whose reply
follows.—ED. L.
SIR,—In considering the significance of organisms cultured after catheterisation, my purpose was to point out that the method of inoculation of catheter specimens into liquid media and subsequent culture gave misleading results. So far as I know this method is never used now. My own experience of suprapubic aspiration specimens, which have been principally from babies and young children, is that contamination with skin commensals is extremely rare; having cultured several hundred of such specimens I cannot remember ever seeing it. I agree with Dove et al. that colony-counts are unnecessary in suprapubic aspiration specimens; the possibility of contamination will be revealed by a mixed growth provided that a suitable culture medium which grows commensals is used. The usual numerical criteria of significance should not be applied because, especially in adults, a diuresis must be induced in order to make suprapubic aspiration technically possible, and the count of organisms may thereby be considerably reduced. I think Mr Hole’s second point is answered by the figures given in my table 11. We are fortunate in this laboratory to serve an area in which the general practitioners are interested in urinary infection, and very conscientious about ensuring that midstream urines are carefully collected. We are also able to provide good specimen collection and refrigeration facilities. Since only 25% of the total number of specimens were classified as positive, and since nearly 60% were sterile on culture, I do not think that the false-positive rate is very high. Lastly, although I agree with Mr Hole that M.S.U. specimens from women who are menstruating may be contaminated with red and white cells, the culture will invariably show a mixed growth of contaminant and commensal organisms provided that a medium such as CLED is used. These specimens will all have been placed in the " doubtful " category and therefore not included in the figures for comparison of pyuria and hsematuria. Public Health Laboratory, St. Mary’s General Hospital, East Wing, Milton Road, R. M. MASKELL. Portsmouth P03 6AQ. MACROCYTOSIS OF CHRONIC ALCOHOLISM SIR,—Dr Wu and his colleagues (May 4, p. 829) report the direct effect of alcohol in producing macrocytosis unrelated to low folate or megaloblastic hsemopoiesis. A third of their cases, however, showed megaloblastic change associated with low folate. The reasons for low folate in alcoholics are not entirely clear, but they could be due to dietary insufficiency, an effect of alcohol on folate absorption, a direct anti-folate effect of alcohol, enhanced utilisation of folate as a co-factor in liver-enzyme activity or a combination of these reasons. Alcohol is a known inducer of liver enzymes1 and has a direct folate-lowering effect.2 A similar acute effect is seen with phenytoin and has been thought to be due to liverenzyme induction.3 In treated epileptics, low folate has been shown to correlate with hepatic microsomal enzyme induction as assessed by the urinary excretion of D-glucaric acid4 which acts as a marker of such enhancement. It would have been of interest to know whether there was any such correlation in the group of patients with low folate.
ROGER HOLE.
Murphy, J. R., J. Lab. clin. Med. 1967, 69, 758. Nathan, D. G., Segel, G. B. Postgrad. Med. 1971, 47, 179. Bailey, R. R., Roberts, A. P., Gower, P. E., de Wardener, H. E. Lancet, 1971, ii, 1112. 5. Dove, G. A., Bailey, A. J., Gower, P. E., Roberts, A. P., de Wardener, H. E. ibid. 1972, ii, 1281.
General Hospital, Steelhouse Lane,
Birmingham, B4 6NH.
J. SCOTT.
1. Lieber, C. S., De Carli, L. M. Science, N. Y. 1968, 162, 919. 2. Eichner, E. R., Hillman, R. S. J. clin. Invest. 1973, 53, 584. 3. Richens, A., Waters, A. H. Br. J. Pharmac. 1971, 41, 414. 4. Maxwell, J. D., Hunter, J., Stewart, D. A., Ardeman, S., Williams, R. Br. med. J. 1972, i, 297.
NON-HODGKIN’S
LYMPHOMAS
(DORFMAN, 1974)
institutional clinicopathological investigations, are impressed by its applicability. The terminology would appear to be
self-explanatory. Department of Pathology, Stanford University School of Medicine,
Stanford, California 94305, U.S.A.
*
Composite lymphomas, comprising two well-defined and apparently different types of lymphoma within the same tissue and lymphomas associated with sclerosis, are suitably designated. "
RONALD F. DORFMAN.
LONG-ARM DELETION WITH FEATURES OF TURNER’S SYNDROME SIR,-We read with interest the letter by Mr Wright and Dr Scanlon (May 11, p. 933). The partial karyotypes of 3 pairs of G-banded X chromosomes presented appear open to a different interpretation to that given in the letter. When compared to the standard G-banding pattern,l the X chromosome on the right side of each pair, designated as a partially deleted X chromosome, is more likely a normal X chromosome placed upside down. The X chromosome on the left side of each pair appears to us to be an isochromosome of the long arm of X,i(Xq); this was interpreted as a normal chromosome by the authors. Since it is known that patients with an isochromosome of the long arm of X have classical Turner’s syndrome, the correlation with the clinical findings is not surprising.
cells in many lymphomas heretofore designated as histiocytic " or " reticulum cell". In-vitro incubation of mature ", " well differentiated lymphocytes with phytohsemagglutinin and other mitogens has shown that these cells are capable of transformation to " large lymphoid cells ". There is increasing evidence to suggest that a similar phenomenon occurs in vivo with the production of large lymphoid cells or so-called immunoblasts. Uncells in the past have erroneously been doubtedly, these " interpreted as reticulum cells ". Like those of Jaffe et al., our studies provide convincing evidence of the origin of nodular lymphomas from follicular B lymphocytes, thus substantiating the term follicular lymphoma. Our reported studies at Stanford University Medical Center 5,6 have emphasised the imperative need to identify lymphomas with a follicular pattern, by virtue of their favourable prognosis, despite their tendency for early widespread dissemination. Clinicopathological observations have further stressed the need for precise cytological identification. Proposed alternative terminology and classifications must therefore make provision for these behavioural differences in order to provide the clinician with adequate information so that appropriate therapy may be instituted. While the emergence of concepts based on a presumed functional capacity of the component cells is clearly recognised, it is questionable whether sufficient information is available to clearly subdivide the malignant lymphomas into B-cell or T-cell types. In order to reach a compromise between the concepts of Rappaport,4 which have been so usefully applied to our collaborative studies, those recently propounded by Lukes,7 and those of Farrer-Brown, Bennett, and Henry8 in England, I presented at the recent meeting of the International Academy of Pathology in San Francisco a new classification of the non-Hodgkin’s lymphomas (see accompanying table). This classification hopefully eliminates controversial terminology, introduces new designations based to some extent on the functional capacity of the component cells, and yet employs terms which will be acceptable to the pathologist in his everyday diagnostic work and to the hsmatologist and oncologist burdened with the choice of therapy for patients affected by the non-Hodgkin’s lymphomas. We are in the process of applying this terminology retrospectively to the series of cases previously reported by us 5,6 and will similarly attempt to do so in a prospective fashion. Until this terminology proves to be valid, we will continue to utilise the classification of Rappaport4 in our routine pathology reports. It will be of great interest to me to determine whether pathologists, in private practice or involved in
to draw attention to a biochemical in our letter (May 25, p. 1055) in the last sentence of the third paragraph. What we meant to write was that the osmolality of 150 ml. of 1 N hydrochloric acid made up to a litre with sterile water is 300 milliosmols per litre, not that " the osmolality of 1 N hydrochloric acid is 300 milliosmols per litre ". We apologise for this oversight. We should like to comment on the letter by Dr Whelton (May 25, p. 1055) who believes this form of therapy to be potentially dangerous. He refers to acute hxmolysis in dogs after " slow intravenous infusions of more dilute hydrochloric acid solutions (0-1 N and 0,3 N HCI) than described in the editorial " (April 20, p. 720). In actual fact the normality of the hydrochloric acid finally infused by Abouna et al.2, on whose article your editorial is based, is 0-15 N-i.e., after allowing for dilution by the vehicle. Thus the 0-3 N HCI used by Dr Whelton is in fact a more concentrated solution of HCI than that described in your editorial. In terms of a variable perhaps more relevant to hoemolysis, the osmolality of the infused solution described in the editorial is 300 milliosmols per litre, which is only slightly hyperosmolar with respect to plasma (285-295 mosmol. per litre) whilst that of the 0-3 N HCI used by Dr Whelton is at least 600 milliosmols per litre, depending on the nature of the vehicle, and is therefore distinctly hyperosmolar. There is no mention of whether a central or a peripheral venous catheter was used, or of the vehicle employed (with its own osmolality), or of the actual rate of infusion in the dogs. These aspects are of importance in seeking for a cause of the hxmolysis in the dogs. The osmotic fragility of canine erythrocytes is apparently similar to that of their human counterparts. In the patient described in our previous letter (May 25, p. 1055) haemolysis did not occur
Lukes, R. J. Monograph, International Academy of Pathology (edited by J. W. Rebuck and C. W. Berard) (in the press). 8. Berard, C. W., Dorfman, R. F. Clin. Hemat. 1974, 3, 39.
1. Paris Conference on Standardization in Human Genetics. National Foundation, New York, 1972. 2. Abouna, G. M., Veazay, P. R., Terry, D. B. Surgery, 1974, 75, 194.
"
7.
"
Division of Medical Genetics, Department of Pediatrics, Mount Sinai School of Medicine, New York, N.Y. 10029, U.S.A.
HYON J. KIM LILLIAN Y. HSU KURT HIRSCHHORN.
INTRAVENOUS HYDROCHLORIC ACID
SIR,—We hasten
error
1297
with infusion of 0-16 N HCl in 5% dextrose (598 mosmol. per litre.) via a central venous catheter. Of course there is one basic difference between Dr Whelton’s research observations and the results of therapy referred to in the editorial. The infusion of HCl in the former situation is to purposely induce an acidosis in dogs which start off with a normal pH, whilst in the editorial reference is made to HCl being infused therapeutically to restore an alkalosis in patients back to a normal pH. Increased haemolysis has been described in the presence of acidosis, but not alkalosis due to red-cell-enzyme inhibition.2,3 We would disagree with Dr Whelton concerning the safety of NH4Cl solutions in patients with gross metabolic alkalosis plus hepatic insufficiency (such as referred to in the editorial) or of NaCl solutions in patients with metabolic alkalosis plus sodium-retaining states. In both these situations we believe that HCl would be contrariwise safe. Division of Clinical Chemistry, Institute of Medical and
Veterinary Science, Adelaide, South Australia. Intensive Care Unit, Anaesthetics Department, Royal Adelaide Hospital, Adelaide, South Australia.
ROY W. PAIN.
L. WORTHLEY.
PATHOGENS IN THE URINARY TRACT SIR,—May I comment on Dr Maskell’s Occasional Survey (June 8, p. 1155) ? First, she rightly draws attention to the importance of quantitative colony-counts in determining if organisms cultured after catheterisation or suprapubic aspiration (S.P.A.) are contaminants. But of the three references cited for S.P.A., one 4 mentions colony-counts and S.P.A. but does not mention the use of one with the other. A second 5 mentions the use of colonycounts on urine obtained from S.P.A. but gives no results. Indeed these authors state later that " because the urine was obtained by S.P.A. colony-counts are unnecessary". The possibility of contamination of urine cultures obtained by S.P.A. with common skin commensals, such as coagulasenegative staphylococci, remains very real. Second, in ideal conditions when so-called midstream urines (M.S.U.) are obtained from women, cultures yielding a pure growth of more than 100,000 organisms per ml. will give about 5% false-positive results. In her survey, the specimens were obtained in the less than ideal conditions of domiciliary practice and she chose to select as " positive " or " showing definite infection " those specimens which gave pure growths of greater than 10,000 organisms per ml. The two factors together will undoubtedly increase the proportion of false positives to an extent that cannot be quantified, but must, I submit, seriously detract from the validity of her conclusions. Third, most of the 10,065 M.s.u. specimens will have come from women who might have been menstruating. With the average menstrual cycle there is a 1-in-5 (20%) chance that microscopic hasmaturia (which she does not define) will occur by simple contamination without any red cells being derived from the urinary tract. Unless it is possible to exclude all specimens obtained from women during or for 2-3 days after menstruation, it is not justifiable to conclude that microscopic hasmaturia and " gross " pyuria indicate acute inflammation of the urinary tract. North Ormesby Hospital, North Ormesby,
Middlesbrough, Teesside TS3 6HJ. 2. 3. 4.
** * This letter
was
shown
to
Dr
Maskell, whose reply
follows.—ED. L.
SIR,—In considering the significance of organisms cultured after catheterisation, my purpose was to point out that the method of inoculation of catheter specimens into liquid media and subsequent culture gave misleading results. So far as I know this method is never used now. My own experience of suprapubic aspiration specimens, which have been principally from babies and young children, is that contamination with skin commensals is extremely rare; having cultured several hundred of such specimens I cannot remember ever seeing it. I agree with Dove et al. that colony-counts are unnecessary in suprapubic aspiration specimens; the possibility of contamination will be revealed by a mixed growth provided that a suitable culture medium which grows commensals is used. The usual numerical criteria of significance should not be applied because, especially in adults, a diuresis must be induced in order to make suprapubic aspiration technically possible, and the count of organisms may thereby be considerably reduced. I think Mr Hole’s second point is answered by the figures given in my table 11. We are fortunate in this laboratory to serve an area in which the general practitioners are interested in urinary infection, and very conscientious about ensuring that midstream urines are carefully collected. We are also able to provide good specimen collection and refrigeration facilities. Since only 25% of the total number of specimens were classified as positive, and since nearly 60% were sterile on culture, I do not think that the false-positive rate is very high. Lastly, although I agree with Mr Hole that M.S.U. specimens from women who are menstruating may be contaminated with red and white cells, the culture will invariably show a mixed growth of contaminant and commensal organisms provided that a medium such as CLED is used. These specimens will all have been placed in the " doubtful " category and therefore not included in the figures for comparison of pyuria and hsematuria. Public Health Laboratory, St. Mary’s General Hospital, East Wing, Milton Road, R. M. MASKELL. Portsmouth P03 6AQ. MACROCYTOSIS OF CHRONIC ALCOHOLISM SIR,—Dr Wu and his colleagues (May 4, p. 829) report the direct effect of alcohol in producing macrocytosis unrelated to low folate or megaloblastic hsemopoiesis. A third of their cases, however, showed megaloblastic change associated with low folate. The reasons for low folate in alcoholics are not entirely clear, but they could be due to dietary insufficiency, an effect of alcohol on folate absorption, a direct anti-folate effect of alcohol, enhanced utilisation of folate as a co-factor in liver-enzyme activity or a combination of these reasons. Alcohol is a known inducer of liver enzymes1 and has a direct folate-lowering effect.2 A similar acute effect is seen with phenytoin and has been thought to be due to liverenzyme induction.3 In treated epileptics, low folate has been shown to correlate with hepatic microsomal enzyme induction as assessed by the urinary excretion of D-glucaric acid4 which acts as a marker of such enhancement. It would have been of interest to know whether there was any such correlation in the group of patients with low folate.
ROGER HOLE.
Murphy, J. R., J. Lab. clin. Med. 1967, 69, 758. Nathan, D. G., Segel, G. B. Postgrad. Med. 1971, 47, 179. Bailey, R. R., Roberts, A. P., Gower, P. E., de Wardener, H. E. Lancet, 1971, ii, 1112. 5. Dove, G. A., Bailey, A. J., Gower, P. E., Roberts, A. P., de Wardener, H. E. ibid. 1972, ii, 1281.
General Hospital, Steelhouse Lane,
Birmingham, B4 6NH.
J. SCOTT.
1. Lieber, C. S., De Carli, L. M. Science, N. Y. 1968, 162, 919. 2. Eichner, E. R., Hillman, R. S. J. clin. Invest. 1973, 53, 584. 3. Richens, A., Waters, A. H. Br. J. Pharmac. 1971, 41, 414. 4. Maxwell, J. D., Hunter, J., Stewart, D. A., Ardeman, S., Williams, R. Br. med. J. 1972, i, 297.