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efficient. One only has to look at the soaring prices inthe USA to see that this notion is seriously flawed.Whatever the Government’s attempts at devolving
responsibility, the NHS will remain a political issue.For patients, what matters is humanity and efficiencyat the point of contact. Doctors will ask how the newproposals will help them to provide a better standardof preventive, curative, and palliative care. The WhitePaper, for all its protestations of commitment to theNHS, offers scant reassurance even to those who donot see it as a curtain raiser for full privatisation.
Trends in Lymphoma DiagnosisIN The Lancet of July 22, 1939, Scott and
Robb-Smith reported a clinical and pathologicalentity in four patients for which they suggested thename histiocytic medullary reticulosis;l the clinicalcourse was rapidly fatal, although it was not clear thatthe underlying disease was neoplastic in nature. Theseworkers referred to the condition as a systemic"proliferation of erythrophagocytic histiocytes andtheir precursors" and carefully avoided labelling it
malignant. Even today, it is unclear whether
histiocytic medullary reticulosis encompasses a rangeof benign and malignant lesions or whether it is
malignant from the outset. Although it is generallybelieved to be part of the lymphoma spectrum, thedisorder has proved difficult to categorise despiteconsiderable advances in recognition andclassification of lymphomas. Much of this difficultyarises from the admixture of different cell types in this
disease, so that it is hard to detect which, if any, are themalignant cells.
Histiocytic medullary reticulosis is by no means theonly unusual lymphoid lesion that continues to defyclassification. The nature of three other disorders-
lymphomatoid granulomatosis, polymorphicreticulosis (or midline granuloma) of the naso-
pharynx, and angioimmunoblastic lymphadeno-pathy-remains equally unclear. The cumbersomenomenclature of these conditions echoes a past age of
pathology, so it may come as a surprise to learn thatthese terms were introduced in the 1970s. All three are
heterogeneous proliferations of macrophages,lymphocytes, and other leucocytes. There has been noagreement about whether the three conditions are
pathologically related and, as with histiocyticmedullary reticulosis, whether they are trulyneoplastic. Such confusion partly reflects the
clinicopathological complexity of this group of lesions,which is not always clarified by their pathologicaldescriptions--eg, lymphomatoid granulomatosis isnot precisely defined in the much-cited paper byLiebow and coUeagues2 in which the entity was first
1. Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis Lancet 1939; ii:
194-98
2. Liebow AA, Carrington CRB, Friedman PJ. Lymphomatoid granulomatosis HumPathol 1972; 3: 457-58.
described in 1972. The concept that emerges is of a
peculiar angiocentric lymphoid lesion in the lung witha lymphoma-like picture (lymphomatoid) in someareas and necrosis (granulomatosis) in others. Liebowet al described involvement of other organs,particularly the skin, and discussed a possible relationto other conditions such as mycosis fungoides andWegener’s granulomatosis. In later reports there isdisagreement about the definition of the disease, onwhether it is benign or malignant, and on whetherother tissues such as the nasopharynx may beinvolved. 3,4What are the current concepts of lymphomatoid
granulomatosis and what is its relation to other
atypical lymphoid proliferations? In 1983, Colby andCarrington5 commented that it was probably only thelack of knowledge of extranodal lymphomas at thattime that had led Liebow to place the condition in sucha twilight zone. When they re-evaluated cases oflymphomatoid granulomatosis they were convincedthat most were lymphomas. Most haematopath-ologists would agree with these conclusions and, basedon the results of immunological phenotyping, believethat most cases of lymphoid granulomatosis are
malignant lymphomas, as are midline granuloma ofthe nasopharynx, angioimmunoblastic lymphadeno-pathy, and histiocytic medullary reticulosis. All theselesions are regarded as examples of the so-calledperipheral or post-thymic T-cell lymphomas.3 Insome cases, rearrangement of the T-cell &bgr;-chaingene6--8 has confirmed their clonal origin.The latest findings reopen the question of how
closely lymphomatoid granulomatosis, midline
granuloma, angioimmunoblastic lymphadenopathy,and histiocytic medullary reticulosis are related toeach other and to other T-cell lymphomas such asmycosis fungoides. Many observations indicate a closeassociation--eg, clinical follow-up studies have shownthat the manifestations of more than one of theseconditions may occur in the same individual. 4,9 Theskin lesions that may develop in lymphomatoidgranulomatosis and also in midline granuloma,angioimmunoblastic lymphadenopathy, and
histiocytic medullary reticulosis are similar to those inmycosis fungoides.2,lo At necropsy, over 70% ofpatients with mycosis fungoides have involvement in
3. Jaffe ES. Post-thymic lymphoid neoplasia. In Jaffe ES, ed Surgical pathology of thelymph nodes and related organs. Philadelphia WB Saunders, 1985. 242.
4. DeRemee RA, Weiland LH, McDonald TJ. Polymorphic reticulosis, lymphomatoidgranulomatosis. Two diseases or one? Mayo Clin Proc 1978; 53: 634-40.
5. Colby TV, Carrington CB Pulmonary lymphomas current concepts Hum Pathol
1983; 14: 884-87.6. Weiss LM, Hu E, Wood GS, et al Clonal rearrangement of T cell receptor genes in
mycosis fungoides and dermatopathic lymphadenopathy N Engl J Med 1985; 313:539-44.
7. O’Connor NTJ, Crick JA, Wamscoat JS, et al Evidence for monoclonal T
lymphocyte proliferation in angioimmunoblastic lymphadenopathy. J Clin Pathol1986; 39: 1229-32
8 Grieser H, Feller AC, Lennert K, et al The structure of the T cell gamma chain genein lymphoproliferative disorders and lymphoma cell lines Blood 1986, 68: 592-94.
9 Katzenstein AA, Carrington CB, Liebow AA Lymphomatoid granulomatosis. Aclinicopathological study of 152 cases. Cancer 1979, 43: 360-73
10. Whittaker S, Forom L, Luzzato L, et al. Lymphomatoid granulomatosis—evidence ofa clonal T cell origin and an association with lethal midline granuloma Q J Med1988, 68: 645-55.
250
other organs, including oropharynx, gastrointestinaltract, bone marrow, and central nervous system.3
Whitaker and colleagueslO now report thecoexistence of lymphomatoid granulomatosis, midlinegranuloma, and erythrophagocytic syndrome in apatient with coeliac disease. These findings raise thepossibility that malignant histiocytosis of the intestine,virtually always found in association with the
histiological features of coeliac disease and latelyestablished as a T-cell lymphoma, is also part of thisconstellation. A study by Spencer et ap1 may hold thekey to understanding how T-cell lymphomas ofsimilar cytological appearance give rise to differentclinical diseases. These workers showed that the
neoplastic cells in cases of enteropathy-associatedT-cell intestinal lymphoma are recognised by a
monoclonal antibody that defines a membranemolecule on intestinal intraepithelial T cells. Theyspeculate that these findings might account for theability of such tumours to remain localised to thegut for a considerable time. Perhaps the
lymphoproliferative disorders affecting the lung, skin,and nasopharynx reflect the expression of surfacemolecules by the neoplastic cells, which keep themlocalised at different sites and so have caused them tobe viewed as distinct clinicopathological entities.
Support for this hypothesis comes from work
(reviewed lately by Janewayl2) showing that the
preferential localisation in epidermis or intestine of theminor subset of T cells that bears the y/5 T-cellreceptor (rather than the cx/(3 receptor) depends uponwhether or not they also express the CD8 antigen.Lack or loss of such receptor molecules would give riseto systemic disease.Of course these findings only account for the
localisation and not for the polymorphous admixtureof cells in the lesions that makes it difficult to
distinguish benign from malignant components.Recruitment of reactive cells into malignantlymphomas is well known in both Hodgkin’s andnon-Hodgkin lymphomas--eg, in the T-cell
lymphoma known as Lennert’s lymphoma,macrophages may outnumber the malignant cellswhile low-grade follicular lymphomas may appearricher in reactive T cells than in malignant B cells.Hodgkin’s disease represents another example inwhich the abnormal mononucleate and binucleatecells are greatly outnumbered by reactive
lymphocytes, macrophages, and leucocytes.These observations remain to be explained, but one
plausible hypothesis is that the cellular compositionreflects the secretion of lymphokines by the malignantlymphoid cells. This view, together with the conceptof differential cellular localisation possibly due to
11 Spencer J, Cerf-Bensussan N, Jarry A, et al. Enteropathy-associated T cell lymphoma(malignant histiocytosis of the intestine) is recognised by a monoclonal antibody(HML-1) that defines a membrane molecule on human mucosal lymphocytes AmJ Pathol 1988; 132: 1-5.
12 Janeway CA. Frontiers of the immune system. Nature 1988; 333: 804-06.
homing molecules on the neoplastic lymphoid cells,offers an explanation for the existence of a group ofrelated polymorphous T-cell lymphomas with a
spectrum of clinical presentations: mycosis fungoides;lymphomatoid granulomatosis; lethal midline
granuloma (polymorphic reticulosis); angioimmuno-blastic lymphadenopathy; enteropathy-associatedT-cell lymphoma (malignant histiocytosis of the
intestine); histiocytic medullary reticulosis; peripheralT-cell lymphoma with or without erythrophago-cytosis.
MITOCHONDRIAL DNA AND GENETICDISEASE
"Mitochondria are stable and responsible lodgers, and I choose totrust them. Without them, we would not move a muscle, drum afmger, think a thought."1
THE latest work suggests that for certain individuals suchtrust is unfortunately misplaced. Mitochondria are
cytoplasmic organelles that may have originated fromintracellular bacteria early in evolution; they play a centralrole in oxidative phosphorylationz and are the only source ofextranuclear DNA in man, contributing about 1 % of thetotal. Each human mitochondrion normally contains severalcopies of an identical circular genome, 16 569 base pairs inlength, that encodes some of the subunits of the electrontransport chain of the inner mitochondrial membrane and
components of ATP synthase.2,3 Each individual inherits hisor her mitochondrial DNA (mtDNA) exclusively via theovum, the sperm apparently contributing no mtDNA to thezygote-a maternal pattern of inheritance.’ Diseasescharacterised by disordered function of respiratory chaincomponents encoded wholly or partly by mtDNA, or thosewith a maternal pattern of inheritance, could therefore becaused by mutations in the mitochondrial genome. In thepast year abnormal mitochondrial genomes have beenidentified in patients with two such diseases-mitochondrialmyopathy (MM) and Leber’s optic neuropathy.The mitochondrial myopathies are a group of disorders
whose features range in severity from mild weakness tosevere multisystem diseased They are often associated withdefects in the electron transport chain and are frequentlymaternally inherited.5-7 The first evidence that some of thesedisorders might be caused by mitochondrial mutations wasthe demonstration of a 2-7 kb deletion in muscle mtDNA in9 of 25 patients with MM.8 All 9 patients were heteroplasmic
1. Thomas L. The wonderful mistake. Oxford: Oxford University Press, 1988.2. Attardi G. Animal mtDNA. An extreme example of genetic economy. Int Rev Cytol
1984; 93: 93-145.3. Anderson S, Bankier AT, Barrell BG, et al. Squence and organisation of the
mitochondrial genome. Nature 1981; 290: 457-65.4. Giles RE, Blanc H, Cann HM, Wallace DC, Epstein CM, Weindenbeim K
Maternally inherited mitochondrial myopathy and myoclonic epilepsy. Ann Neurol1985; 17: 228-37.
5. Petty RKH, Harding AE, Morgan-Hughes JA. The clinical features of mitochondrialmyopathy. Brain 1986; 109: 915-38
6. Wallace DC, Singh G, Hopkins LC, Novotny EJ. Maternally inherited diseases ofman. In: Quagliariello E, et al, eds Achievements and perspectives ofmitochondrial research, vol II. Biogenesis. Amsterdam: Elsevier, 1985: 427-36
7. Egger J, Wilson J. Mitochondrial inheritance in a mitochondrially mediated diseaseN Engl J Med 1983; 309: 142-46.
8. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNAin patients with mitochondrial myopathies. Nature 1988; 331: 717-19.