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Immunopathology and immunotherapy in leukaemia
Pathology (1979), 11, pp :10115
ABSTRACTS OF PAPERS PRESENTED AT THE ANNUAL MEETING OF THE ROYAL COLLEGE OF PATHOLOGISTS OF AUSTRALIA HELD IN CANBERRA August 1978
PLENARY SESSIONS
1. CARCINOMA OF THE BREAST SURGERY FOR THE PATIENT WITH BREAST SYMPTOMS
C. 1.
MAGAREY
St George Hospital, Sydne)'
Cure of breast cancer happens when the host maintains superiority in her relationship with her tumour. Since breast cancer is a disseminated disease host defences are as important in the surgery of breast cancer as is adaquate removal of the primary tumour. Radical local treatment alone is insufficient. Psychological factors and emotional stress have a powerful effect on behaviour, such as delay in reporting breast symptoms, and on the endocrine and immune systems important in host defences. The surgical approach to breast symptoms should, therefore, aim to provoke the least emotional stress and encourage appropriate behaviour such as the early reporting of symptoms. The management of the patient with breast symptoms should, therefore, include prompt investigation and a decision as to whether cancer is a possibility, pre-operative histological diagnosis and counselling, appropriately conservative operation, and sensitive rehabilitation. 2. ADULT LEUKAEMIA IMMUNOPATHOLOGY AND IMMUNOTHERAPY IN LEUKAEMIA
A.
BASTEN
Department of Clinical Immunology, Royal Prince Alfred Hospital. Sydney
Expression of distinctive antigens on the membrane ofleukaemic cells is essential if the host is to mount a significant immune response against the leukaemia. In the case of adult leukaemia, the existence of such antigens has been difficult to demonstrate despite the use of a multiplicity of techniques. Thus the cytotoxic antibodies raised against leukaemic cells during immunotherapy with allogeneic blasts have been shown to be directed not against leukaemic specific antigens, but rather against HLA antigens shared by immunizing and test target cells. Furthermore, it has not been easy to demonstrate cytotoxic Iymphocytes against autologous blasts unless third party allogeneic cells are added to the system. The latter observation is particularly interesting for two reasons. First it suggests that leukaemia specific antigens are demonstrable given the right experimental conditions; secondly it implies that the host's immune system will not normally recognize these antigens in vivo owing to the lack of an essential second signal and/or to the presence of inhibitory (suppressor) influences. In view of the above findings, the overall lack of success of immunotherapy in adult leukaemia comes as no surprise. The only notable exception to this is the Barts 3 trial where a significant prolongation in median survival time of patients receiving immunotherapy was demonstrable. It should, however, be stressed that the chemotherapy used in this trial was suboptimal by modern day criteria and less effective than that used in other studies including the national trial recently completed here. The only role for nonspecific immunotherapy may therefore be in prevention and treatment of opportunistic infections particularly in patients who have achieved a remission.
302
ROYAL COLLEGE OF PATHOLOGISTS OF AUSTRALIA
Pathology (1979), 11, April
Future improvements in immunological methods for diagnosis and therapy will depend on better definition of leukaemic antigens and markers. The recent demonstration of elevated levels of terminal transferase in blasts frOIU ALL but not in those from AML holds promise as a method for distinguishing the two. Furthermore, the availability of hybridomas as a source of monoclonal antibodies to membrane antigens on both blasts and lymphocyte subclasses may prove a useful tool for analysis of antileukaemic immune responses. CYTOGENETICS IN ACUTE LEUKAEMIA
O. M. GARSON University olMelbourne Department of Medicine, St Vincent's Hospital, Melhourne Chromosome studies in acute leukaemia, prior to the introduction of banding techniques, showed that approximately 50% of patients had chromosome abnormalities in their leukaemic cells. In general these abnormalities were marked hyperdiploidy in acute lymphoblastic leukaemia, and hypodiploidy or mild hyperdiploidy in acute non-lymphoblastic leukaemia. In some cases, both normal and abnormal cell lines existed together in the one patient. No cytogenetic change was found in the other 50% of patients. With the increased precision of chromosome identification made possible by banding techniques, many of the varied changes previously described in acute leukaemic cells are found to be non-random. The chromosomes involved specifically are 5, 7, 8, 9, and 21, with alterations being either in number, mainly trisomy or monosomy, or in structure, i.e. deletion or translocation. Additional random changes also occured. It is now possible to assign specific karyotypes to certain types ofleukaemia, thus making the cytogenetic analysis of bone marrow cells in acute leukaemia a useful diagnostic procedure. A lack of mitoses in chomosome preparations at diagnosis appears to carry a poor prognosis, as does the presence of many random chromosome changes in the leukaemic cell lines. Chemotherapy may be altered according to the detection of these features. The fact that non-random chromosome changes occur in acute leukaemia and in the acute or blastic phase of chronic granulocytic leukaemia, suggests that a genetic factor may be involved in the development of the disease. In addition there appears to be a relationship between virus combining sites and virus induced changes in particular human chromosomes, and the non-random changes present in leukaemia. 3. BIOCHEMICAL MARKERS IN MALIGNANT DISEASE TUMOUR ASSOCIATED ANTIGENS
K. D.
BAGSHAWE
Department ol Medical Oncology, Charing Cross Hospital, London
The identification of substances in the serum that are indicative of the presence of tumours and that relate quantitatively to viable tumour cell mass has been an objective for several years. Diagnostic methods, like treatment methods are begining to emerge along tumour specific lines and there is an important interaction between diagnosis, monitoring and therapy. Three broad approaches have been used. The first is the detection of biochemical responses by host tissues to the presence of tumour; the second is the measurement of tumour export products, particularly the polypeptides; the third is the detection of cell mediated responses to tumour associated antigens. Collectively these already present a formidable list but the number of unequivocally useful marker systems remains few. Tumour products may be eutopic or ectopic and the present discussion will be largely confined to the eutopic. Their serum concentrations are the product of secretion and clearance rates. Localization of tumours by selective venous sampling is theoretically possible but rarely useful in practice. HCG as the marker for trophoblastic tumours remains the archetype of tumour markers and can be used to illustrate their considerable potential and their limitations. Other tumour associated antigens which will be considered include pregnancy glycoprotein SPI, placental alkaline phosphatase, prostatic acid phosphatase, alpha fetoprotein, K-Cascin, carcino-embryonic antigen and new antigens extracted from ovary and bronchial tumours. HORMONES PRODUCED BY TUMOURS
T. V.
STEPANAS
Endocrine Unit, Woden Valley Hospital, Canherra
There are 2 broad areas of tumour-related endocrinology: (I) Appropriate hormones secreted in inappropriate quantities by recognizable endocrine tumours, and (2) Inappropriate hormones secreted in any quantity by overtly non-endocrine tumours (the so-called 'ectopic hormones'). In either case, the hormones secreted, and the clinical syndrome resulting from such secretion may serve as a tumour marker for early detection of the tumour and for follow-up reassessment of adequacy of treatment. Recognition of ectopic hormone production is limited only by the interests and intuition of the clinician and the
ABSTRACTS OF PAPERS PRESENTED AT THE ANNUAL MEETING OF THE ROYAL COLLEGE OF PATHOLOGISTS OF AUSTRALIA HELD IN CANBERRA August 1978
PLENARY SESSIONS
1. CARCINOMA OF THE BREAST SURGERY FOR THE PATIENT WITH BREAST SYMPTOMS
C. 1.
MAGAREY
St George Hospital, Sydne)'
Cure of breast cancer happens when the host maintains superiority in her relationship with her tumour. Since breast cancer is a disseminated disease host defences are as important in the surgery of breast cancer as is adaquate removal of the primary tumour. Radical local treatment alone is insufficient. Psychological factors and emotional stress have a powerful effect on behaviour, such as delay in reporting breast symptoms, and on the endocrine and immune systems important in host defences. The surgical approach to breast symptoms should, therefore, aim to provoke the least emotional stress and encourage appropriate behaviour such as the early reporting of symptoms. The management of the patient with breast symptoms should, therefore, include prompt investigation and a decision as to whether cancer is a possibility, pre-operative histological diagnosis and counselling, appropriately conservative operation, and sensitive rehabilitation. 2. ADULT LEUKAEMIA IMMUNOPATHOLOGY AND IMMUNOTHERAPY IN LEUKAEMIA
A.
BASTEN
Department of Clinical Immunology, Royal Prince Alfred Hospital. Sydney
Expression of distinctive antigens on the membrane ofleukaemic cells is essential if the host is to mount a significant immune response against the leukaemia. In the case of adult leukaemia, the existence of such antigens has been difficult to demonstrate despite the use of a multiplicity of techniques. Thus the cytotoxic antibodies raised against leukaemic cells during immunotherapy with allogeneic blasts have been shown to be directed not against leukaemic specific antigens, but rather against HLA antigens shared by immunizing and test target cells. Furthermore, it has not been easy to demonstrate cytotoxic Iymphocytes against autologous blasts unless third party allogeneic cells are added to the system. The latter observation is particularly interesting for two reasons. First it suggests that leukaemia specific antigens are demonstrable given the right experimental conditions; secondly it implies that the host's immune system will not normally recognize these antigens in vivo owing to the lack of an essential second signal and/or to the presence of inhibitory (suppressor) influences. In view of the above findings, the overall lack of success of immunotherapy in adult leukaemia comes as no surprise. The only notable exception to this is the Barts 3 trial where a significant prolongation in median survival time of patients receiving immunotherapy was demonstrable. It should, however, be stressed that the chemotherapy used in this trial was suboptimal by modern day criteria and less effective than that used in other studies including the national trial recently completed here. The only role for nonspecific immunotherapy may therefore be in prevention and treatment of opportunistic infections particularly in patients who have achieved a remission.
302
ROYAL COLLEGE OF PATHOLOGISTS OF AUSTRALIA
Pathology (1979), 11, April
Future improvements in immunological methods for diagnosis and therapy will depend on better definition of leukaemic antigens and markers. The recent demonstration of elevated levels of terminal transferase in blasts frOIU ALL but not in those from AML holds promise as a method for distinguishing the two. Furthermore, the availability of hybridomas as a source of monoclonal antibodies to membrane antigens on both blasts and lymphocyte subclasses may prove a useful tool for analysis of antileukaemic immune responses. CYTOGENETICS IN ACUTE LEUKAEMIA
O. M. GARSON University olMelbourne Department of Medicine, St Vincent's Hospital, Melhourne Chromosome studies in acute leukaemia, prior to the introduction of banding techniques, showed that approximately 50% of patients had chromosome abnormalities in their leukaemic cells. In general these abnormalities were marked hyperdiploidy in acute lymphoblastic leukaemia, and hypodiploidy or mild hyperdiploidy in acute non-lymphoblastic leukaemia. In some cases, both normal and abnormal cell lines existed together in the one patient. No cytogenetic change was found in the other 50% of patients. With the increased precision of chromosome identification made possible by banding techniques, many of the varied changes previously described in acute leukaemic cells are found to be non-random. The chromosomes involved specifically are 5, 7, 8, 9, and 21, with alterations being either in number, mainly trisomy or monosomy, or in structure, i.e. deletion or translocation. Additional random changes also occured. It is now possible to assign specific karyotypes to certain types ofleukaemia, thus making the cytogenetic analysis of bone marrow cells in acute leukaemia a useful diagnostic procedure. A lack of mitoses in chomosome preparations at diagnosis appears to carry a poor prognosis, as does the presence of many random chromosome changes in the leukaemic cell lines. Chemotherapy may be altered according to the detection of these features. The fact that non-random chromosome changes occur in acute leukaemia and in the acute or blastic phase of chronic granulocytic leukaemia, suggests that a genetic factor may be involved in the development of the disease. In addition there appears to be a relationship between virus combining sites and virus induced changes in particular human chromosomes, and the non-random changes present in leukaemia. 3. BIOCHEMICAL MARKERS IN MALIGNANT DISEASE TUMOUR ASSOCIATED ANTIGENS
K. D.
BAGSHAWE
Department ol Medical Oncology, Charing Cross Hospital, London
The identification of substances in the serum that are indicative of the presence of tumours and that relate quantitatively to viable tumour cell mass has been an objective for several years. Diagnostic methods, like treatment methods are begining to emerge along tumour specific lines and there is an important interaction between diagnosis, monitoring and therapy. Three broad approaches have been used. The first is the detection of biochemical responses by host tissues to the presence of tumour; the second is the measurement of tumour export products, particularly the polypeptides; the third is the detection of cell mediated responses to tumour associated antigens. Collectively these already present a formidable list but the number of unequivocally useful marker systems remains few. Tumour products may be eutopic or ectopic and the present discussion will be largely confined to the eutopic. Their serum concentrations are the product of secretion and clearance rates. Localization of tumours by selective venous sampling is theoretically possible but rarely useful in practice. HCG as the marker for trophoblastic tumours remains the archetype of tumour markers and can be used to illustrate their considerable potential and their limitations. Other tumour associated antigens which will be considered include pregnancy glycoprotein SPI, placental alkaline phosphatase, prostatic acid phosphatase, alpha fetoprotein, K-Cascin, carcino-embryonic antigen and new antigens extracted from ovary and bronchial tumours. HORMONES PRODUCED BY TUMOURS
T. V.
STEPANAS
Endocrine Unit, Woden Valley Hospital, Canherra
There are 2 broad areas of tumour-related endocrinology: (I) Appropriate hormones secreted in inappropriate quantities by recognizable endocrine tumours, and (2) Inappropriate hormones secreted in any quantity by overtly non-endocrine tumours (the so-called 'ectopic hormones'). In either case, the hormones secreted, and the clinical syndrome resulting from such secretion may serve as a tumour marker for early detection of the tumour and for follow-up reassessment of adequacy of treatment. Recognition of ectopic hormone production is limited only by the interests and intuition of the clinician and the