Gastric lymphomas

Gastric

lymphomas

SIR—Wotherspoon (Sept 4, p 575) and Hussell (Sept 4, p 571) colleagues’ reports describing the regression of low grade gastric lymphomas on eradication of Helicobacter pylori infection and the dependence of the growth of cells in vitro on the presence of H pylori-specific T cells raise major issues about the diagnosis of malignant disease, tumour nomenclature, and therapy.

and their

*Two doses given; THR =total hip replacement. Table: Patient details and outcome after intravenous

neostigmine

supply of the colon with guanethidine and neostigmine. We have managed ACPO with neostigmine alone. 8 consecutive patients with ACPO proven by contrast enema were resuscitated and electrolyte imbalances corrected. With informed consent, patients were given 2-5 mg intravenous neostigmine over 1-3 min. Time to pass flatus ranged from 3-20 min. Adverse effects included sweating in 2 patients and a transient bradycardia in 1. Clinical resolution of ACPO occurred in all patients (table), although 1 patient (38, F) required a second dose 12 h later. In 1 diabetic patient (68, F), distension recurred 1 week later and, despite attempting decompression with a second dose of neostigmine, she required a hemicolectomy. Because the features of ACPO may be unrecognised and some cases resolve spontaneously, its true incidence is difficult to estimate. Nevertheless, ACPO is associated with morbidity and mortality. 1,3,4 Although ACPO is associated with a variety of medical conditions,1,3 one hypothesis about its pathogenesis is a temporary interruption of the sacral parasympathetic nerves (SZ,S3,S4) rendering the distal colon and rectum atonic. Indeed, the splenic flexure is the most common radiological site for the transition between dilated and collapsed bowel,3aa finding which supports this theory. In the original report of its use/ neostigmine (a parasympathomimetic anticholinesterase) was given after an infusion of guanethidine (an adrenergic blocker). Although successful in 8 of 11 patients, deflation occurred only after neostigmine was given. Our pilot study aimed to determine the effects of neostigmine alone on the assumption that the dysmotility or inertia was due to parasympathetic dysfunction. Although initially achieving colonic decompression in all cases, 1 patient (38, F) required a second dose. However, when the distension recurred in the diabetic patient, it was clear that the response to a second dose was inadequate and surgery was necessary. The success of this prokinetic drug is encouraging and our results support the theory’-3 that ACPO results from excessive parasympathetic suppression rather than sympathetic overactivity. Although an uncommon condition, we believe this approach to ACPO should be further evaluated. In addition, it would be worth considering treating patients with oral neostigmine or pyridostigmine (which, although having a weaker muscarinic effect, has a longer duration of action) after intravenous neostigmine in the hope of avoiding recurrent distension and possible surgery. Brian M

Stephenson, A Roger Morgan,

Salaman,

Nicola

Drake, John R

Malcolm H Wheeler

Department of Surgery, Cardiff Royal Infirmary, Cardiff CF2 1SZ, UK Dorudi S, Berry AR, Kettlewell MGW. Acute colonic pseudoobstruction. Br J Surg 1992; 79: 99-103. 2 Hutchinson R, Griffiths C. Acute colonic pseudo-obstruction: a pharmacological approach. Ann R Coll Surg Engl 1992; 74: 364-67. 3 Vanek VW, Al-Salti M. Acute pseudo-obstruction of the colon (Ogilvie’s syndrome): an analysis of 400 cases. Dis Colon Rectum 1986; 29: 203-10. 4 Datta SN, Havard TJ, Stephenson BM, Salaman JR. Acute colonic pseudo-obstruction. Lancet 1993; 341: 690. 1

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Classic definitions of a tumour include criteria such as "growth which persists after cessation of the stimuli which evoked the change".1.2 Because of this growth, and because of the difficulty in separating a heavy benign lymphoid infiltrate from a low-grade lymphoma when even the normal cells can infiltrate epithelium,3 a diagnosis of low-grade lymphoma could be called into question. Whatever diagnostic label is used, it is important to show that the condition is one step on the ladder of clonal progression leading to high-grade

lymphoma. The observations should be interpreted with the recognition that malignant disease is the end result of a series of somatic mutations conferring successive selective growth advantage. We have shown that experimental thyroid adenomas and

carcinomas induced by a mutagen and long-term growth stimulation regress when that growth stimulation is withdrawn. The adenomas were monoclonal, and the carcinomas were defined by vascular invasion.4 These findings were explained on the basis of a simple model of clonal progression, requiring three key events for the development of a sporadic thyroid carcinoma-loss of tumour suppressor gene function, development of autonomous growth, and acquisition of invasiveness. The presence of continuous exogenous growth stimulation diminishes the selective advantage of a mutation leading to autonomous growth; it increases the chance that loss of suppressor gene function and continued growth stimulation will give sufficient clonal expansion for mutation leading to invasiveness to occur. The order in which oncogene mutations arise in tumour development probably depends on local factors. In the absence of growth stimulation, the development of autonomous growth is a probable early abnormality, in its presence the loss of tumour suppressor gene function is likely to be early and autonomous growth late. Under these circumstances removal of the stimulus to growth may lead to regression of the tumour. The definition of the various stages in tumour development and the assessment of the chance of progression from one to the next is important for our understanding of neoplasia, and for treatment and for screening. The definition must integrate the identification of the key oncogene changes with classic morphology, on which most of our knowledge of tumour behaviour is based. The recognition that withdrawal of the stimulus that led to lymphocyte growth can lead to regression of an early stage on the pathway to a high grade lymphoma should serve as an encouragement to seek other early tumours where the same logic might apply. It is also a reminder of the need to rethink the classic definitions of malignant disease and to define the stages of tumour development by both morphological and molecular biological techniques. G A Thomas, Dillwyn Williams Department of Histopathology, Addenbrooke’s Hospital, Cambridge CB2 2QQ 1 2

3 4

Willis RA. The spread of tumours in the human body. London: Butterworth, 1952. Cotran RS, Kumar V, Robbins SL. Neoplasia. In: Robbins pathologic basis of disease, IV ed. London: WB Saunders, 1989: 239. Isaacson PG, Wright DH. Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer 1984; 53: 2515-24. Thomas GA, Williams D, Williams ED. Reversibility of the malignant phenotype in monoclonal tumours in the mouse. Br J Cancer 1991; 63: 213-16.

Wotherspoon and their colleagues hint at a meaningful aetiopathological relation between H pylori and low-grade B cell lymphoma of MALT type in the stomach. Briefly, Hussell and co-workers show that in-vitro tumour cells reacted in several ways to the presence of H pylori antigen. Wotherspoon and colleagues show that the eradicaton of H pylori is followed by a regression of the MALTOMA (my word). In both reports the word tumour is used synonymously with the much more specific wording low-grade B cell gastric MALT lymphoma. The late Sir Rupert Willis’ definition of a tumour was: "a tumour is an abnormal mass of tissue, the growth of which SIR-Hussell and

exceeds and is uncoordinated with that of the normal tissues, and persists in the same excessive manner after cessation of the stimuli which evoked the change". On balance, I believe that this definition has been generally accepted by the medical world and has stood the test of time. Yet now we are informed that a low grade gastric MALT lymphoma can apparently be switched on and off, in some measure at least, by the antigenic properties vested in H pylori. Interestingly, however, this seems not to be true for high-grade gastric lymphomas (Hussell

et al).

P G Isaacson, J

R Menai-Williams Histopathology Laboratory, Royal Berkshire Hospital, Reading RG1 5AN, UK

Pathology of tumours. London: Butterworth, 1948: 1.

Authors’ reply SIR-Our finding that the growth of low-grade B-cell gastric lymphoma of MALT type can be affected by stimuli provided by H pylori has provoked Thomas and Williams to question whether these lesions are indeed lymphomas-ie, tumourseither as judged by histology or as defined by Willis. They imply that low grade MALT lymphomas could be, rather, a step towards a true tumour in the spirit of Willis’ definition1

-namely, a high-grade B-cell lymphoma. The histological criteria for the diagnosis of low-grade MALT lymphomas consist of many more features than simple infiltration of the epithelium and include invasiveness and tissue destruction.2 These features were carefully recorded in all our cases and backed up by the objective demonstration of monoclonality. Thus, the proliferation of a single clone of B cells in each case was not down regulated by normal immunoregulatory mechanisms, a property that was not shared by the patients’ other B cells. Therefore, the B cell from which the clone was derived in each case had an advantage probably gained by genetic mutation. There is evidence that mutations have occurred in low grade MALT lymphomaand these are currently being investigated in greater detail. Although it is true that some low-grade MALT lymphomas evolve into high-grade lesions, others progress and disseminate without

Spencer

Department of Histopathology, University College London Medical School, London WC1E 6JJ, UK

1 2 3

What should we deduce from all this? Firstly, is it time to revise Willis’ definition of tumour. Presumably one should, because the very precept on which Willis based his definition seems to be overturned by the observations that the MALTOMA regressed after treatment and removal of the antigenic stimuli. On the other hand, and this is my second point, if we accept Willis’ definition then should we reappraise our understanding of low-grade gastric B cell MALT lymphoma? In other words, are we seeing just another expression of a hyperplasia? Finally, in addition if the observations and conclusions of Hussell and Wotherspoon are correct, are they also asking us to conclude a more fundamental biological question-ie, is cancer reversible? Certainly, Stolte and Eidt in their accompanying commentary (p 568) were somewhat confused on this point.

1 Willis RA.

morphological or, as yet, detectable genetic change.4,5 To fail to call such lesions tumours could be dangerous. We do not know the full extent to which growth of the monoclonal B cells in low-grade gastric MALT lymphomas is dependent on help from H pylori-specific T cells. A capacity for autonomous growth might already be present, and it is possible that the tumours, having regressed after eradication of H pylori, will recur in the same way as have other tumours shown to be sensitive to growth factors. Low-grade MALT lymphoma may still fulfil Willis’ definition that "the growth [of a tumour] persists ... after cessation of the stimuli which evoked the change".’ Chronic gastritis caused by H pylori is very common; the stimuli that cause a few cases to progress to malignant lymphoma remain unknown. any

4

5

Willis RA. Pathology of tumours, 4th ed. London: Butterworths, 1967. Isaacson PG, Spencer J. Malignant lymphoma of mucosa-associated lymphoid tissue. Histopathology 1987; 11: 445-62. Wotherspoon AC, Pan LX, Diss TC, Isaacson PG. Cytogenetic study of B-cell lymphoma of mucosa-associated lymphoid tissue. Cancer Genet Cytogenet 1992; 58: 35-38. Falzon M, Isaacson PG. The natural history of benign lymphoepithelial lesion of the salivary gland in which there is a monoclonal population of B cells. Am J Surg Pathol 1991; 15: 59-65. Diss TC, Peng H, Wotherspoon AC, Pan LX, Speight P, Isaacson PG. A single neoplastic clone with sequential biopsy specimens from a patient with primary gastric mucosa-associated lymphoid tissue lymphoma and Sjögren’s syndrome. N Engl J Med 1993; 329: 172-75.

SiR-The reports from Hussell and Wotherspoon and their colleagues and Stolte and Eidt’s commentary show a possible link between gastric lymphoma and H pylori infection. To my knowledge, the first attempt to find a link between gastrointestinal lymphomas and prolonged exposure to bacterial antigens and/or toxins was my hypothesis in The Lancet more than fifteen years ago.1 Then, I presented what I regarded as epidemiological, clinical, morphological, and immunological evidence associating Mediterranean lymphoma (MDL) to Vibrio cholerae. These recent reports seem to complement my views that the mucosal lymphoplasmacytic infiltration in MDL can probably be best regarded as an excessive immune response of aberrant B-lymphocyte clone(s), homing to the presumed sites of bacterial antigenic stimulation, and differentiating into relatively mature plasma cells that produce alpha heavy chains.1,2 My experienceand that of others,4 confirmed the original observations in various centres that prolonged remissions can be achieved with tetracyclines alone or in combination with steroids and small doses of chemotherapy. But, in response to Stolte and Eidt’s commentary, I have not seen any case of complete or permanent regression of the lymphoplasmacytic

proliferation if the muscularis mucosa was unequivocally invaded (unpublished observation). This invasion of the muscularis mucosae is almost always associated with cytological evidence of transformation-ie, the appearance of atypical plasma cells, plasmablasts, and immunoblasts.2 Thus, the important question that remains to be answered is, can the administration of antimicrobials cause a complete and permanent regression of a "true" lymphoma, or does it merely control a proliferative process responding to bacterial antigens and thus decreasing the possibility of neoplastic transformation? As I have previously postulated, eradication of the bacterial infection and possible prophylactic effect of antibiotics against any further bacterial colonisation in the case of tetracyclines in MDL may restore the mucosal immune balance that could have been disturbed by the exposure to bacterial toxins and/or antigens.

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I feel confident that the long international experience with MDL can positively contribute to knowledge about the part that antimicrobials can play to control and hopefully prevent some of the lymphoproliferative diseases of the gastrointestinal tract in certain clinicopathological and/or geographical

settings. Tahseen Al-Saleem Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PN 19111, USA

Al-Saleem T. Evidence of acquired immune deficiencies in Mediterranean lymphoma: a possible etiological link. Lancet 1978; ii: 709-12. 2 Al-Saleem T, Zardawi IM. Primary lymphomas of the small intestine in Iraq. A pathological study of 145 cases. Histopathology 1979; 3: 89-106. 3 Al-Bahrani ZR, Al-Mondhiry H, Bakir F, Al-Saleem T. Clinical and pathologic subtypes of primary intestinal lymphoma: experience with 132 patients over a 14-year period. Cancer 1983; 52: 1666-72. 4 Ben-Ayed F, Halphen M, Najjar T, et al. Treatment of &agr;-chain disease, results of a prospective study in 21 Tunisian patients by the Tunisian-French intestinal lymphoma study group. Cancer 1989; 63: 1251-56. 1

Genetic alterations in bladder cancer SiR-Dalbagni and colleagues (Aug 21, p 469) address the important issue of whether there is an identifiable sequence of genetic events leading to bladder cancer progression. We have accumulated data on many genetic changes, including the frequencies of deletion of all autosomal chromosome arms for a large series of tumours.n2 Our findings, like those of Dalbagni and others, identify several frequent genetic alterations, all of which, apart from deletions of chromosome 9, are present at higher frequency in invasive bladder tumours. Changes that present in the more aggressive tumours may be "late" genetic events, but what is known about the natural history of bladder cancer precludes this interpretation. As stated by Dalbagni, transitional cell tumours are characterised by two distinct modes of presentation associated with different prognoses. Most tumours are superficial (Ta), papillary tumours at presentation, and estimates of the frequency of progression of such lesions vary from only 5 to 25% according to the definition of superficial adopted (which may include Ta lesions only or both Ta and Tl lesions). By contrast, most invasive bladder tumours are invasive at presentation and progression is common. These two broad groups probably represent genetically different entities, and genetic changes identified only in invasive tumours are probably important differences between the groups. However, these groups are clinically distinct, and since a clear developmental continuum does not exist, no conclusions can be drawn about the temporal sequence of events. Essentially, we have a series of genetic snapshots of large numbers of bladder tumours at a single point in their development; we have information on the frequency of particular changes and their association with pathological indices, but to attempt to draw temporal conclusions at this stage, seems premature. Dalbagni’s figure depicting the well-known stage classification for bladder tumours combined with a representation of the possible natural history of the disease with proposed temporal sequence of genetic deletions is worrying, since it suggests that many genetic changes (eg, LOH of 5q, 3p, 17p, &c) occur late in tumour progression-ie, at the Ta/T1 transition or later. That these changes are present in such tumours is not in dispute-but when did they occur? An example of the possible dangers and implications of this interpretation are illustrated by considering the timing of p53 mutation in these tumours. When a large series of tumours is studied, it is clear that p53 mutations (and/or 17p deletions) are 1184

frequent in high-grade invasive bladder tumours (ref 3 and Dalbagni et al). Thus, Dalbagni suggests that this may be related to tumour progression. However, as stated by Dalbagni and widely believed by others, some invasive tumours probably have carcinoma in situ (CIS) as a precursor lesion. Since p53 mutation is common in CIS,4 an alternative interpretation is that p53 mutation occurs early in the development of at least some invasive tumours; this does not preclude the possibility that p53 mutation arises late in papillary lesions that progress to muscle invasion, but shows the possible complexities that could exist. How are we to differentiate between primary or initiating events and secondary events that contribute to tumour progression in bladder cancer and determine whether there is a particular sequence of events? An obvious approach seems to be to examine tumours throughout their clinical course, which may be possible for the few patients presenting with CIS as sole lesion that then progresses to invasive carcinoma. For most bladder tumours, however, this approach should be tempered with caution. Multiple tumours may be available from many patients presenting with superficial disease and in some of these, subsequent invasive tumours might be obtained. These tumours may arise at different sites within the bladder, either simultaneously or sequentially, and despite the use of molecular genetic approaches"5 to examine the role of cell seeding, so-called field change, and clonality of bladder tumours, the genetic relation between such tumours remains in question. Combined clinical and molecular studies based on careful interpretation of existing results should provide a full understanding of the natural history of bladder cancer.

more

Margaret A Knowles, Graham A Currie Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 OTL, UK

Cairns P, Shaw ME, Knowles MA. Initiation of bladder cancer may involve deletion of a tumour suppressor gene on chromosome 9. Oncogene 1993; 8: 1083-85. 2 Knowles MA, Elder PA, Williamson MP, Cairns JP, Shaw ME, Law MG. Allelotype of human bladder cancer. Cancer Res (in press). 3 Fujimoto K, Yamada Y, Okajima E, et al. Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res 1992; 52: 1393-98. 4 Miyao N, Tsai YC, Lerner SP, et al. Role of chromosome 9 in human bladder cancer. Cancer Res 1993; 53: 4066-70. 5 Sidransky D, Frost P, von Eschenbach A, Oyasu R, Preisinger AC, Vogelstein B. Clonal origin of bladder cancer. N Engl J Med 1992; 326: 737-40. 1

SiR-Dalbagni and colleagues describe a progression of genetic events in bladder cancer that are analogous to those in colorectal cancer. They state that deletions in 3p, 5q, and 17p are "clearly associated with the transition from pTa to pTI" disease. However, there is considerable evidence that pTa tumours only rarely progress to pTl tumours. In one series with long follow-up, only 19 of 414 (4-6%) pTa tumours showed infiltrative progression.2 This finding is in contrast with pTl tumours, in which up to 40% progress.3 The 5-year survival figures of these two groups are also strikingly different: in one series of 176 patients, disease-related mortality was less than 1 % for pTa tumours and 24% for pT 1 tumours. 4 The chromosomal deletions that Dalbagni et al describe are highly unlikely to be related to stage progression. In their attempt to define an association between specific chromosomal abnormalities and pathological indices of poor outcome, they analysed deletions at 9 separate chromosomal loci and 4 pathological predictors-a total of 36 subgroups. By having such a large number of subgroups analyses and maintaining a significant value of p 0 05 the chances of a type 1 error were greatly increased. As it was, only 3 analyses were reported to achieve significance. =