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MyelofibrosisHISTOLOGISTS recognise two grades of bone-mar-

row fibrosis. Reticulin fibrosis is, at least in its earlystages, simply an exaggeration of the pattern pres-ent in the normal marrow; it is found in a wide var-

iety of blood disorders-both benign and malig-nantl-and is of little diagnostic value, though ithas been used as a prognostic marker in acute

leukxmia. Reticulin fibrosis, however, may be theprecursor of collagen fibrosis, which is restricted toa much smaller group of conditions. Here fibroustissue, and in some cases new bone formation, leadsto disruption and obliteration of the sinusoidalarchitecture of hsemopoietic marrow. Scarring ofthis type is seen in patients with carcinomatous orlymphomatous infiltrations, in granulomatous dis-orders involving marrow, in certain bone diseases,such as osteopetrosis, Paget’s disease, and osteoma-lacia, and, rarely, in autoimmune connective-tissuedisorders.2 The most enigmatic type of collagenfibrosis, however, is surely that which arises in thecondition known to British haematologists as idio-pathic myelofibrosis and to their American col-

leagues as agnogenic myeloid metaplasia. Theseterms are but two of a much larger number (onereviewer3 found 37) used to describe a group ofcases within the spectrum of the myeloproliferativesyndrome-itself a concept which helped createorder out of nosological chaos4-with more or lessdistinctive hxmatological and histological findings.These include anaemia, a leucoerythroblastic blood-picture, massive splenomegaly and sometimes hepa-tomegaly, with extramedullary erythropoiesis, andsclerotic bone changes.The chronic myeloproliferative disorders (MPD)

—polycythsemia vera, idiopathic thrombo-

cythaemia, idiopathic myelofibrosis, and chronic

granulocytic leukaemia—may be regarded as dis-eases resulting from an irreversible changein the proliferative behaviour of the hxmo-poietic stem cell in both medullary and potentialextramedullary sites.5 The haematological features

1. Burston J, Pinniger JL. The reticulin content of bone marrow in hæmatolo-gical disorders. Br J Hœmatol 1963; 9:172-84.

2. Gisser SD, Chung KB. Am J Med 1979; 67:151-54.3. Ward HP, Block MH. The natural history of agnogenic myeloid metaplasia

and a critical evaluation of its relationship with the myeloproliferativesyndrome. Medicine 1971; 50: 357-420.

4. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood1951; 6:372-75.

5. Gilbert HS. The spectrum of myeloproliferative disorders. Med Clin N Am1973; 57:355-93.

in an individual case might then reflect the

response of cells in the proliferating clone to.

normal or abnormal regulatory influences.

Although it has been argued that some members ofthe group are not true neoplasms, but rather repre-sent the response of an intrinsically normal stemcell to an unidentified stimulus,3 the use of geneticmarkers such as chromosome patterns and glucose-6-phosphate dehydrogenase isoenzyme analysis,has shown that blood cells in polycythaemia veraand idiopathic myelofibrosis, like those in chronicgranulocytic leukaemia, are derived from a singleclone of cells. 6, Originally it was thought that the,marrow fibrosis seen in some cases of this type wasalso part of the disordered haemopoietic cell

growth. However, studies with the same markersreveal that cultured fibroblasts taken from the mar-rows of patients with idiopathic myelofibrosis andchronic granulocytic leukaemia are not usually de-rived from the neoplastic clone; thus it seems thatmyelofibrosis in these syndromes is a reaction bynormal stromal cells to abnormal haemopoieticcells, or their environment. It has even been sug-gested that megakaryocytes, which often persist inlarge numbers until the late stages of myelofibrosis,might elaborate substances which promotefibrosis.8 Though a virus-induced myelofibrosishas been described in mice,9 attempts with varioustoxins to produce in animals a syndrome exactly re-sembling idiopathic myelofibrosis have not beenvery successful. Benzene and X-rays, which arealso leukaemogens, have been incriminated in a fewhuman cases of myelofibrosis with myeloid meta-plasia. Myelofibrosis was a common accompani-ment of myeloid leukaemia in the Japanese atom-bomb survivors,10 and was also seen as a late sequelof ’Thorotrast’ administration." On the other hand,in idiopathic myelofibrosis, it has been argued thatterminal myeloblastic leukaemia may be as muchrelated to therapy as pa:-t of the natural history ofthe disease.6 6

Why are myelofibrosis and myelosclerosis suchdominant features in some patients with MPD butinconspicuous in others? Perhaps those patientswith rapidly progressive acute, or "malignant",marrow fibrosis,12 who show only minimal myeloidmetaplasia, are really examples of acute leukaemia

6. Barr RD, Fialkow PJ. Clonal origin of chronic myelocytic leukemia. N EngJ Med 1973, 289:307.

7. Adamson JW, Fialkow PJ. The pathogenesis of myeloproliferauve syn-dromes. Br J Hœmatol 1978;38:299-303.

8. Hickling RA. Chronic non-leukæmic myelosis. Quart J Med 1937; 6:

253-75.9. Upton AC, Firth J. A transmissible disease of mice characterised by anæmia,

leukopenia, splenomegaly, and myelosclerosis. Acta Hœmatol 1955; 13:65-76.

10. Block MH. Incidence of acute leukaemia and myelofibrosis in Japanese sur-vivors of the atom-bomb explosions. Proc XVII Congr Int Soc Haematol1978; 879.

11. Johnson SAN, Bateman CJT, Beard MEJ, et al. Long-term hæmatologicalcomplications of Thorotrast. Quart J Med 1977; 46:259-69.

12. Lewis SM, Szur L. Malignant myelosclerosis. Br Med J 1963; ii: 472-77.

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in which the stromal reaction is particularly vigor-ous; 13 megakaryoblastic leukxmia seems to be

closely related to this syndrome." MANOHARAN andhis colleagues15 found that reticulin fibrosis presentin some cases of acute leukaemia diminished whenremission of the leukaemia was achieved, while itsreappearance seemed to herald relapse. If marrowfibrosis is a nonspecific reaction to inflammatory orneoplastic cells of various kinds, or even a physiolo-gical response to increased haemopoietic activity,how are we to explain those cases of MPD,accounting for almost a third in one series,16 whohave the typical blood leucoerythroblastosis, mye-loid metaplasia in spleen and liver, but show bone-marrow hyperplasia and only slight fibrosis on tre-phine biopsy? While myeloid metaplasia in liverand spleen may represent part of the proliferativeprocess involving all potential sites for blood-cellformation, another possibility is that it results fromseeding of stem cells that are released prematurelyfrom the disorganised marrow. 17The overlapping haematological and histological

patterns found in the MPD are perplexing, and thesearch is on for distinctive features which can becorrelated with clinical course and response to

‘

treatment. Two recent papers have drawn atten-tion to "transitional" forms within the spectrum ofthe MPD which might be regarded as clinical enti-ties. PETTIT and his colleagues18 describe 11 pa-tients with clinical features of both polycythsemiavera and myelofibrosis. Repeated hmmatologicaland isotopic investigation, including studies of thedistribution of erythropoietic marrow in the skele-ton using 52Fe, over a ten-year period, showed thatpatients who present with this syndrome mayremain in status quo for several years: this transit-ional state does not always imply inexorable pro-gression into classic myelofibrosis, as is oftenassumed. In these cases, splenectomy, splenic irra-diation, or chemotherapy with alkylating agentsreduced the extent of extramedullary hsemopoiesis,and even caused some patients to revert to typicalpolycythsemia. One patient showed a response tooxymethalone, another to folic acid.

Radioactive phosphorus is best avoided in suchcases, say PETTIT et al., because its preferentialmedullary action may actually encourage extrame-dullary erythropoiesis. These workers confirmedthe observations of others that progression from a

13. Bird T, Procter S. Malignant myelosclerosis: myeloproliferative disorder orleukemia? Am J Clin Path 1977; 67:512-20.

14. Ottolander GJ, den Velde Jte, Brederoo P, et al. Megakaryoblastic leukaemia(acute myelofibrosis). A report of three cases. Br J Hœmatol 1979; 42:9-20.

15. Manoharan A, Horsley R, Pitney WR. The reticulin content of bone marrowin acute leukaemia in adults. Br J Hœmatol 1979; 43:185-90.

16. Laszlo J. Myeloproliferative disorders (MPD): myelofibrosis, myelosclerosis,extramedullary haematopoiesis, undifferentiated MPD, and haemorrhagicthrombocythaemia. Semin Hematol 1975; 12:75-98.

17. Leblond PF, Weed RI. The peripheral blood in polycythaemia vera and mye-lofibrosis. Clin Hœmatol 1975; 4:353-71.

18. Pettit JE, Lewis SM, Nicholas AW. Transitional myeloproliferative disorder.

Br J Hœmatol 1979; 43: 167-84.

picture of panhyperplasia to one of myeloid atro-phy with severe collagen fibrosis is uncommon inpolycythaemia vera;3,19 however, WARD and BLOCK3noted a rough correlation between spleen size andduration of the disease. When anaemia supervenesin late polycythaemia, it is often due to a combina-tion of ineffective erythropoiesis and hypersplenismleading to plasma volume expansion and seques-tration of red cells (with often a haemolytic com-ponent)20 as much as to obliterative marrow

fibrosis: Gastrointestinal haemorrhage is especiallylikely in -patients with the portal hypertensionwhich may result from postsinusoidal obstructionin the Budd-Chiari syndrome, from presinusoidalthrombotic obstruction, or from sinusoidal obstruc-tion secondary to myeloid metaplasia and highportal bloodflow.16

Although chronic granulocytic leukaemia (CGL)has traditionally been included as a type of myelo-proliferative disorder, there are clearly sufficientfeatures, such as the presence of the Philadelphiachromosome and the very high frequency of ter-minal acute leukaemia, to justify its separation fromother members of the group. Nevertheless, marrowfibrosis is common during the evolution of the dis-ease. CLOUGH and her colleagues21 performed serialtrephine biopsies in 45 cases of CGL to determineits import; they found that a progressive increase inreticulin fibrosis often preceded the onset of acuteleukxmia. Fibrosis did not seem to be related to theamount of chemotherapy given, or to survival time;one patient whose disease had been present for

eight years showed no reticulin increase. Severalpatients were found to have advanced collagenfibrosis at the time of diagnosis: paradoxically, thisgroup did not always have a bad prognosis, and intwo cases, the leukaemia proceeded indolently forseveral years with very little treatment. These pa-tients showed the cytogenetic features of CGL, butthe blood picture was often leucoerythroblastic,while marrow, and in some cases splenic, histologywas indistinguishable from that of idiopathic mye-lofibrosis. These patients, most of whom eventuallydied of acute myeloblastic leukaemia, might be

regarded as having another form of transitionalMPD: the rare cases of "Philadelphia-positive mye-lofibrosis" described in the past probably belongedto this group.A cooperative clinical study of the natural his-

tory of the MPD is in progress in the U.S.A.,16 andwill help to answer questions about the signifi-cance of myeloid metaplasia, whether only patientswho show proliferation of the haemopoietic "tri-

19. Pitcock JA, Reinhard EH, Justus BW, Mendelsohn RH. A clinical andpathological study of seventy cases of myelofibrosis. Ann Intern Med1962, 57: 73-84.

20. Milner GR, Geary CG, Wadsworth LD, Doss A. Erythrokinetic studies asa guide to the value of splenectomy in primary myeloid metaplasia Br JHœmatol 1973; 25: 467-84.

21. Clough V, Geary CG, Hashini K, Davson J, Knowlson T. Myeloribrosis inchronic granulocytic leukæmia. Br J Hœmatol 1979; 42:515-25.

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lineage" of erythroid, granulocyte and megakaryo-cytes should be included, the relationship of mye-loid leukaemia to the group, and the role of

chemotherapy, splenectomy, and splenic irradia-tion in treatment. Biochemical and histologicalanalysis of bone-marrow collagen in myelofibrosiswill provide information about the dynamics of col-lagen formation and its relation to the underlyingdisease.22 Finally, it should not be forgotten that,although many cases of MPD seem to be clonal dis-eases, idiopathic myelofibrosis has very occa-

sionally regressed spontaneously,23 or as a result ofcytotoxic immunosuppressive therapy, and that im-mune complexes have been demonstrated in somecases.24 The marrow has a strictly limited way ofresponding to injury: morphological similarity doesnot imply xtiological unity. 25

STRESS IN MEDICAL STUDENTS

MEDICAL students have a long and sometimes arduoustraining, in which for successful completion staminaranks as high as intelligence and motivation. Parts ofthe course can be very stressful,’ and not merely becausea mass of knowledge and clinical skills must be acquiredrapidly in a host of different subjects. The seeming irrel-evance of parts of the course engenders boredom andfrustration,2 which are stressful sensations in their ownright. Our puritanical forebears used to declare suchstress good for the character and a means of weeding outunsuitable students. This "assault-course" view of medi-cal training is out of fashion and most people are tryinghard to lessen the stress. Teachers are more sensitive tostudents’ own views of the strains imposed by their med-ical training,3,4 and one result has been the greater in-tegration between preclinical and clinical aspects ofmedical teaching. Nevertheless the most stressful periodof medical training is still the first two years. Anatomy,despite its decline in the curricular hierarchy, is still

fiercely criticised, and students continue to feel deprivedof opportunities to tell teachers what they think of thecourse. In general, male students are more critical oftheir teachers and suffer more from stress than femaleones. This may have something to do with former admis-sion procedures, whereby women were at a disadvantageand therefore needed a higher level of competence to getin.6 All the same, male students in general do seem to

22. Charron D, Robert L, Couty MC, Binet JL. Biochemical and histologicalanalysis of bone marrow collagen in myelofibrosis. Br J Hœmatol 1979;41:151-61.

23. Tobin MS, Kim K, Lu F, Spain D. Reversibility in myelofibrosis with mye-loid metaplasia (abstract). Proc XIII Int Cong Hœmarol 1970; 249.

24. Lewis CM, Pegrum GD. Immune complexes in myeloproliferative diseases.Lancet 1977; ii: 1151-53.

25. Hunstein W. Experimental myelofibrosis. Clin Hœmatol 1975; 4:457-78.1. Nichols EJ, Spielberger CD. Effects of medical education on anxiety in stu-

dents. Ment Hyg 1967;51:74-79.2. Pickering G. Quest for excellence in medical education. London: Oxford Uni-

versity Press, 1978.3. Lucas CJ. Psychological problems of students. Br Med J 1976;ii:1431-33.4. Walton HJ. Measurement of medical students’ attitudes. Br J Med Educ

1967, 1:330-40.5. Alexander DA, Haldane JD. Medical education; a student perspective. Med

Educ 1979; 13:336-41.6. Walton HJ. Sex differences in ability and outlook of senior medical students.

Br J Med Educ 1968; 2:156-62.

have a higher incidence’of mental illness in response tostress than do female students. 7,8

Other common student criticisms of the medicalcourse include impressions that nonconformist attitudesare penalised by the teachers, that medical staff are notsensitive enough to students’ stress problems, detectingthem only when it is too late, and that the timing of ex-aminations is arranged so that students are inadequatelyprepared. It would be wrong to accept these criticismsas inevitably valid because they come from the con-sumer. Mechanic9 made a seminal contribution to thesocial psychology of education when he observed andrecorded the feelings and attitudes of students duringthe final year of a PH.D. course.9 He showed that stu-dents and teachers naturally take up different positionsabout the value of their training and examinations. Theteachers view examinations as an intellectual challengeand a good discriminator of student abilities, whereasstudents feel they have too much to learn and that exam-ination strategy is an important component of success.Much greater stress is seen in "pre-candidates" whohave not passed any preliminary exams than by "candi-dates" who have passed their first examinations of thecourse and are accepted by faculty and other students aspotentially successful. The high drop-out rate in the firsttwo years of medical training is in keeping with thisobservation; for it is only when intermediate examina-tions are completed that students can regard themselvesas potential doctors. Students who do badly in examsand have had failures naturally lose self-esteem and aremore inclined to blame the examiners and the trainingsystem than themselves.

Mechanic9 has shown that failure or the threat of fail-ure in examination leads students to adopt coping mech-anisms which are critical of the teachers and the educa-tional courses. These are healthy reactions and shouldnot be confused with pathological stress. A more rele-vant criticism made by students is that medical teachersfail to detect abnormal stress reactions until they arewell established. Because the medical school and its staffare frequently regarded as the cause of the stress it is notsurprising that the student will only go to a staffmember for help if his counselling role is seen to be quiteindependent of his academic one. A practice of allocat-ing tutors responsible for the "moral welfare" of stu-dents is therefore not particularly successful, becausethe tutor is too often identified with the source of stress.Student health services are more independent and areprobably better placed to give professional advice. Self-help schemes, run by students themselves in some uni-versity centres, can provide supplementary help alongSamaritan lines. Above all, medical schools need to beflexible in dealing with stress in students. Abnormalstress is an individual reaction and cannot always bepredicted. Rigidity in the curriculum should be avoided.For example, the introduction of research into themedical course where the student does a project in anarea of his own choosing.,10 although admirable for thebudding scientist, may be quite unsuitable for the plod-

7. Carpenter RG. Statistical analysis of suicide and other mortality rate of stu-dents. Br J Prev Soc Med 1959; 13:163-74.

8. Rook A. Student suicides. Br Med J 1959;i:599-603.9. Mechanic D. Students under stress; a study in the social psychology of adap-

tation. Wisconsin: University of Wisconsin Press 1978 (originally pub-lished in 1962).

10. Editorial. Southampton away. Lancet 1976; ii: 80.