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PROGRESSIVE HYPERPLASIAS OF THE BLOOD-FORMING ORGANS
871 internal secretions of the are
THE LANCET LONDON:SATURDA Y, OCTOBER 14, 1933
DIET AND WEIGHT of " slimming " there is no more of discussion amongst the laity than the reduction of weight, and each victim of obesity, real or imaginary, has his (or more often her) panacea to offer, In this fashion plays a great part. At one time the system of the late Mr. BANTING is all the vogue ; at another, some more special " cure," such as the " potato " or "milk" plan, or the " dry " diet. Physical methods are popular, probably because they involve less self-denial than restriction of diet, and accordingly we find that the advocates of Turkish baths, massage, or the wearing of indiarubber corsets always have a large following. And yet, as Prof. E. C. DoDDS points out in an address summarised in our last issue, the problem of weight reduction is essentially a mathematical one, the principles of which are perfectly well understood by physiologists. The amount of energy, measured in calories, required to run the bodily machine under different conditions is definitely known, and any habitual intake in excess of this results in the gradual accumulation of fat. The obese person, therefore, who complains that he continues to gain weight even although he is a small eater is, as Prof. DoDDS says, usually self-deceived. The clinician, however, who has to deal with individual patients and not with mere bodily machines, may be excused if he thinks that the problem of obesity and its treatment is not quite He so simple as this statement of it would imply. has a shrewd suspicion that people vary very much in their capacity for storing fat, apart altogether from the question of how much they eat, even although he cannot explain such individual differences. It may perhaps be a question of metabolic peculiarity. Some persons seem to be more economical machines than others ; they do, as it were, more " miles to the gallon," and we know that this greater economy can to some extent be acquired by training and is also developed spontaneously in diabetes. Further, the influence of the endocrine glands cannot be left out of consideration, although Prof. DoDDS, deliberately simplifying the issues, hardly touched upon it. The most troublesome cases of obesity which the clinician has to deal with are those met with in children and in young women, and in these it is certainly not a mere question of diet. In these endogenous cases, as they are called, the fault most probably lies in some endocrine defect or imbalance, although its exact nature is obscure. It is not a mere deficiency of thyroid secretion, for they do not respond very well to treatment by thyroid ; possibly it is the anterior pituitary or the IN these days popular subject
at
reproductive system
fault, but that the problem is
that
in them not
a purely mathematical one the therapist has no doubt. Nor can mathematical considerations alone be taken into account in dealing with the " exogenous " cases which, of course, include by far the larger number of obese patients. The form in which the energy is consumed has to be reckoned with. A given intake of calories in the form of protein, for instance, is much less likely to lead to fat deposition than an equivalent intake in the form of carbohydrate. In this connexion we should like to hear the views of other physiologists on Prof. DODDS’S statement as to the fattening effect of alcohol. Is it true that a " double whisky " is only to be balanced by playing a full half-hour of squash ? Alcohol, of course, is oxidised in the body and serves as a source of heat and energy, but, unless it is taken in a very dilute form and the intake spread over some time, part of it easily escapes oxidation altogether. Further, by dilating surface blood-vessels, may it not actually cause more heat to be lost to the body than it supplies ? We raise these questions not to impugn in any degree Prof. DODDS’S main contention, but only to enter a caveat against an impression which his remarks may have left that any form of obesity the can be reduced by suitable application of principles he outlines. This is quite true of the exogenous obesity commonly met with in middleaged persons, but it is certainly not true of the endogenous cases. About these there is still an element of obscurity which it is well to recognise.
PROGRESSIVE HYPERPLASIAS OF THE BLOOD-FORMING ORGANS AMONG diseases of the which are characterised proliferation, the leukaemias,
blood-forming organs by progressive cell plasma cell myelomas, Hodgkin’s lymphogranulomatosis, and Gaucher’s splenomegaly are the best known. Although their clinical course and macroscopic structure may at times be confused, a final differential diagnosis can be made on the basis of well-marked microscopic structures, and we have little difficulty That this list does not now in defining them. by any means exhaust the possible variations in histological appearance which progressively hyperplastic lymphoid tissue and bone-marrow are able to provide, is shown by numerous case reports in various journals on the Continent, in this country, and in America of unrecognised conditions which defy classification, as well as by attempts to frame a comprehensive classification which will include all newly described varieties. The prognosis of most of the newer diseases appears to be hopeless, like that of most of the older group, for, as a rule, accounts include autopsy findings. Here and there, however, an individual recovers after splenectomy, and in all probability many cases that survive for any length of time after excision of lymphatic glands for diagnosis fail to be recorded because the patients disappear, and too little is known about their condition to
872
make it worth while describing it. If only for the immediate purpose of ascertaining the prognosis these obscure hyperplasias deserve study. The difficulties with which the histologist is faced in attempting to interpret the microscopic appearances can hardly be realised by those who have not been in a position of having to report on these unusual conditions. The whole architecture of the haemopoietic organs becomes changed and the cells are so varied in shape and size, and may differ so greatly from normal adult cells, that it is often impossible to say whence they are derived. Consequently many cases have been labelled vaguely as endothelioma without justification. More recently the term reticuloendotheliosis, favoured by some, has come to the rescue, while others, following E. LETTEBER/ consider reticulosis to be a more logical name, because the basic cell of the blood-forming tissue is a reticulum cell. There is a danger that many will become labelled only by the authors’ names, as in Gaucher’s splenomegaly, Christian syndrome, and Niemann-Pick disease. According to a suggestion of W. G. MACCALLUM2 the proper solution would be a classification based on normal histology. For every type of normal cell, if we knew them all, it might be possible to find a corresponding progressive hyperplasia in the same way that malignant tumours are differentiated according to their origin. A similar suggestion was put forward by B. D. PULLRNGER3 in an attempt to elucidate the histogenesis of lymphadenoma and atypical examples of this condition. That knowledge of the normal development and adult histology of the haemopoietic organs is sufficiently well advanced to enable such a course to be pursued is evident from the work of A. MAXIMOW4 and his collaborators, who have assembled the facts established by the research of many others and have added many original observations of their own. In the September issue of the Journal of Pathology and Bacteriology Dr. J. M. Ross reports two unusual cases which fall into the class of hyperplasias under discussion, and she proposes a scheme of classification based on MAXiMOW’s views, of which she gives a short summary. The progressive hyperplasias of the blood-forming organs are divided into two main groups, the one including those cases in which no disturbance of metabolism is known to exist, and the other in which metabolic disturbances can be demonstrated. In this second group we meet with Gaucher’s disease among lipoid’ or storage histiocytoses. Subdivisions in the first group are made according to the type of cell which has been proliferating and to its state of differentiation. For example, the undifferentiated reticulum cell is capable of giving rise to lymphoid follicles, fibril-bearing
cells, histiocytes, myeloid cells, giant cells, and mixtures of any or all of these. As an example of reticulum cells which have already specialised and
then proliferated, we find sinus lining cells (formerly known as endothelium) and it is suggested that these give rise to both leukaemic and aleukaemic hyperplasia, the former being a monocyte leukaemia. In the same specialised subgroup one supposes that lymphoid and myelogenous leukaemia might be
included, though Ross does not specifically say this. It would, however, be logical, for although the granular and non-granular leucocytes are parenchymatous elements, they are ultimately derived from reticulum. From cases reported by other authors Ross is able to give instances from the literature of most of these potential hyperplasias. Two of her own cases correspond closely with others that have been recorded. The first is a lymphoid hyperplasia from follicular reticulum and the second a fibrillary reticulosis. In considering lymphadenoma as an example of unrestricted differentiation, she is in agreement with PuLLrnGER.3 Ross’s article is profusely and clearly illustrated by macroscopic and microscopic preparations, so that all who are specially concerned with this obscure branch of pathology will find it profitable and easy to compare their own examples with hers, and also to test the usefulness of the scheme. It is worthy of note that the authors quoted by Ross have not recorded second examples of their cases, and therefore it seems probable that the individual conditions are rare, although the group as a whole is not. For this reason complete records of any examples of unusual hyperplasia of lymphoid and myeloid tissue are valuable and will enable some sort of order to be reached when a sufficient number has been collected. A final classification must wait for knowledge of aetiology, and when we remember the depths of our ignorance of the normal physiology of this system it seems that we have a long way to go. Equally regrettable is the fact that so far no experimental animal has been found whose tissues can be made to produce anything remotely resembling the hyperplasias of human blood-forming organs. Fowl leukaemia and mouse lymphoma are clues which have probably not yet been thoroughly followed up. When they are, the experimental pathologists may well be thankful for the clearing of the ground which work on normal and pathological reticulum is gradually
effecting. UNTRACEABLE
published last week at the request of the Registrar of the General Medical Council a list of the medical practitioners whose names at the present time appear in the Medical Register, but who have failed to reply to official inquiries WE
as
duty
Frankfurt. Zeits. f. Path., 1924, xxx., 377. 2 Text-book of Pathology, London, 1932, p. 849. 3 Rose Research on Lymphadenoma, London, 1932. 4 Handbuch d. mikr. Anat. d. Mensch., 1927, Bd. II., Berlin ; also Maximow and Bloom : Text-book of Histology, Philadelphia and London, 1930.
erase
to
the
and of the
Registrar, keep the respective Registers correct, names of all persons on the Register
and from time to time to make the necessary alterations in the addresses or qualification of the persons included in the list. To effect this the Medical Act empowers the officers of the General Medical Council to write to any persons as
1
of the
Scotland, to
It is the Registrar for
to the accuracy of their addresses.
they die,
.
THE LANCET LONDON:SATURDA Y, OCTOBER 14, 1933
DIET AND WEIGHT of " slimming " there is no more of discussion amongst the laity than the reduction of weight, and each victim of obesity, real or imaginary, has his (or more often her) panacea to offer, In this fashion plays a great part. At one time the system of the late Mr. BANTING is all the vogue ; at another, some more special " cure," such as the " potato " or "milk" plan, or the " dry " diet. Physical methods are popular, probably because they involve less self-denial than restriction of diet, and accordingly we find that the advocates of Turkish baths, massage, or the wearing of indiarubber corsets always have a large following. And yet, as Prof. E. C. DoDDS points out in an address summarised in our last issue, the problem of weight reduction is essentially a mathematical one, the principles of which are perfectly well understood by physiologists. The amount of energy, measured in calories, required to run the bodily machine under different conditions is definitely known, and any habitual intake in excess of this results in the gradual accumulation of fat. The obese person, therefore, who complains that he continues to gain weight even although he is a small eater is, as Prof. DoDDS says, usually self-deceived. The clinician, however, who has to deal with individual patients and not with mere bodily machines, may be excused if he thinks that the problem of obesity and its treatment is not quite He so simple as this statement of it would imply. has a shrewd suspicion that people vary very much in their capacity for storing fat, apart altogether from the question of how much they eat, even although he cannot explain such individual differences. It may perhaps be a question of metabolic peculiarity. Some persons seem to be more economical machines than others ; they do, as it were, more " miles to the gallon," and we know that this greater economy can to some extent be acquired by training and is also developed spontaneously in diabetes. Further, the influence of the endocrine glands cannot be left out of consideration, although Prof. DoDDS, deliberately simplifying the issues, hardly touched upon it. The most troublesome cases of obesity which the clinician has to deal with are those met with in children and in young women, and in these it is certainly not a mere question of diet. In these endogenous cases, as they are called, the fault most probably lies in some endocrine defect or imbalance, although its exact nature is obscure. It is not a mere deficiency of thyroid secretion, for they do not respond very well to treatment by thyroid ; possibly it is the anterior pituitary or the IN these days popular subject
at
reproductive system
fault, but that the problem is
that
in them not
a purely mathematical one the therapist has no doubt. Nor can mathematical considerations alone be taken into account in dealing with the " exogenous " cases which, of course, include by far the larger number of obese patients. The form in which the energy is consumed has to be reckoned with. A given intake of calories in the form of protein, for instance, is much less likely to lead to fat deposition than an equivalent intake in the form of carbohydrate. In this connexion we should like to hear the views of other physiologists on Prof. DODDS’S statement as to the fattening effect of alcohol. Is it true that a " double whisky " is only to be balanced by playing a full half-hour of squash ? Alcohol, of course, is oxidised in the body and serves as a source of heat and energy, but, unless it is taken in a very dilute form and the intake spread over some time, part of it easily escapes oxidation altogether. Further, by dilating surface blood-vessels, may it not actually cause more heat to be lost to the body than it supplies ? We raise these questions not to impugn in any degree Prof. DODDS’S main contention, but only to enter a caveat against an impression which his remarks may have left that any form of obesity the can be reduced by suitable application of principles he outlines. This is quite true of the exogenous obesity commonly met with in middleaged persons, but it is certainly not true of the endogenous cases. About these there is still an element of obscurity which it is well to recognise.
PROGRESSIVE HYPERPLASIAS OF THE BLOOD-FORMING ORGANS AMONG diseases of the which are characterised proliferation, the leukaemias,
blood-forming organs by progressive cell plasma cell myelomas, Hodgkin’s lymphogranulomatosis, and Gaucher’s splenomegaly are the best known. Although their clinical course and macroscopic structure may at times be confused, a final differential diagnosis can be made on the basis of well-marked microscopic structures, and we have little difficulty That this list does not now in defining them. by any means exhaust the possible variations in histological appearance which progressively hyperplastic lymphoid tissue and bone-marrow are able to provide, is shown by numerous case reports in various journals on the Continent, in this country, and in America of unrecognised conditions which defy classification, as well as by attempts to frame a comprehensive classification which will include all newly described varieties. The prognosis of most of the newer diseases appears to be hopeless, like that of most of the older group, for, as a rule, accounts include autopsy findings. Here and there, however, an individual recovers after splenectomy, and in all probability many cases that survive for any length of time after excision of lymphatic glands for diagnosis fail to be recorded because the patients disappear, and too little is known about their condition to
872
make it worth while describing it. If only for the immediate purpose of ascertaining the prognosis these obscure hyperplasias deserve study. The difficulties with which the histologist is faced in attempting to interpret the microscopic appearances can hardly be realised by those who have not been in a position of having to report on these unusual conditions. The whole architecture of the haemopoietic organs becomes changed and the cells are so varied in shape and size, and may differ so greatly from normal adult cells, that it is often impossible to say whence they are derived. Consequently many cases have been labelled vaguely as endothelioma without justification. More recently the term reticuloendotheliosis, favoured by some, has come to the rescue, while others, following E. LETTEBER/ consider reticulosis to be a more logical name, because the basic cell of the blood-forming tissue is a reticulum cell. There is a danger that many will become labelled only by the authors’ names, as in Gaucher’s splenomegaly, Christian syndrome, and Niemann-Pick disease. According to a suggestion of W. G. MACCALLUM2 the proper solution would be a classification based on normal histology. For every type of normal cell, if we knew them all, it might be possible to find a corresponding progressive hyperplasia in the same way that malignant tumours are differentiated according to their origin. A similar suggestion was put forward by B. D. PULLRNGER3 in an attempt to elucidate the histogenesis of lymphadenoma and atypical examples of this condition. That knowledge of the normal development and adult histology of the haemopoietic organs is sufficiently well advanced to enable such a course to be pursued is evident from the work of A. MAXIMOW4 and his collaborators, who have assembled the facts established by the research of many others and have added many original observations of their own. In the September issue of the Journal of Pathology and Bacteriology Dr. J. M. Ross reports two unusual cases which fall into the class of hyperplasias under discussion, and she proposes a scheme of classification based on MAXiMOW’s views, of which she gives a short summary. The progressive hyperplasias of the blood-forming organs are divided into two main groups, the one including those cases in which no disturbance of metabolism is known to exist, and the other in which metabolic disturbances can be demonstrated. In this second group we meet with Gaucher’s disease among lipoid’ or storage histiocytoses. Subdivisions in the first group are made according to the type of cell which has been proliferating and to its state of differentiation. For example, the undifferentiated reticulum cell is capable of giving rise to lymphoid follicles, fibril-bearing
cells, histiocytes, myeloid cells, giant cells, and mixtures of any or all of these. As an example of reticulum cells which have already specialised and
then proliferated, we find sinus lining cells (formerly known as endothelium) and it is suggested that these give rise to both leukaemic and aleukaemic hyperplasia, the former being a monocyte leukaemia. In the same specialised subgroup one supposes that lymphoid and myelogenous leukaemia might be
included, though Ross does not specifically say this. It would, however, be logical, for although the granular and non-granular leucocytes are parenchymatous elements, they are ultimately derived from reticulum. From cases reported by other authors Ross is able to give instances from the literature of most of these potential hyperplasias. Two of her own cases correspond closely with others that have been recorded. The first is a lymphoid hyperplasia from follicular reticulum and the second a fibrillary reticulosis. In considering lymphadenoma as an example of unrestricted differentiation, she is in agreement with PuLLrnGER.3 Ross’s article is profusely and clearly illustrated by macroscopic and microscopic preparations, so that all who are specially concerned with this obscure branch of pathology will find it profitable and easy to compare their own examples with hers, and also to test the usefulness of the scheme. It is worthy of note that the authors quoted by Ross have not recorded second examples of their cases, and therefore it seems probable that the individual conditions are rare, although the group as a whole is not. For this reason complete records of any examples of unusual hyperplasia of lymphoid and myeloid tissue are valuable and will enable some sort of order to be reached when a sufficient number has been collected. A final classification must wait for knowledge of aetiology, and when we remember the depths of our ignorance of the normal physiology of this system it seems that we have a long way to go. Equally regrettable is the fact that so far no experimental animal has been found whose tissues can be made to produce anything remotely resembling the hyperplasias of human blood-forming organs. Fowl leukaemia and mouse lymphoma are clues which have probably not yet been thoroughly followed up. When they are, the experimental pathologists may well be thankful for the clearing of the ground which work on normal and pathological reticulum is gradually
effecting. UNTRACEABLE
published last week at the request of the Registrar of the General Medical Council a list of the medical practitioners whose names at the present time appear in the Medical Register, but who have failed to reply to official inquiries WE
as
duty
Frankfurt. Zeits. f. Path., 1924, xxx., 377. 2 Text-book of Pathology, London, 1932, p. 849. 3 Rose Research on Lymphadenoma, London, 1932. 4 Handbuch d. mikr. Anat. d. Mensch., 1927, Bd. II., Berlin ; also Maximow and Bloom : Text-book of Histology, Philadelphia and London, 1930.
erase
to
the
and of the
Registrar, keep the respective Registers correct, names of all persons on the Register
and from time to time to make the necessary alterations in the addresses or qualification of the persons included in the list. To effect this the Medical Act empowers the officers of the General Medical Council to write to any persons as
1
of the
Scotland, to
It is the Registrar for
to the accuracy of their addresses.
they die,
.