CASE REPORTS
615
British Journal of Obstetrics and Gynaecology July 1992, Vol. 99, pp. 615-617
The treatment of microscopic residual ovarian cancer with intraperitoneal interferon: a clinical and flow cytometric study J . S. W H E L A N ICRF Department of Medical Oncology P. A. VAN DAM J. H. SHEPHERD The Gynaecological Oncology Unit M. L. S L E V I N ICRF Department of Medical Oncology St. Bartholomew’s Hospital London E C l A 7BE, UK
Case report A 29-year-old woman presented in 1981 with post-coital bleeding and an abnormal smear. Colposcopy was negative and a diagnostic cone biopsy was performed. Histology of the specimen revealed a well differentiated Stage la papillary adenocarcinoma of the cervix which was treated by extended total abdominal hysterectomy; both ovaries were preserved. In February, 1988, a mass at the vaginal vault was noted at routine follow-up. At laparotomy, a mobile 10 cm x 12 cm right ovarian tumour was found. Frozen section examination of the neoplasm suggested a primary serous papillary adenocarcinoma; this was later confirmed on paraffin sections. A radical oophorectomy, consisting of a bilateral salpingo-ophorectomy, infracolic omentectomy, multiple biopsies and washings, was carried out. Peritoneal washings taken at the time of laparotomy contained adenocarcinoma cells, but diaphragmatic brushings were negative. The tumour was staged as Stage l c according to the FIG0 criteria. Comparison with sections from the cone biopsy in 198 1 did not suggest concordance between the two tumours. Intermittent chlorambucil(l0 mg/day) was given for a total of 12 weeks, but although at subsequent laparoscopy no macroscopic abnormality was identified, peritoneal washings were again positive. After five cycles of intraperitoneal carboplatin (400 mg/m’ every 4 weeks), peritoneal washings still contained malignant cells. Laparoscopy was otherwise normal, as were abdominal and pelvic CT scans. In August, 1989, she began treatment with intraperitoneal a - 2 interferon (Intron A, Kirby-Warwick). Fifty million units were instilled in 1 5. litres of warmed dialysate via a Tenchkoff catheter, weekly for 16 weeks. Before each course of treatment peritoneal washings were taken for cytological and flow cytometric examination. Toxicity predominantly consisted of influenza-like symptoms: fever, fatigue and muscular aches. While most of these symptoms abated within 72 h each week, fatigue persisted Correspondence: Dr J. S. Whelan.
throughout the period of treatment. Haematological toxicity is shown in Fig. I. Viable adenocarcinoma cells disappeared from the peritoneal washings after the first week of therapy. On two subsequent occasions (weeks 5 and s), there was difficulty distinguishing viable malignant cells from dead tumour cells and mesothelial cells. Flow cytometric multiparameter analysis of the peritoneal washings revealed a pretreatment DNA diploid cell population. In addition, a second, near-diploid, tumour cell population was suspected from the high coefficient of variation (CV, 6.78) and a skewed GO/Gl peak. The analysis of tumourassociated antigen and oncoprotein expression showed that epidermal growth factor receptor (EGFR) expression was moderately high before treatment but became strikingly elevated after the first week of interferon therapy. After two weeks of treatment, however, there was a dramatic fall in EGFR expression and this coincided with a change in the DNA histogram as the near-diploid population disappeared and the CV fell ( 4 . 2 3 4 4 6 ) . Only low levels of tumour-associated antigens and transmembrane oncoprotein, c-erbB-2, were found before therapy (Table I). Serum CA 125 levels fell rapidly to within normal limits (Fig. 2). The patient remains in complete remission, with a normal serum CA 125,28 months after completing treatment.
Discussion In advanced ovarian cancer, combination chemotherapy given after initial debulking surgery is often unsuccessful in completely eradicating disease (Neijit et al. 1984; Dembo 1986). Adjuvant therapy may prolong survival in patients with early stage disease (Young et al. 1990). However, if there is residual tumour after chemotherapy, the effective treatment of epithelial ovarian cancer is seldom achieved (Berek 1989). Theoretically, intraperitoneal administration of drugs may offer a pharmacological advantage over the intravenous route
=
-
2
0
1 1 0 =:
300 r 250
X
; 200 * al
5 150 c
-a -
100
1
0
.
,a
‘-hw----
= = =,-Y
4 ;
I
2 50 0 1 2 3 4 5 6 7 8 91011121314151617161920
Weeks of therapy
Fig. 1. Effect of intraperitoneal a-interferon treatment on haematological indices: ( 0 )haemoglobin (Hb); (+) white blood cells; (*) platelets.
616
C A S E REPORTS
Table 1. Tumour associated antigen and oncoprotein expression (in arbitary fluorescence units) in cells retrieved from peritoneal washings during intraperitoneal a-interferon therapy) Week of therapy Marker EGFR C-erbB-2 C-myc SM3 CA 125 HMFG 1
0
1
2
4
16
65 36 42 7 24 35
195 30 35 10 84 18
33 69 6 28 48 22
28 51 26 0 43 6
13 38 2 3 3 17
EGFR = epidermal growth factor receptor. HMFGl = human milk for globulin 1. SM3 = stripped mucin 3. C-erbB-2 and c-myc are oncoproteins.
in the management of ovarian cancer (Los & McVie 1990). However, data from several studies suggest that worthwhile responses are limited to patients with minimal residual (< 5 mm) or microscopic disease (Berek et a/. 1985; Howell et al. 1987. Nardi et al. 1990). Methods to optimize this approach include the use of combinations of cytotoxic agents, and the instillation of biological response modifiers, in particular a-interferon. Berek et al. (1985) first reported the use of intraperitoneal a-interferon for the treatment oE ovarian cancer. The rationale for this approach was supported by in vitro studies which suggested a specific cytostatic and cytolytic role for this agent against ovarian carcinoma cells (Epstein et al. 1980; Allavena et al. 1982). Subsequently, a significant increase in peritoneal ‘natural killer cell’ activity has been demonstrated after the intraperitoneal administration of @-interferon(Lichtenstein et al. 1988). Four of 11 patients had complete remission confirmed surgically; all four had disease less than 5 mm in diameter. There was no benefit observed in those with more extensive disease (Berek et al. 1985). Despite the promise of this first report and confirmation from another small study (Willemse eta/. 1989), no larger studies have been initiated to better define the role of intraperitoneal a-interferon alone in
microscopic ovarian cancer. Others have, however, begun to use it in combination intraperitoneal therapy (Nardi et a/. 1990). Monitoring response to such treatment may be difficult. Conventional cytology of peritoneal fluid may be misleading (Sagae eta/. 1988). Furthermore, serum CA 125 levels may be normal in the presence of microscopic disease (Welander et al. 1988). It has been suggested that flow cytometric DNA analysis is an accurate method for the detection of malignant cells within peritoneal washings and may augment cytological examination (Lovecchio et al. 1986; Sinton e t a / . 1990). However, the value of these measurements is limited in the absence of a tumour cell population with a DNA content that is clearly distinguishable from the normal diploid population. This was illustrated in this case when pretreatment analysis of DNA content did not clearly separate an abnormal cell population. Hence, measurement of other variables, such as oncoprotein expression, has been employed in an attempt to increase sensitivity. In this report, the initial rise followed by a spectacular drop in EGFR expression shortly after the start of treatment coincided with a disappearance of tumour cells, as determined by cytological examination and suspected from flow cytometric DNA analysis, thus providing further evidence of response. Therefore, multiparameter flow cytometry in conjunction with classic immunocytology may be a powerful tool for the study of cell subpopulations in these heterogenous cell systems (see Commentary by van Dam & Lowe in this issue of the Journal p. 545). Despite having early stage disease (Ic), a dismal prognosis was predictable for our patient. This report confirms that intraperitoneal a-interferon may be used successfully for the treatment of microscopic ovarian cancer remaining after optimal chemotherapy, and that, even when high doses are used for a sustained period, this treatment has acceptable toxicity. Further studies of its use are therefore warranted. These should be accompanied by the assessment of more sensitive techniques for monitoring response, such as single and multiparameter flow cytometric assays.
Acknowledgments The authors are grateful for the invaluable help and support of the nursing staff of the Renal Unit and Stanmore Ward at St Bartholomew’s Hospital. Dr P. van Dam was supported by a Belgisch Werk Teken Kanker grant.
References
0
I
I
1
2
4
6
I
I
I
I
8 10 12 14 Weeks of therapy
I
I
I
16
18
20
Fig. 2. Serum CA 125 levels (normal range < 30 unitsflitre) during intraperitoneal a-interferon therapy.
Allavena P., Introna M., Sessa C., Mangioni C & Mantovani A. (1982) Interferon effect on cytotoxicity of peripheral blood and turnorassociated lymphocytes against human ovarian carcinoma cells. J Natl Cancer Inst 68, 552-562. Berek J. S. (1989) Epithelial ovarian cancer. In. Practical Gynecologic Oncology (Berek J. S., Hacker N. F. eds), Williams & Wilkins, Baltimore, 327-364. Berek J. S. Hacker N. V., Lichtenstein A. et al. (1986) Intraperitoneal recombinant a-Interferon for ’salvage’ immunotherapy in stage 111 ovarian cancer: a gynecologic oncology group study. Cancer Res 45,4447-4453. Dembo A. J. (1986) Controversy over combination chemotherapy: what we learn from reports of matured data. J Clin Oncol 4, 1573-1576.
C A S E REPORTS
Epstein L. B., Shen J-T., Abele J. S. & Rese C. C. (1980) Sensitivity of human ovarian cancer cells to interferon and other anti-tumor agents as assessed by an in vitro semi-solid agar technique. Ann NY Acad Sci 350,228-244. Howell S. B., Simm S., Markman M., Abramson I. S., Cleary S., Lucas W. E. & Weiss R. J. (1987) Long-term survival of advanced refractory ovarian cancer patients with small volume disease treated with intraperitoneal chemotherapy. J Clin Oncol 6, 1607-1612. Lichtenstein A., Spina C., Berek J. S., Jung T. & Zighelboim J. (1988) Intraperitoneal administration of human recombinant interferon-a in patients with ovarian cancer: Effects on lymphocyte phenotype and cytotoxicity. Cancer Res 48,5853-5859. Los G. & McVie J. G. (1990) Experimental and clinical status of intraperitoneal chemotherapy. Eur J Cancer 26,755-762. Lovecchio J. L., Budman D. R., Susin M., Grueneberg D. & Fenton A. N. (1986) Flow cytometry of peritoneal washings in gynecologic neoplasia. Obstet Gynecol81,55-59. Nardi M., Cognetti F., Pollera C. F., Della Guila M., Lombardi A,, Atlante G. & Calabresi F. (1990) Intraperitoneal recombinant alpha-2-interferon alternating with cisplatin as salvage therapy for minimal residual disease ovarian cancer: a phase I1 study. J Clin Oncol8, 1036-1041. Neijit J. P., Van Der Berg M. E. L., Vriesendorp R. et al. (1984). Randomized trial comparing two combination chemotherapy regimens (hexa-CAF vs CHAP-5) in advanced ovarian cancer. Lancet ii, 594-600.
617
Sagae S., Berek J. S., Fu Y. S., Chang N., Dauplat J. & Hacker N. F. (1988) Peritoneal cytology of ovarian cancer patients receiving intraperitoneal therapy: quantitation of malignant cells and response. Obstet Gynecol75, 782-788. Sinton E. B., Carver R. K., Morgan D. L., Philpott P. S., True11 J. E., Riemann D. & Ashton M. E. (1990) Prospective study of concurrent ploidy analysis and routine cytopathology in body cavity fluids. Arch Pathol Lab Med 114, 188-191. van Dam P. A. & Lowe D. G. (1992) Flow cytometry, commentary. Br J Obset Gynaecol99,545-546. Welander C., Geisinger K., Barrett R., Homesley H. & Grossberg H. (1988) Peritoneal cytology as a means of response evaluation for intraperitoneal therapy of minimal residual ovarian cancer. Proc ASCO 7,545a. Willemse P. H. B., de Vries E. G. E., Oosterhuis B. E., Aalders J. G., Bourma J., Mulder N. H. & Sleijfer D. T. (1989) Intraperitoneal human r-IFN-2ab in patients with stage 111 minimal residual ovarian cancer. Proc ASCO 8, 155. Young R. C., Walton L. A., Ellenberg S. S. et al. (1990). Adjuvant therapy in Stage I and Stage I1 ovarian cancer: results of two randomized trials. N En81 J Med 322, 1021-1027.
Received 19 July 1991 Accepted 12 December 1991
British Journal of Obstetrics and Gynaecology July 1992, Vol. 99, pp. 617419
Primary serous carcinoma of the female peritoneum. Report of a case with a re-examination of a histogenetic problem based on the use of a specific antimesothelial-cell antibody P. G . BETTA Service of Pathological Anatomy Santo Spirito Hospital, Casale Monferrato, Italy S. C O V E R L I Z Z A Service of Pathological Anatmomy Giovanni Bosco Hospital Turin, Italy A. DONNA Service of Pathological Anatomy City Hospital, Alessandria, Italy M. RISIO Service of Pathological Anatomy San Giovanni Vecchio Hospital Turin, Italy Correspondence: Dr P. G. Betta, Service of Pathological Anatomy and Cytopathology, Santo Spirito Hospital, Vale Giolitti 2. 1-15033, Casale Monferrato, Italy.
Case report A 75-year-old woman was admitted because of ascites, weight loss, nausea and severe asthenia of 2-month duration. Her health had been good. She had worked as a wool weaver in a textile factory for more than 30 years. Radiological studies, including ultrasound and computerized tomography of the abdomen, were non-contributory. The finding of malignant epithelial cells in the ascitic fluid suggested a possible metastatic involvement of the peritoneum from an unknown primary carcinoma. At laparotomy, almost 4 litres of haemorrhagic fluid were removed from the peritoneal cavity and abdominopelvic carcinomatosis was apparrent. Widespread tumour implants were found on both the visceral and parietal peritoneum and the omentum. A partial surgical debulking was performed, consisting of total hysterectomy, bilateral oophorectomy and omentectomy together with biopsies of two neoplastic nodules on the lower surface of the liver. Postoperatively the patient received chemotheraphy with 5-fluorouracil (600 mg/m2/week for 12 cycles) and she was still
615
British Journal of Obstetrics and Gynaecology July 1992, Vol. 99, pp. 615-617
The treatment of microscopic residual ovarian cancer with intraperitoneal interferon: a clinical and flow cytometric study J . S. W H E L A N ICRF Department of Medical Oncology P. A. VAN DAM J. H. SHEPHERD The Gynaecological Oncology Unit M. L. S L E V I N ICRF Department of Medical Oncology St. Bartholomew’s Hospital London E C l A 7BE, UK
Case report A 29-year-old woman presented in 1981 with post-coital bleeding and an abnormal smear. Colposcopy was negative and a diagnostic cone biopsy was performed. Histology of the specimen revealed a well differentiated Stage la papillary adenocarcinoma of the cervix which was treated by extended total abdominal hysterectomy; both ovaries were preserved. In February, 1988, a mass at the vaginal vault was noted at routine follow-up. At laparotomy, a mobile 10 cm x 12 cm right ovarian tumour was found. Frozen section examination of the neoplasm suggested a primary serous papillary adenocarcinoma; this was later confirmed on paraffin sections. A radical oophorectomy, consisting of a bilateral salpingo-ophorectomy, infracolic omentectomy, multiple biopsies and washings, was carried out. Peritoneal washings taken at the time of laparotomy contained adenocarcinoma cells, but diaphragmatic brushings were negative. The tumour was staged as Stage l c according to the FIG0 criteria. Comparison with sections from the cone biopsy in 198 1 did not suggest concordance between the two tumours. Intermittent chlorambucil(l0 mg/day) was given for a total of 12 weeks, but although at subsequent laparoscopy no macroscopic abnormality was identified, peritoneal washings were again positive. After five cycles of intraperitoneal carboplatin (400 mg/m’ every 4 weeks), peritoneal washings still contained malignant cells. Laparoscopy was otherwise normal, as were abdominal and pelvic CT scans. In August, 1989, she began treatment with intraperitoneal a - 2 interferon (Intron A, Kirby-Warwick). Fifty million units were instilled in 1 5. litres of warmed dialysate via a Tenchkoff catheter, weekly for 16 weeks. Before each course of treatment peritoneal washings were taken for cytological and flow cytometric examination. Toxicity predominantly consisted of influenza-like symptoms: fever, fatigue and muscular aches. While most of these symptoms abated within 72 h each week, fatigue persisted Correspondence: Dr J. S. Whelan.
throughout the period of treatment. Haematological toxicity is shown in Fig. I. Viable adenocarcinoma cells disappeared from the peritoneal washings after the first week of therapy. On two subsequent occasions (weeks 5 and s), there was difficulty distinguishing viable malignant cells from dead tumour cells and mesothelial cells. Flow cytometric multiparameter analysis of the peritoneal washings revealed a pretreatment DNA diploid cell population. In addition, a second, near-diploid, tumour cell population was suspected from the high coefficient of variation (CV, 6.78) and a skewed GO/Gl peak. The analysis of tumourassociated antigen and oncoprotein expression showed that epidermal growth factor receptor (EGFR) expression was moderately high before treatment but became strikingly elevated after the first week of interferon therapy. After two weeks of treatment, however, there was a dramatic fall in EGFR expression and this coincided with a change in the DNA histogram as the near-diploid population disappeared and the CV fell ( 4 . 2 3 4 4 6 ) . Only low levels of tumour-associated antigens and transmembrane oncoprotein, c-erbB-2, were found before therapy (Table I). Serum CA 125 levels fell rapidly to within normal limits (Fig. 2). The patient remains in complete remission, with a normal serum CA 125,28 months after completing treatment.
Discussion In advanced ovarian cancer, combination chemotherapy given after initial debulking surgery is often unsuccessful in completely eradicating disease (Neijit et al. 1984; Dembo 1986). Adjuvant therapy may prolong survival in patients with early stage disease (Young et al. 1990). However, if there is residual tumour after chemotherapy, the effective treatment of epithelial ovarian cancer is seldom achieved (Berek 1989). Theoretically, intraperitoneal administration of drugs may offer a pharmacological advantage over the intravenous route
=
-
2
0
1 1 0 =:
300 r 250
X
; 200 * al
5 150 c
-a -
100
1
0
.
,a
‘-hw----
= = =,-Y
4 ;
I
2 50 0 1 2 3 4 5 6 7 8 91011121314151617161920
Weeks of therapy
Fig. 1. Effect of intraperitoneal a-interferon treatment on haematological indices: ( 0 )haemoglobin (Hb); (+) white blood cells; (*) platelets.
616
C A S E REPORTS
Table 1. Tumour associated antigen and oncoprotein expression (in arbitary fluorescence units) in cells retrieved from peritoneal washings during intraperitoneal a-interferon therapy) Week of therapy Marker EGFR C-erbB-2 C-myc SM3 CA 125 HMFG 1
0
1
2
4
16
65 36 42 7 24 35
195 30 35 10 84 18
33 69 6 28 48 22
28 51 26 0 43 6
13 38 2 3 3 17
EGFR = epidermal growth factor receptor. HMFGl = human milk for globulin 1. SM3 = stripped mucin 3. C-erbB-2 and c-myc are oncoproteins.
in the management of ovarian cancer (Los & McVie 1990). However, data from several studies suggest that worthwhile responses are limited to patients with minimal residual (< 5 mm) or microscopic disease (Berek et a/. 1985; Howell et al. 1987. Nardi et al. 1990). Methods to optimize this approach include the use of combinations of cytotoxic agents, and the instillation of biological response modifiers, in particular a-interferon. Berek et al. (1985) first reported the use of intraperitoneal a-interferon for the treatment oE ovarian cancer. The rationale for this approach was supported by in vitro studies which suggested a specific cytostatic and cytolytic role for this agent against ovarian carcinoma cells (Epstein et al. 1980; Allavena et al. 1982). Subsequently, a significant increase in peritoneal ‘natural killer cell’ activity has been demonstrated after the intraperitoneal administration of @-interferon(Lichtenstein et al. 1988). Four of 11 patients had complete remission confirmed surgically; all four had disease less than 5 mm in diameter. There was no benefit observed in those with more extensive disease (Berek et al. 1985). Despite the promise of this first report and confirmation from another small study (Willemse eta/. 1989), no larger studies have been initiated to better define the role of intraperitoneal a-interferon alone in
microscopic ovarian cancer. Others have, however, begun to use it in combination intraperitoneal therapy (Nardi et a/. 1990). Monitoring response to such treatment may be difficult. Conventional cytology of peritoneal fluid may be misleading (Sagae eta/. 1988). Furthermore, serum CA 125 levels may be normal in the presence of microscopic disease (Welander et al. 1988). It has been suggested that flow cytometric DNA analysis is an accurate method for the detection of malignant cells within peritoneal washings and may augment cytological examination (Lovecchio et al. 1986; Sinton e t a / . 1990). However, the value of these measurements is limited in the absence of a tumour cell population with a DNA content that is clearly distinguishable from the normal diploid population. This was illustrated in this case when pretreatment analysis of DNA content did not clearly separate an abnormal cell population. Hence, measurement of other variables, such as oncoprotein expression, has been employed in an attempt to increase sensitivity. In this report, the initial rise followed by a spectacular drop in EGFR expression shortly after the start of treatment coincided with a disappearance of tumour cells, as determined by cytological examination and suspected from flow cytometric DNA analysis, thus providing further evidence of response. Therefore, multiparameter flow cytometry in conjunction with classic immunocytology may be a powerful tool for the study of cell subpopulations in these heterogenous cell systems (see Commentary by van Dam & Lowe in this issue of the Journal p. 545). Despite having early stage disease (Ic), a dismal prognosis was predictable for our patient. This report confirms that intraperitoneal a-interferon may be used successfully for the treatment of microscopic ovarian cancer remaining after optimal chemotherapy, and that, even when high doses are used for a sustained period, this treatment has acceptable toxicity. Further studies of its use are therefore warranted. These should be accompanied by the assessment of more sensitive techniques for monitoring response, such as single and multiparameter flow cytometric assays.
Acknowledgments The authors are grateful for the invaluable help and support of the nursing staff of the Renal Unit and Stanmore Ward at St Bartholomew’s Hospital. Dr P. van Dam was supported by a Belgisch Werk Teken Kanker grant.
References
0
I
I
1
2
4
6
I
I
I
I
8 10 12 14 Weeks of therapy
I
I
I
16
18
20
Fig. 2. Serum CA 125 levels (normal range < 30 unitsflitre) during intraperitoneal a-interferon therapy.
Allavena P., Introna M., Sessa C., Mangioni C & Mantovani A. (1982) Interferon effect on cytotoxicity of peripheral blood and turnorassociated lymphocytes against human ovarian carcinoma cells. J Natl Cancer Inst 68, 552-562. Berek J. S. (1989) Epithelial ovarian cancer. In. Practical Gynecologic Oncology (Berek J. S., Hacker N. F. eds), Williams & Wilkins, Baltimore, 327-364. Berek J. S. Hacker N. V., Lichtenstein A. et al. (1986) Intraperitoneal recombinant a-Interferon for ’salvage’ immunotherapy in stage 111 ovarian cancer: a gynecologic oncology group study. Cancer Res 45,4447-4453. Dembo A. J. (1986) Controversy over combination chemotherapy: what we learn from reports of matured data. J Clin Oncol 4, 1573-1576.
C A S E REPORTS
Epstein L. B., Shen J-T., Abele J. S. & Rese C. C. (1980) Sensitivity of human ovarian cancer cells to interferon and other anti-tumor agents as assessed by an in vitro semi-solid agar technique. Ann NY Acad Sci 350,228-244. Howell S. B., Simm S., Markman M., Abramson I. S., Cleary S., Lucas W. E. & Weiss R. J. (1987) Long-term survival of advanced refractory ovarian cancer patients with small volume disease treated with intraperitoneal chemotherapy. J Clin Oncol 6, 1607-1612. Lichtenstein A., Spina C., Berek J. S., Jung T. & Zighelboim J. (1988) Intraperitoneal administration of human recombinant interferon-a in patients with ovarian cancer: Effects on lymphocyte phenotype and cytotoxicity. Cancer Res 48,5853-5859. Los G. & McVie J. G. (1990) Experimental and clinical status of intraperitoneal chemotherapy. Eur J Cancer 26,755-762. Lovecchio J. L., Budman D. R., Susin M., Grueneberg D. & Fenton A. N. (1986) Flow cytometry of peritoneal washings in gynecologic neoplasia. Obstet Gynecol81,55-59. Nardi M., Cognetti F., Pollera C. F., Della Guila M., Lombardi A,, Atlante G. & Calabresi F. (1990) Intraperitoneal recombinant alpha-2-interferon alternating with cisplatin as salvage therapy for minimal residual disease ovarian cancer: a phase I1 study. J Clin Oncol8, 1036-1041. Neijit J. P., Van Der Berg M. E. L., Vriesendorp R. et al. (1984). Randomized trial comparing two combination chemotherapy regimens (hexa-CAF vs CHAP-5) in advanced ovarian cancer. Lancet ii, 594-600.
617
Sagae S., Berek J. S., Fu Y. S., Chang N., Dauplat J. & Hacker N. F. (1988) Peritoneal cytology of ovarian cancer patients receiving intraperitoneal therapy: quantitation of malignant cells and response. Obstet Gynecol75, 782-788. Sinton E. B., Carver R. K., Morgan D. L., Philpott P. S., True11 J. E., Riemann D. & Ashton M. E. (1990) Prospective study of concurrent ploidy analysis and routine cytopathology in body cavity fluids. Arch Pathol Lab Med 114, 188-191. van Dam P. A. & Lowe D. G. (1992) Flow cytometry, commentary. Br J Obset Gynaecol99,545-546. Welander C., Geisinger K., Barrett R., Homesley H. & Grossberg H. (1988) Peritoneal cytology as a means of response evaluation for intraperitoneal therapy of minimal residual ovarian cancer. Proc ASCO 7,545a. Willemse P. H. B., de Vries E. G. E., Oosterhuis B. E., Aalders J. G., Bourma J., Mulder N. H. & Sleijfer D. T. (1989) Intraperitoneal human r-IFN-2ab in patients with stage 111 minimal residual ovarian cancer. Proc ASCO 8, 155. Young R. C., Walton L. A., Ellenberg S. S. et al. (1990). Adjuvant therapy in Stage I and Stage I1 ovarian cancer: results of two randomized trials. N En81 J Med 322, 1021-1027.
Received 19 July 1991 Accepted 12 December 1991
British Journal of Obstetrics and Gynaecology July 1992, Vol. 99, pp. 617419
Primary serous carcinoma of the female peritoneum. Report of a case with a re-examination of a histogenetic problem based on the use of a specific antimesothelial-cell antibody P. G . BETTA Service of Pathological Anatomy Santo Spirito Hospital, Casale Monferrato, Italy S. C O V E R L I Z Z A Service of Pathological Anatmomy Giovanni Bosco Hospital Turin, Italy A. DONNA Service of Pathological Anatomy City Hospital, Alessandria, Italy M. RISIO Service of Pathological Anatomy San Giovanni Vecchio Hospital Turin, Italy Correspondence: Dr P. G. Betta, Service of Pathological Anatomy and Cytopathology, Santo Spirito Hospital, Vale Giolitti 2. 1-15033, Casale Monferrato, Italy.
Case report A 75-year-old woman was admitted because of ascites, weight loss, nausea and severe asthenia of 2-month duration. Her health had been good. She had worked as a wool weaver in a textile factory for more than 30 years. Radiological studies, including ultrasound and computerized tomography of the abdomen, were non-contributory. The finding of malignant epithelial cells in the ascitic fluid suggested a possible metastatic involvement of the peritoneum from an unknown primary carcinoma. At laparotomy, almost 4 litres of haemorrhagic fluid were removed from the peritoneal cavity and abdominopelvic carcinomatosis was apparrent. Widespread tumour implants were found on both the visceral and parietal peritoneum and the omentum. A partial surgical debulking was performed, consisting of total hysterectomy, bilateral oophorectomy and omentectomy together with biopsies of two neoplastic nodules on the lower surface of the liver. Postoperatively the patient received chemotheraphy with 5-fluorouracil (600 mg/m2/week for 12 cycles) and she was still
