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Influence of origin of ovarian cancer on efficacy of screening
COMMENTARY
COMMENTARY
Influence of origin of ovarian cancer on efficacy of screening See page 1060
Knowledge about the genesis and evolution of ovarian cancer is limited. Its numerous subtypes differ in their cellular lineage, mode of origin, rate of progression, and susceptibility to early detection.1,2 Like most investigations pertaining to early detection of ovarian cancer, the report by Timothy Crayford and colleagues in today’s Lancet involves a subset of women who were mostly in an age-group in which epithelial cancers are by far the commonest subtype (over 90%), and in which most of these tumours (64%) are serous or undifferentiated carcinomas.3 An unknown but probably predominant proportion of tumours of these cellular subtypes arises de novo from the surface epithelium of the ovary or its inclusion cysts in the peripheral ovarian cortex (figure). These sites of origin enable these neoplasms to spread rapidly, sometimes when they are only microscopical in size,4 and to present clinically at advanced stages (73% serous and 78% undifferentiated carcinomas do so).3 Not surprisingly, therefore, screening for ovarian cancer by ultrasonography, tumour-marker measurements, or both has been disappointing. By contrast with a de novo origin, some ovarian epithelial cancers, probably a minority, arise within or contiguous to benign epithelial tumours (cystadenomas and adenofibromas) or endometriotic tissue1,2,5,6 and could therefore be prevented by excision of these lesions when they have been detected on ultrasonography. In their introduction, Crayford and colleagues present the circumstantial evidence that some ovarian carcinomas arise secondarily in benign lesions, but they share an opinion held by some that no precursor lesions of ovarian cancer have been established. However, pathologists who have identified dysplasia in the surface epithelium of the
ovary or its inclusion cysts6,7 or who have studied the relation of benign (and borderline) epithelial lesions to carcinomas within the same specimen1,2,5,6 have presented persuasive evidence that dysplasia and benign and borderline lesions are precancerous in some cases, even though the frequency and speed of their evolution into cancer remain unknown. The proportion of ovarian cancers that have evolved from benign lesions is unknown for two reasons. First, there have been no prospective pathological investigations directed specifically to the relations between benign, borderline, and malignant epithelial components within ovariancancer specimens. Second, truly benign epithelium in cancer specimens cannot always be distinguished from malignant epithelium that has undergone maturation into benign-looking epithelium. Preliminary molecular genetic investigations have been directed towards resolving the second issue.8 Serous carcinomas arise in benign (and borderline) serous epithelial tumours in some cases, probably a minority. However, mucinous carcinomas, which are much less common (13% of epithelial cancers3) than serous and undifferentiated carcinomas in the western world and may be of either surface-epithelial, germ-cell, or possibly other cellular lineage, seem to arise much more often in cystadenomas than do serous carcinomas, and only rarely do they develop de novo on or near the ovarian surfaces. The results of molecular genetic studies support the view that serous and mucinous carcinomas arise predominantly from contrasting sites.8,9 Endometrioid and clear-cell carcinomas, which together account for 20% of epithelial cancers,3 seem to occupy an intermediate position between serous and mucinous carcinomas as regards their sites of origin; in a
Modes of origin of most ovarian epithelial cancers
De novo carcinoma Borderline epithelial tumour
Surface epithelium and its inclusion cysts
Benign epithelial tumour Carcinoma Endometriosis
1028
THE LANCET • Vol 355 • March 25, 2000
COMMENTARY
substantial number of cases, they arise either in endometriotic tissue or within or contiguous to adenofibromas.1,2 Compared with serous and undifferentiated carcinomas, mucinous, endometrioid, and clear-cell carcinomas generally grow more slowly and present less frequently (33–48%) in advanced stages,3 and because they more commonly have benign epithelial lesions as precursors, they should be more easily detectable at an early stage. Crayford and colleagues’ study was aimed at investigating whether the removal of benign epithelial tumors and non-tumorous lesions lowers the likelihood of development of ovarian cancer. They used the data from an abdominal-ultrasonographic screening study, done between 1981 and 1987, of over 5000 symptomfree women,10 and found that removal of, mostly, benign ovarian cysts that had been detected ultrasonographically was associated with only a slightly lower than expected rate of death from subsequent ovarian cancer during a follow-up period that averaged 15 years. They conclude that this finding does not make the detection and removal of such cysts a cost-effective means of preventing ovarian cancer. In the population that they studied, 59% of the ultrasonographically detected cysts that were removed were physiological or simple cysts (cysts without specific linings), and only 30% were benign epithelial tumours or endometriotic cysts (which in the original study were combined under the rubric “benign epithelial tumours”10). Since physiological cysts and simple cysts have not been implicated in the genesis of ovarian cancer, there is no reason to believe that their removal would have influenced the frequency of development of ovarian cancer. Removal of the benign epithelial tumours and endometriotic cysts may have contributed a little to the slight reduction in death rate from that expected. The bilateral salpingo-oophorectomy done in 90% of the patients who underwent an operation probably had a greater impact on the outcome. Therefore, although Crayford and colleagues’ findings do not contradict evidence that benign epithelial tumours and endometriotic tissue can be sites of origin of some ovarian cancers, they diminish the importance of this pathogenetic route and are consistent with the premise that most ovarian epithelial cancers probably arise de novo and not from benign, generally large, epithelial lesions that are easily detectable on ultrasonography. Although the sensitivity and specificity of ovarian ultrasonography have increased considerably since the early study analysed by Crayford and colleagues, early detection of ovarian cancer remains a major challenge.11 Unfortunately, from the viewpoint of a pathologist, there are only scanty data in published reports on the gross and microscopical features of the lesions that have been detected. Such lesions are commonly reported only as “benign” or “malignant”. The malignant ones, are, in many cases, given only generic designations; if a specific diagnosis is given, the grade of the tumour is often not included, and there is no information about the size of the cancer and whether the tumour arose on the background of a benign or borderline epithelial lesion. Likewise, data are lacking about the pathology of the ovarian cancers that have presented clinically after having been missed by screening. Detailed pathological analysis could contribute important information about the types of cancer that are being detected and the potential
THE LANCET • Vol 355 • March 25, 2000
impact of their detection on reduction of mortality from ovarian cancer. R E Scully James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114, USA 1
Russell P, Farnsworth A, eds. Surgical pathology of the ovaries, second edn. New York: Churchill Livingstone, 1997. 2 Scully RE,Young RH, Clement PB. Atlas of tumor pathology, third series, fascicle 23. Tumors of the ovary, maldeveloped gonads, fallopian tube and broad ligament. Washington, DC: Armed Forces Institute of Pathology, 1998. 3 Pecorelli S (ed). FIGO annual report on the results of treatment in gynaecological cancer, volume 23. J Epidemiol Biostatistics 1998; 3: 1–135. 4 Bell DA, Scully RE. Early de novo ovarian carcinoma: a study of fourteen cases. Cancer 1994; 73: 1859–64. 5 Puls LE, Powell DE, DePriest PD, et al. Transition from benign to malignant epithelium in mucinous and serous ovarian cystadenocarcinoma. Gynecol Oncol 1992; 47: 53–57. 6 Scully RE, Bell DA, Abu-Jawdeh G. Update on early ovarian cancer and cancer developing in benign ovarian tumors. In: Sharp F, Mason P, Blackett T, Berek J. eds. Ovarian cancer 3. London: Chapman and Hall, 1995: 139–44. 7 Deligdisch L. Ovarian dysplasia: a review. Int J Gynaecol Cancer 1997; 7: 89–94. 8 Bell DA, Scully RE. Ovary. In: Henson DE, Albores-Saavedra J, eds. Pathology of incipient neoplasia, 3rd edn. New York: Oxford University Press (in press). 9 Caduff RF, Svoboda-Newman SM, Ferguson AW, Johnson CM, Frank TS. Comparison of mutations of Ki Ras and p53 immunoreactivity in borderline and malignant epithelial ovarian tumors. Am J Surg Pathol 1999; 23: 323–28. 10 Bhan V, Amso N, Whitehead MI, Campbell S, Roynton, P, Collins WP. Characteristics of persistent ovarian masses in asymptomatic women. Br J Obstet Gynaecol 1989; 96: 1384–91. 11 Rosenthal A, Jacobs I. Ovarian cancer screening. Semin Oncol 1998; 25: 315–25.
No role for NO in asthma? Nitric oxide (NO) is formed in the airways by constitutive nitric-oxide synthase (cNOS), of which there are two isoforms, in vascular endothelial cells and neurons, and by an inducible form of nitric-oxide synthase (iNOS) in epithelial cells and various inflammatory cells.1 Upregulation of iNOS in inflamed airways is thought to increase the concentration of exhaled NO in patients with untreated asthma.2 NO is involved in mast-cell activation, cell chemotaxis, lymphocyte differentiation and may be an endogenous suppressor of inflammation. Interest in the role of NO in asthma has focused on its use as a marker to guide therapy and the possible beneficial effect of its modulation of airway inflammation. In many patients mild asthma is well controlled with the use of inhaled corticosteroids, the mainstay of asthma therapy, and the occasional use of inhaled bronchodilators. However, it is difficult to determine when patients need additional treatment, such as an increase in dose of inhaled steroids, or addition of a long-acting 2-adrenergic agonist or another class of drug. Despite little evidence, quantification of airway inflammation is believed to be clinically useful. Fibreoptic bronchoscopy with biopsy of endothelium for counts of inflammatory cells is too time consuming and invasive to be of general application, and sputum induction with measurement of cell counts and soluble mediators requires a high degree of technical skill to obtain reproducible results. Patients with untreated asthma have high concentrations of exhaled NO, which fall on treatment with inhaled steroids.2,3 Thus, a simple measurement of NO in exhaled air is an attractive 1029
COMMENTARY
Influence of origin of ovarian cancer on efficacy of screening See page 1060
Knowledge about the genesis and evolution of ovarian cancer is limited. Its numerous subtypes differ in their cellular lineage, mode of origin, rate of progression, and susceptibility to early detection.1,2 Like most investigations pertaining to early detection of ovarian cancer, the report by Timothy Crayford and colleagues in today’s Lancet involves a subset of women who were mostly in an age-group in which epithelial cancers are by far the commonest subtype (over 90%), and in which most of these tumours (64%) are serous or undifferentiated carcinomas.3 An unknown but probably predominant proportion of tumours of these cellular subtypes arises de novo from the surface epithelium of the ovary or its inclusion cysts in the peripheral ovarian cortex (figure). These sites of origin enable these neoplasms to spread rapidly, sometimes when they are only microscopical in size,4 and to present clinically at advanced stages (73% serous and 78% undifferentiated carcinomas do so).3 Not surprisingly, therefore, screening for ovarian cancer by ultrasonography, tumour-marker measurements, or both has been disappointing. By contrast with a de novo origin, some ovarian epithelial cancers, probably a minority, arise within or contiguous to benign epithelial tumours (cystadenomas and adenofibromas) or endometriotic tissue1,2,5,6 and could therefore be prevented by excision of these lesions when they have been detected on ultrasonography. In their introduction, Crayford and colleagues present the circumstantial evidence that some ovarian carcinomas arise secondarily in benign lesions, but they share an opinion held by some that no precursor lesions of ovarian cancer have been established. However, pathologists who have identified dysplasia in the surface epithelium of the
ovary or its inclusion cysts6,7 or who have studied the relation of benign (and borderline) epithelial lesions to carcinomas within the same specimen1,2,5,6 have presented persuasive evidence that dysplasia and benign and borderline lesions are precancerous in some cases, even though the frequency and speed of their evolution into cancer remain unknown. The proportion of ovarian cancers that have evolved from benign lesions is unknown for two reasons. First, there have been no prospective pathological investigations directed specifically to the relations between benign, borderline, and malignant epithelial components within ovariancancer specimens. Second, truly benign epithelium in cancer specimens cannot always be distinguished from malignant epithelium that has undergone maturation into benign-looking epithelium. Preliminary molecular genetic investigations have been directed towards resolving the second issue.8 Serous carcinomas arise in benign (and borderline) serous epithelial tumours in some cases, probably a minority. However, mucinous carcinomas, which are much less common (13% of epithelial cancers3) than serous and undifferentiated carcinomas in the western world and may be of either surface-epithelial, germ-cell, or possibly other cellular lineage, seem to arise much more often in cystadenomas than do serous carcinomas, and only rarely do they develop de novo on or near the ovarian surfaces. The results of molecular genetic studies support the view that serous and mucinous carcinomas arise predominantly from contrasting sites.8,9 Endometrioid and clear-cell carcinomas, which together account for 20% of epithelial cancers,3 seem to occupy an intermediate position between serous and mucinous carcinomas as regards their sites of origin; in a
Modes of origin of most ovarian epithelial cancers
De novo carcinoma Borderline epithelial tumour
Surface epithelium and its inclusion cysts
Benign epithelial tumour Carcinoma Endometriosis
1028
THE LANCET • Vol 355 • March 25, 2000
COMMENTARY
substantial number of cases, they arise either in endometriotic tissue or within or contiguous to adenofibromas.1,2 Compared with serous and undifferentiated carcinomas, mucinous, endometrioid, and clear-cell carcinomas generally grow more slowly and present less frequently (33–48%) in advanced stages,3 and because they more commonly have benign epithelial lesions as precursors, they should be more easily detectable at an early stage. Crayford and colleagues’ study was aimed at investigating whether the removal of benign epithelial tumors and non-tumorous lesions lowers the likelihood of development of ovarian cancer. They used the data from an abdominal-ultrasonographic screening study, done between 1981 and 1987, of over 5000 symptomfree women,10 and found that removal of, mostly, benign ovarian cysts that had been detected ultrasonographically was associated with only a slightly lower than expected rate of death from subsequent ovarian cancer during a follow-up period that averaged 15 years. They conclude that this finding does not make the detection and removal of such cysts a cost-effective means of preventing ovarian cancer. In the population that they studied, 59% of the ultrasonographically detected cysts that were removed were physiological or simple cysts (cysts without specific linings), and only 30% were benign epithelial tumours or endometriotic cysts (which in the original study were combined under the rubric “benign epithelial tumours”10). Since physiological cysts and simple cysts have not been implicated in the genesis of ovarian cancer, there is no reason to believe that their removal would have influenced the frequency of development of ovarian cancer. Removal of the benign epithelial tumours and endometriotic cysts may have contributed a little to the slight reduction in death rate from that expected. The bilateral salpingo-oophorectomy done in 90% of the patients who underwent an operation probably had a greater impact on the outcome. Therefore, although Crayford and colleagues’ findings do not contradict evidence that benign epithelial tumours and endometriotic tissue can be sites of origin of some ovarian cancers, they diminish the importance of this pathogenetic route and are consistent with the premise that most ovarian epithelial cancers probably arise de novo and not from benign, generally large, epithelial lesions that are easily detectable on ultrasonography. Although the sensitivity and specificity of ovarian ultrasonography have increased considerably since the early study analysed by Crayford and colleagues, early detection of ovarian cancer remains a major challenge.11 Unfortunately, from the viewpoint of a pathologist, there are only scanty data in published reports on the gross and microscopical features of the lesions that have been detected. Such lesions are commonly reported only as “benign” or “malignant”. The malignant ones, are, in many cases, given only generic designations; if a specific diagnosis is given, the grade of the tumour is often not included, and there is no information about the size of the cancer and whether the tumour arose on the background of a benign or borderline epithelial lesion. Likewise, data are lacking about the pathology of the ovarian cancers that have presented clinically after having been missed by screening. Detailed pathological analysis could contribute important information about the types of cancer that are being detected and the potential
THE LANCET • Vol 355 • March 25, 2000
impact of their detection on reduction of mortality from ovarian cancer. R E Scully James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114, USA 1
Russell P, Farnsworth A, eds. Surgical pathology of the ovaries, second edn. New York: Churchill Livingstone, 1997. 2 Scully RE,Young RH, Clement PB. Atlas of tumor pathology, third series, fascicle 23. Tumors of the ovary, maldeveloped gonads, fallopian tube and broad ligament. Washington, DC: Armed Forces Institute of Pathology, 1998. 3 Pecorelli S (ed). FIGO annual report on the results of treatment in gynaecological cancer, volume 23. J Epidemiol Biostatistics 1998; 3: 1–135. 4 Bell DA, Scully RE. Early de novo ovarian carcinoma: a study of fourteen cases. Cancer 1994; 73: 1859–64. 5 Puls LE, Powell DE, DePriest PD, et al. Transition from benign to malignant epithelium in mucinous and serous ovarian cystadenocarcinoma. Gynecol Oncol 1992; 47: 53–57. 6 Scully RE, Bell DA, Abu-Jawdeh G. Update on early ovarian cancer and cancer developing in benign ovarian tumors. In: Sharp F, Mason P, Blackett T, Berek J. eds. Ovarian cancer 3. London: Chapman and Hall, 1995: 139–44. 7 Deligdisch L. Ovarian dysplasia: a review. Int J Gynaecol Cancer 1997; 7: 89–94. 8 Bell DA, Scully RE. Ovary. In: Henson DE, Albores-Saavedra J, eds. Pathology of incipient neoplasia, 3rd edn. New York: Oxford University Press (in press). 9 Caduff RF, Svoboda-Newman SM, Ferguson AW, Johnson CM, Frank TS. Comparison of mutations of Ki Ras and p53 immunoreactivity in borderline and malignant epithelial ovarian tumors. Am J Surg Pathol 1999; 23: 323–28. 10 Bhan V, Amso N, Whitehead MI, Campbell S, Roynton, P, Collins WP. Characteristics of persistent ovarian masses in asymptomatic women. Br J Obstet Gynaecol 1989; 96: 1384–91. 11 Rosenthal A, Jacobs I. Ovarian cancer screening. Semin Oncol 1998; 25: 315–25.
No role for NO in asthma? Nitric oxide (NO) is formed in the airways by constitutive nitric-oxide synthase (cNOS), of which there are two isoforms, in vascular endothelial cells and neurons, and by an inducible form of nitric-oxide synthase (iNOS) in epithelial cells and various inflammatory cells.1 Upregulation of iNOS in inflamed airways is thought to increase the concentration of exhaled NO in patients with untreated asthma.2 NO is involved in mast-cell activation, cell chemotaxis, lymphocyte differentiation and may be an endogenous suppressor of inflammation. Interest in the role of NO in asthma has focused on its use as a marker to guide therapy and the possible beneficial effect of its modulation of airway inflammation. In many patients mild asthma is well controlled with the use of inhaled corticosteroids, the mainstay of asthma therapy, and the occasional use of inhaled bronchodilators. However, it is difficult to determine when patients need additional treatment, such as an increase in dose of inhaled steroids, or addition of a long-acting 2-adrenergic agonist or another class of drug. Despite little evidence, quantification of airway inflammation is believed to be clinically useful. Fibreoptic bronchoscopy with biopsy of endothelium for counts of inflammatory cells is too time consuming and invasive to be of general application, and sputum induction with measurement of cell counts and soluble mediators requires a high degree of technical skill to obtain reproducible results. Patients with untreated asthma have high concentrations of exhaled NO, which fall on treatment with inhaled steroids.2,3 Thus, a simple measurement of NO in exhaled air is an attractive 1029