GYNECOLOGIC
ONCOLOGY
39, 99-102
(1990)
CASE REPORT Simultaneous Small Cell Carcinoma of the Cervix and Adenocarcinoma of the Ovary BRIGITTE Depariment
MILLER,
M.D.,
of Gynecology
MAHMOUD
and Pathology,
M.D.,
EL-TORKY,
College
of Medicine,
Received
March
PH.D.,
University
AND
GUY PHOTOPULUS, M.D.
of Tennessee,
Memphis,
Tennessee
38103
26, 1990
nodes. Total abdominal hysterectomy, bilateral salpingooophorectomy, omentectomy, and staging biopsies were performed. Postoperatively the patient received six courses of chemotherapy consisting of cisplatin, cyclophosphamide, and doxorubicin. Seven months after the diagnosis she developed seizures due to cerebral metastases, which were radiated. One month later she developed an obstruction of the common bile duct due to tumor. This was treated again, now with interstitial radiation. The patient died 11 months after the diagnosis from widespread metastatic disease. An autopsy was not granted.
INTRODUCTION Multiple synchronous primary tumors of the female genital tract are uncommon. The combination of an ovarian malignancy and an endometrial malignancy is the most frequent, and can be found in up to 4% of the patients [ 11. Combinations of cervical and ovarian tumors are rare, the largest number of cases reported involving mutinous ovarian and cervical tumors [2]. Metastatic disease from the cervix to the ovary is quite rare in squamous carcinoma, but can be as high as 12% in patients with adenocarcinoma [3]. On the other hand it is very unusual for an ovarian malignancy to present as a cervical metastasis [4].
PATHOLOGY Initial cervical and endometrial biopsies revealed small cell undifferentiated carcinoma with admixtures of adenocarcinoma (see Figs. l-4). Gross appearance of the surgical specimen. The uterus measured 9 x 5 x 3 cm and weighed 90 g. Cervical mucosa showed focal hemorrhage and erosions between the 12 and 3 o’clock positions. The endometrium was moderately hemorrhagic and measured 0.4 cm in thickness. The myometrium was unremarkable and varied between 2.5 and 4 cm in thickness. The left ovary contained a large cystic structure measuring 19 x 17 x 7 cm. The serosal surface was focally hemorrhagic. The internal surface was papillary with focal necrosis. The right ovary with attached tube measured 3 cm in diameter. Also, the largest of several small lymph nodes from the right external iliac area measured 0.9 x 0.7 x 0.2 cm. Microscopic examination. The uterine cervix showed extensive stromal infiltration by monomorphic tumor cells with minimal adhesion. Tumor cells were arranged
CASE REPORT A 33-year-old gravida 1, para 1 was referred because of weight loss, ascites, and pelvic mass. The patient had noted irregular vaginal spotting for about 1 year. Past medical and surgical history was not contributory. On admission, general physical examination revealed marked ascites and a pelvic-abdominal mass about 20 weeks size. The lungs were clear; no adenopathies were noted. On pelvic exam the cervix was displaced anteriorly; a friable lesion bleeding on contact covered the external OS. On palpation the cervix was very firm; no parametrial extension was noted, however. A firm mass was felt to originate from the right ovary and fill the entire pelvis. CT scan of the abdomen and pelvis revealed a 30 x 30-cm multiloculated pelvic mass with normal findings regarding the paraaortic area and liver. This was confirmed at the time of exploratory laparotomy, when metastatic disease was also noted on the peritoneum, in the omentum, and in the pelvic lymph 99
oo!90-8258/90 $1.50 Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
100
MILLER,
FIG. 1. Small cell carcinoma of the cervix. H&E,
EL-TORKY,
x200.
AND PHOTOPULUS
in small nests and sheets, some with a central focal necrosis. No evidence of an organoid pattern was found. The tumor was extremely cellular, consisting of small cells with hyperchromatic nuclei, scanty cytoplasm, and a high nuclear-cytoplasmic ratio. Both polygonal and oat cell-like subtypes were identified. The oat cell subtype has hyperchromatic nuclei with evenly dispersed chromatin and indistinct nucleoli. Several smudge cells and abnormal mitoses were identified. The polygonal cells were more pleomorphic, with layers of irregular nuclei and occasional nucleoli. A characteristic deposition of chromatin (Azzopardi phenomenon) around blood vessels was occasionally observed. There was no evidence of any differentiation in any cervical sections. The tumor demonstrated extension into the lower and upper uterine segments and the parametrial tissue. Furthermore, the neoplasm showed extensive vascular invasion. Immunohistochemistry performed on formalin-fixed, paraffin-embedded tissue demonstrated ciusters of cells positive for neuron-specific enolase (NSE), but negative for cytokeratin. Electron microscopic examination showed an irregular nuclear pattern; nuclei varied from round to oval and contained coarse chromatin, some clumped at the nuclear membrane. The cytoplasm is scant and shows many dense core granules. Sections through the ovary showed a moderately differentiated papillary seromucinous cystadenocarcinoma invading the ovarian stroma and parametrial and myometrial tissue. The tumor cells ranged from columnar to cuboidal with hyperchromatic nuclei and prominent nucleoli. These cells were arranged in acinar and tubular patterns and surrounded by extensive desmoplastic reaction. No psammoma bodies were identified. Immunocytochemistry was positive for cytokeratin and negative for NSE. Tumor nests from both tumors, seromucinous papillary cystadenocarcinoma of ovarian origin and undifferentiated small cell malignant neoplasm of cervical origin, were identified in all seven right external iliac lymph nodes. DISCUSSION
FIG. 2. Small cell carcinoma of the cervix. H&E,
x400.
This case is exceptional for several reasons. First, a small cell carcinoma of the cervix is quite rare. It constitutes between 1% [5] and 6.5% [6] of all invasive cervical carcinomas. Epithelial tumors of the ovary are more frequent, but still rare in younger patients, with an incidence of 8 to 10 per 100,000 in the fourth decade [7]. Second, the tumor distribution is typical for each tumor. Small cell carcinoma is very aggressive, so deep infiltration, parametrial involvement, and nodal metastasis are not uncommon, even in small-appearing tumors [S]. Epithelial ovarian malignancies spread primarily to
CASE REPORT
101
FIG. 3. Small cell carcinoma of the cervix. Electron micrograph.
FIG. 4. Adenocarcinoma
of the ovary. H&E,
x200.
the peritoneum and omentum. Lymph node involvement is not unusual, however, and is reported in 42% of stage III cases [9]. Parametrial involvement, however, is very rare, as epithelial ovarian cancer remains confined to the peritoneal surfaces for a long time. It is conceivable that infiltration by the small cell tumor destroyed the peritoneal lining and impaired the local defense mechanisms to such an extent that earlier infiltration became possible. In addition the high tumor volume may be a sign of decreased host response. Although desmoplastic reaction was significant within the ovarian tumor, it was not seen around the small cell carcinoma. Third, it could be confirmed that we are dealing with two separate tumors and not different patterns of one very undifferentiated tumor. The microscopic appearances are quite different regarding architectural aspects, such as papillary versus diffusely infiltrating patterns, and cellular aspects, such as cell size and nuclear-cytoplasmic ratio. The possibility of cervical metastasis by an undifferentiated portion of the ovarian carcinoma can be excluded by immunocytochemistry and electron microscopy. NSE is seen in the majority of small cell carcinomas. It is also found in a variety of other tumors, such as sarcomas and melanoma, but it has not been described in adenocarcinoma of the ovary [lo]. Small cell carcinoma of the ovary, on the other hand, mostly
102
MILLER,
EL-TORKY,
shows evidence of NSE [ll]. Neurosecretory granules have been described since the initial report as one of the characteristics of undifferentiated small cell carcinoma of the cervix [ 121. Rarely have they also been seen in other non-small cell cervical carcinomas [13]; however, they have not been reported in ovarian tumors. The clinical course seems to be determined mainly by the small cell carcinoma, where distant metastasis have been described as occurring early in the course of the disease and as being widespread, including brain metastases [7,141. Cerebral metastases from ovarian cancer occur mainly after prolonged chemotherapy and used to be quite rare. Recently, however, due to improved local control, the incidence has been reported to be as high as 11.6% [15], compared to a rate of 0.29% in a large series of patients treated between 1944 and 1984 [ 161. REFERENCES 1. Axerol, J. H., Fruchter, R., and Boyce, J. G. Multiple primaries among gynecologic malignancies, Gynecol. &co/. 18, 359-372 (1984). 2. Young, R. H., and Scully, R. Mutinous ovarian tumors associated with mutinous adenocarcinomas of the cervix, Int. J. Gynecol. Pathol. 7, 99-111 (1988). 3. Tabata, M., Ichinoe, K., Sakuragi, N., Shina, Y., Yamaguchi, T., and Mabuchi, Y. Incidence of ovarian metastasis in patients with cancer of the uterine cervix, Gynecol. Oncol. 28, 255-261 (1987). 4. McComas, B. C., Farnum, J. B., and Donaldson, R. C. Ovarian carcinoma presenting as a cervical metastasis, Obstet. Gynecol. 63, 593-596 (1984). 5. Saul, P. The clinical management of small cell carcinoma of the cervix, Gynecol. Cancqr 29, 245-250 (1987).
AND PHOTOPULUS
6. Yamasaki, M., Tateishi, R., and Hongo, J. Argyrophil small cell carcinomas of the uterine cervix, Znt. J. Gynecol. Pathol. 3, 146152 (1984). 7. Silverberg, E. Statistical and epidemiological information on gynecologic cancer, American Cancer Society, New York (1986). 8. Sheets, E. E., Berman, M. L., Hrountas, C. K., Liao, S. Y., and DiSaia, P. J. Surgically treated, early-stage neuroendocrine smallcell cervical carcinoma, Obsret. Gynecol. 7, lo-14 (1988). 9 Chen, S. S., and Lee, L. Incidence of positive periaortic and pelvic ’ nodes in epithelial cancers of the ovary, Gynecol. Oncol. 16, 95 (1983). to. Leader, M., Collins, M., Pate], J., and Henry, K. Antineuron specific enolase staining reactions in sarcomas and carcinomas: Its lack of neuroendocrine specificity, J. C/in. Pathol. 39, 1186-I 192 (1986). 11. Abeler, V., Kjorstad, K. E., and Nesland, J. M. Small cell carcinoma of the ovary: A report of six cases, Int. J. Gynecol. Parhol. 7, 315-329 (1988). 12. Albores-Saavedra, J., Larraza, O., Poucell, S., and Martinez, H. A. Carcinoid of the uterine cervix: Additional observations on a new tumor entity, Cancer 38, 2328-2342 (1976). 13. Barrett, P., II, Davos, I., Leuchter, R. S., and Lagasse, L. D. Neuroendocrine features in poorly differentiated and undifferentiated carcinomas of the cervix, Cancer 60, 2325-2330 (1987). 14. Gersell, D. J., Mazouijan, G., Mutch, D. G., and Rudloff, M. A. Small cell undifferentiated carcinoma of the cervix, Amer. J. Surg. Pathol., 684-698 (1988). 15. Hardy, J. R., and Harvey, V. J. Cerebral metastasis in patients with ovarian cancer treated with chemotherapy, Gynecol. Oncol. 33, 296-300 (1989). 16. Larson, D. M., Copeland, L. J., Moser, R. P., Malone, J. M., Gershenson, D. M., and Wharton, J. T. Central nervous system metastasis in epithelial ovarian cancer, Obstet. Gynecol. 68, 746750 (1986).
ONCOLOGY
39, 99-102
(1990)
CASE REPORT Simultaneous Small Cell Carcinoma of the Cervix and Adenocarcinoma of the Ovary BRIGITTE Depariment
MILLER,
M.D.,
of Gynecology
MAHMOUD
and Pathology,
M.D.,
EL-TORKY,
College
of Medicine,
Received
March
PH.D.,
University
AND
GUY PHOTOPULUS, M.D.
of Tennessee,
Memphis,
Tennessee
38103
26, 1990
nodes. Total abdominal hysterectomy, bilateral salpingooophorectomy, omentectomy, and staging biopsies were performed. Postoperatively the patient received six courses of chemotherapy consisting of cisplatin, cyclophosphamide, and doxorubicin. Seven months after the diagnosis she developed seizures due to cerebral metastases, which were radiated. One month later she developed an obstruction of the common bile duct due to tumor. This was treated again, now with interstitial radiation. The patient died 11 months after the diagnosis from widespread metastatic disease. An autopsy was not granted.
INTRODUCTION Multiple synchronous primary tumors of the female genital tract are uncommon. The combination of an ovarian malignancy and an endometrial malignancy is the most frequent, and can be found in up to 4% of the patients [ 11. Combinations of cervical and ovarian tumors are rare, the largest number of cases reported involving mutinous ovarian and cervical tumors [2]. Metastatic disease from the cervix to the ovary is quite rare in squamous carcinoma, but can be as high as 12% in patients with adenocarcinoma [3]. On the other hand it is very unusual for an ovarian malignancy to present as a cervical metastasis [4].
PATHOLOGY Initial cervical and endometrial biopsies revealed small cell undifferentiated carcinoma with admixtures of adenocarcinoma (see Figs. l-4). Gross appearance of the surgical specimen. The uterus measured 9 x 5 x 3 cm and weighed 90 g. Cervical mucosa showed focal hemorrhage and erosions between the 12 and 3 o’clock positions. The endometrium was moderately hemorrhagic and measured 0.4 cm in thickness. The myometrium was unremarkable and varied between 2.5 and 4 cm in thickness. The left ovary contained a large cystic structure measuring 19 x 17 x 7 cm. The serosal surface was focally hemorrhagic. The internal surface was papillary with focal necrosis. The right ovary with attached tube measured 3 cm in diameter. Also, the largest of several small lymph nodes from the right external iliac area measured 0.9 x 0.7 x 0.2 cm. Microscopic examination. The uterine cervix showed extensive stromal infiltration by monomorphic tumor cells with minimal adhesion. Tumor cells were arranged
CASE REPORT A 33-year-old gravida 1, para 1 was referred because of weight loss, ascites, and pelvic mass. The patient had noted irregular vaginal spotting for about 1 year. Past medical and surgical history was not contributory. On admission, general physical examination revealed marked ascites and a pelvic-abdominal mass about 20 weeks size. The lungs were clear; no adenopathies were noted. On pelvic exam the cervix was displaced anteriorly; a friable lesion bleeding on contact covered the external OS. On palpation the cervix was very firm; no parametrial extension was noted, however. A firm mass was felt to originate from the right ovary and fill the entire pelvis. CT scan of the abdomen and pelvis revealed a 30 x 30-cm multiloculated pelvic mass with normal findings regarding the paraaortic area and liver. This was confirmed at the time of exploratory laparotomy, when metastatic disease was also noted on the peritoneum, in the omentum, and in the pelvic lymph 99
oo!90-8258/90 $1.50 Copyright 0 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
100
MILLER,
FIG. 1. Small cell carcinoma of the cervix. H&E,
EL-TORKY,
x200.
AND PHOTOPULUS
in small nests and sheets, some with a central focal necrosis. No evidence of an organoid pattern was found. The tumor was extremely cellular, consisting of small cells with hyperchromatic nuclei, scanty cytoplasm, and a high nuclear-cytoplasmic ratio. Both polygonal and oat cell-like subtypes were identified. The oat cell subtype has hyperchromatic nuclei with evenly dispersed chromatin and indistinct nucleoli. Several smudge cells and abnormal mitoses were identified. The polygonal cells were more pleomorphic, with layers of irregular nuclei and occasional nucleoli. A characteristic deposition of chromatin (Azzopardi phenomenon) around blood vessels was occasionally observed. There was no evidence of any differentiation in any cervical sections. The tumor demonstrated extension into the lower and upper uterine segments and the parametrial tissue. Furthermore, the neoplasm showed extensive vascular invasion. Immunohistochemistry performed on formalin-fixed, paraffin-embedded tissue demonstrated ciusters of cells positive for neuron-specific enolase (NSE), but negative for cytokeratin. Electron microscopic examination showed an irregular nuclear pattern; nuclei varied from round to oval and contained coarse chromatin, some clumped at the nuclear membrane. The cytoplasm is scant and shows many dense core granules. Sections through the ovary showed a moderately differentiated papillary seromucinous cystadenocarcinoma invading the ovarian stroma and parametrial and myometrial tissue. The tumor cells ranged from columnar to cuboidal with hyperchromatic nuclei and prominent nucleoli. These cells were arranged in acinar and tubular patterns and surrounded by extensive desmoplastic reaction. No psammoma bodies were identified. Immunocytochemistry was positive for cytokeratin and negative for NSE. Tumor nests from both tumors, seromucinous papillary cystadenocarcinoma of ovarian origin and undifferentiated small cell malignant neoplasm of cervical origin, were identified in all seven right external iliac lymph nodes. DISCUSSION
FIG. 2. Small cell carcinoma of the cervix. H&E,
x400.
This case is exceptional for several reasons. First, a small cell carcinoma of the cervix is quite rare. It constitutes between 1% [5] and 6.5% [6] of all invasive cervical carcinomas. Epithelial tumors of the ovary are more frequent, but still rare in younger patients, with an incidence of 8 to 10 per 100,000 in the fourth decade [7]. Second, the tumor distribution is typical for each tumor. Small cell carcinoma is very aggressive, so deep infiltration, parametrial involvement, and nodal metastasis are not uncommon, even in small-appearing tumors [S]. Epithelial ovarian malignancies spread primarily to
CASE REPORT
101
FIG. 3. Small cell carcinoma of the cervix. Electron micrograph.
FIG. 4. Adenocarcinoma
of the ovary. H&E,
x200.
the peritoneum and omentum. Lymph node involvement is not unusual, however, and is reported in 42% of stage III cases [9]. Parametrial involvement, however, is very rare, as epithelial ovarian cancer remains confined to the peritoneal surfaces for a long time. It is conceivable that infiltration by the small cell tumor destroyed the peritoneal lining and impaired the local defense mechanisms to such an extent that earlier infiltration became possible. In addition the high tumor volume may be a sign of decreased host response. Although desmoplastic reaction was significant within the ovarian tumor, it was not seen around the small cell carcinoma. Third, it could be confirmed that we are dealing with two separate tumors and not different patterns of one very undifferentiated tumor. The microscopic appearances are quite different regarding architectural aspects, such as papillary versus diffusely infiltrating patterns, and cellular aspects, such as cell size and nuclear-cytoplasmic ratio. The possibility of cervical metastasis by an undifferentiated portion of the ovarian carcinoma can be excluded by immunocytochemistry and electron microscopy. NSE is seen in the majority of small cell carcinomas. It is also found in a variety of other tumors, such as sarcomas and melanoma, but it has not been described in adenocarcinoma of the ovary [lo]. Small cell carcinoma of the ovary, on the other hand, mostly
102
MILLER,
EL-TORKY,
shows evidence of NSE [ll]. Neurosecretory granules have been described since the initial report as one of the characteristics of undifferentiated small cell carcinoma of the cervix [ 121. Rarely have they also been seen in other non-small cell cervical carcinomas [13]; however, they have not been reported in ovarian tumors. The clinical course seems to be determined mainly by the small cell carcinoma, where distant metastasis have been described as occurring early in the course of the disease and as being widespread, including brain metastases [7,141. Cerebral metastases from ovarian cancer occur mainly after prolonged chemotherapy and used to be quite rare. Recently, however, due to improved local control, the incidence has been reported to be as high as 11.6% [15], compared to a rate of 0.29% in a large series of patients treated between 1944 and 1984 [ 161. REFERENCES 1. Axerol, J. H., Fruchter, R., and Boyce, J. G. Multiple primaries among gynecologic malignancies, Gynecol. &co/. 18, 359-372 (1984). 2. Young, R. H., and Scully, R. Mutinous ovarian tumors associated with mutinous adenocarcinomas of the cervix, Int. J. Gynecol. Pathol. 7, 99-111 (1988). 3. Tabata, M., Ichinoe, K., Sakuragi, N., Shina, Y., Yamaguchi, T., and Mabuchi, Y. Incidence of ovarian metastasis in patients with cancer of the uterine cervix, Gynecol. Oncol. 28, 255-261 (1987). 4. McComas, B. C., Farnum, J. B., and Donaldson, R. C. Ovarian carcinoma presenting as a cervical metastasis, Obstet. Gynecol. 63, 593-596 (1984). 5. Saul, P. The clinical management of small cell carcinoma of the cervix, Gynecol. Cancqr 29, 245-250 (1987).
AND PHOTOPULUS
6. Yamasaki, M., Tateishi, R., and Hongo, J. Argyrophil small cell carcinomas of the uterine cervix, Znt. J. Gynecol. Pathol. 3, 146152 (1984). 7. Silverberg, E. Statistical and epidemiological information on gynecologic cancer, American Cancer Society, New York (1986). 8. Sheets, E. E., Berman, M. L., Hrountas, C. K., Liao, S. Y., and DiSaia, P. J. Surgically treated, early-stage neuroendocrine smallcell cervical carcinoma, Obsret. Gynecol. 7, lo-14 (1988). 9 Chen, S. S., and Lee, L. Incidence of positive periaortic and pelvic ’ nodes in epithelial cancers of the ovary, Gynecol. Oncol. 16, 95 (1983). to. Leader, M., Collins, M., Pate], J., and Henry, K. Antineuron specific enolase staining reactions in sarcomas and carcinomas: Its lack of neuroendocrine specificity, J. C/in. Pathol. 39, 1186-I 192 (1986). 11. Abeler, V., Kjorstad, K. E., and Nesland, J. M. Small cell carcinoma of the ovary: A report of six cases, Int. J. Gynecol. Parhol. 7, 315-329 (1988). 12. Albores-Saavedra, J., Larraza, O., Poucell, S., and Martinez, H. A. Carcinoid of the uterine cervix: Additional observations on a new tumor entity, Cancer 38, 2328-2342 (1976). 13. Barrett, P., II, Davos, I., Leuchter, R. S., and Lagasse, L. D. Neuroendocrine features in poorly differentiated and undifferentiated carcinomas of the cervix, Cancer 60, 2325-2330 (1987). 14. Gersell, D. J., Mazouijan, G., Mutch, D. G., and Rudloff, M. A. Small cell undifferentiated carcinoma of the cervix, Amer. J. Surg. Pathol., 684-698 (1988). 15. Hardy, J. R., and Harvey, V. J. Cerebral metastasis in patients with ovarian cancer treated with chemotherapy, Gynecol. Oncol. 33, 296-300 (1989). 16. Larson, D. M., Copeland, L. J., Moser, R. P., Malone, J. M., Gershenson, D. M., and Wharton, J. T. Central nervous system metastasis in epithelial ovarian cancer, Obstet. Gynecol. 68, 746750 (1986).
![[Small cell carcinoma of the ovary].](/assets/img/hold.png)
