Case 37-2004 — A 52-Year-Old Woman with Postmenopausal Bleeding and a Cystic Ovarian Mass
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《新英格兰医药杂志》
Presentation of Case
A 52-year-old woman visited her gynecologist because of a single episode of painless postmenopausal bleeding. Her last menstrual period had been more than one year previously. A pelvic ultrasonogram showed the endometrial stripe to be thickened, at 8 mm, and revealed a complex cystic mass, 12 cm in diameter, with a mural nodule in the right adnexa (Figure 1A). This finding was confirmed by computed tomographic (CT) scanning (Figure 1B). An endometrial-biopsy specimen revealed that the endometrium was normal.
Figure 1. Radiologic Studies.
A pelvic ultrasonogram (Panel A) shows a large cystic mass in the right ovary with a mural nodule (arrow). The contrast-enhanced CT scan (Panel B) confirms the finding of a unilocular cystic mass in the right ovary and shows the enhancement in the mural nodule (arrow).
The patient had no gastrointestinal or urinary symptoms. Her weight was stable, and she reported no symptoms other than shortness of breath attributed to obesity. She had had normal Papanicolaou smears on a regular basis and two normal pregnancies 27 and 29 years previously. She had hypertension, which was controlled with metoprolol tartrate, and hypercholesterolemia, which was managed by diet. She had smoked in the distant past and she drank alcohol in moderation. Her 27-year-old daughter had been treated with radioactive iodine for thyroid cancer. Her father had died of renal-cell carcinoma at 72 years of age.
On physical examination, the patient's weight was 108.9 kg and the temperature 37.11°C. The blood pressure was 148/84 mm Hg and the heart rate 103 beats per minute with a regular rhythm. The results of an examination of the head, eyes, ears, nose, and throat were normal. Examination of the chest and heart revealed no abnormalities. The breasts appeared normal, and there was no axillary or supraclavicular lymphadenopathy. The abdomen was not distended. There was suprapubic fullness on palpation at the pelvic inlet, but no discrete mass, organomegaly, or inguinal lymphadenopathy. There was no tenderness, fluid wave, or shifting dullness. The bowel sounds were normal. There was no edema or calf tenderness, and the distal pulses were normal. A pelvic examination revealed normal external genitalia with minimal atrophy and good support. The cervix appeared normal, with no mucosal lesion. The uterus was normal in size and contour, nontender, but was deviated posteriorly by a prominent smooth anterior mass. There was no nodularity in the cul-de-sac on rectovaginal examination. The pelvic sidewalls were smooth and unremarkable. A rectal examination disclosed small hemorrhoids.
The hemoglobin level was 11.8 g per deciliter and the hematocrit 33.6 percent. Laboratory measurements of the levels of blood chemicals yielded the following results: alanine aminotransferase, 58 U per liter; aspartate aminotransferase, 38 U per liter; and alkaline phosphatase, 118 U per liter. The level of CA-125 was 49.6 U per milliliter. The results of other laboratory tests were within normal ranges.
A surgical procedure was planned to begin with laparoscopy, followed, if the findings were benign, by hysteroscopy to rule out an occult endometrial tumor and therapeutic endometrial ablation. The patient consented to undergo laparotomy, hysterectomy, and oophorectomy, if these procedures were required.
During an examination performed while the patient was under anesthesia, the uterus was found moved posteriorly and to the left by a mass that was fixed to the uterine fundus on the right side. The diameter of the mass was approximately 18 cm, and it was palpable above the umbilicus on abdominal examination. Because of the large size of the mass, its fixation to the uterus, and the elevated level of CA-125, an exploratory laparotomy was performed, rather than the planned laparoscopy.
On exploration, there was a right adnexal mass that originated from the right infundibulopelvic ligament. It was adherent to the superior aspect of the uterus with no evidence of other surface involvement. The left ovary and the remainder of the abdomen appeared normal.
The mass and uterus were removed en bloc. Microscopic examination of an intraoperative frozen section disclosed a serous papillary cystic tumor, which was thought probably to be a low-grade cystadenocarcinoma. A total abdominal hysterectomy, bilateral oophorectomy, gastrocolic omentectomy, appendectomy, and a full staging procedure were performed, including examination and palpation of all peritoneal surfaces. Multiple random biopsy specimens were obtained from the diaphragms, the pericolic gutters, and the pelvis. Enlarged lymph nodes that appeared to be hyperplastic rather than containing metastatic carcinoma were present in both obturator fossae. Therefore, lymph nodes were removed up to the bifurcation of the aorta.
The patient's postoperative recovery was uneventful, and she was discharged on the sixth hospital day.
Differential Diagnosis
Dr. Richard T. Penson: May we review the imaging studies?
Dr. Dushyant Sahani: Imaging studies included transabdominal and transvaginal pelvic ultrasonography. A large, unilocular cystic mass with a mural nodule was identified in the right adnexa, involving the right ovary (Figure 1A). The left ovary could not be identified. The uterus was normal, and the endometrial stripe measured approximately 10 mm. The differential diagnosis includes a primary cystic ovarian neoplasm, which could be benign, malignant, or borderline. Metastases to the ovary are usually bilateral and solid. Endometriosis was considered unlikely because of the large size of the mass.
An abdominal pelvic CT scan was obtained, and again showed a large cystic mass with a posterior mural nodule (Figure 1B). There was no evidence of metastasis to the peritoneum, to the lymphatics, or to other abdominal or pelvic organs. Again, the left ovary was not identified.
Pathological Discussion
Dr. Debra A. Bell: The specimens received in the pathology department were the uterus with attached left fallopian tube and ovary, the right fallopian tube and ovary, the omentum, and dissections of both the right and left pelvic lymph nodes. An examination of the right ovary revealed a cystic ovary, 13 by 12 by 9 cm, with a smooth surface and an attached and unremarkable fallopian tube. The opened specimen revealed that ovarian tissue had been replaced by a unilocular cyst that contained cloudy yellow fluid. The wall of the cyst was predominantly smooth and ranged from 0.2 to 1.5 cm in thickness. Protruding into this large cyst was a single polypoid mass measuring 1.5 by 1.0 cm. Two centimeters from this intracystic mass, the cyst wall was thickened and contained a smaller 1.5-cm cyst filled with a 1.3-cm papillary excrescence. The left ovary measured 3.0 by 2.2 by 1.7 cm and had a bosselated unremarkable surface. The cut surface of the ovary revealed several smooth-walled cysts measuring from 0.8 to 1 cm in diameter. The attached fallopian tube was unremarkable. The uterine cavity contained an endometrial polyp measuring 3.8 by 3.5 by 0.3 cm, and several grossly typical leiomyomas ranging from 0.8 to 2.8 cm in diameter were present in the myometrium. The omentum was unremarkable.
Microscopical examination (Figure 2) revealed that the large unilocular cyst in the right ovary was lined by a single layer of ciliated cells that ranged in shape from cuboidal to columnar. The polypoid mass that extended into the cyst was composed of sheets of cells and closely apposed glands and cysts. The cells were cuboidal to polygonal and contained highly pleomorphic nuclei with prominent and irregular nucleoli. The presence of solid masses of cells with a marked degree of nuclear atypia was sufficient for a diagnosis of serous carcinoma, grade 2 to 3 of 3. The 1.5-cm intramural cyst contained a papillary proliferation.
Figure 2. Histopathological Features of the Tumor (Hematoxylin and Eosin).
Panel A shows a typical area in a serous borderline tumor. There are irregular, branching papillae that progressively decrease in size (hierarchical branching). At higher magnification (Panel B), the papillae are lined with mildly to moderately atypical columnar and cuboidal cells. Detached clusters of similar cells are present. Panel C shows a micropapillary area in the serous borderline tumor. Smoothly contoured papillae are lined with fine micropapillae. At higher magnification (Panel D), the micropapillae are five times as long as they are wide, and they are lined with polygonal cells with an elevated nuclear-to-cytoplasmic ratio. Panel E shows an area of serous carcinoma. Sheets of cells and closely apposed glands are present. At higher magnification (Panel F), the cells have irregular pleomorphic, highly atypical nuclei with prominent nucleoli.
In some areas, hierarchically branching fibrous papillae with irregular contours were present. These papillae were lined with moderately atypical cuboidal and columnar cells. Detached clusters of similar atypical cells were present as well. These histologic features are those of a serous borderline tumor, typical type. In other areas, the papillae were broader and had smooth contours. These were lined by elongated micropapillae that emanated directly from the broad fibrous papillae. The micropapillae were five times as long as they were wide and did not contain fibrovascular cores. The cells lining the papillae and also present in the micropapillae were polygonal, with a high nuclear-to-cytoplasmic ratio and moderate cytologic atypia. These features are those of a serous borderline tumor, micropapillary type. Microscopical examination of the left ovary revealed a small serous borderline tumor, typical type.
Tumors of the epithelium of the ovary are categorized by the World Health Organization according to epithelial type and degree of epithelial differentiation.1 The classification according to epithelial type is based on the resemblance of the epithelium in the tumor to normal epithelium. Thus, serous tumors have epithelium that resembles the fallopian-tube type of epithelium, endometrioid tumors resemble endometrium, mucinous tumors resemble either endocervical or gastrointestinal mucinous epithelium, clear-cell tumors resemble renal-cell carcinoma or hypersecretory endometrium or endometrium associated with pregnancy, transitional-cell tumors resemble urothelium, and squamous-cell carcinomas resemble squamous epithelium (Table 1). These tumors are also classified on the basis of their degree of differentiation as benign, borderline, or malignant tumors (Table 1). Benign serous tumors of the ovary are characterized by a single layer of cuboidal or columnar cells that often contain cilia. Borderline tumors are defined as tumors that show a degree of epithelial proliferation that is intermediate between obviously benign tumors and malignant tumors. These tumors are characterized by the presence of epithelial atypia and tufting, and they contain detached clusters of atypical epithelial cells, without stromal invasion. Serous carcinomas of the ovary are characterized by the confluence or close approximation of glands and cysts that are lined with cells that have a high degree of nuclear atypia; they usually have irregular nests of highly pleomorphic and atypical cells infiltrating a desmoplastic, fibrous, or edematous stroma.1
Table 1. Classification of Ovarian Epithelial Tumors.
The morphologic features of particular interest in this case are, first, the presence of both typical and micropapillary variants in the borderline areas of the tumor and, second, the presence of a moderately differentiated or a poorly differentiated carcinoma arising in a neoplasm that shows a spectrum of abnormalities that range from benign to typical borderline to micropapillary borderline tumors.
Serous borderline tumors of the ovary, which are also referred to as tumors of low malignant potential or atypical proliferative tumors, have two distinct histologic patterns that may be present either in isolation or, more commonly, admixed with the other histologic types.2,3,4,5,6,7,8,9,10 The typical pattern is characterized by hierarchically branching, fibrous papillae with irregular contours that end in detached clusters of atypical cells. The architectural pattern of a micropapillary tumor is that of smoothly contoured, large, fibrous papillae from which thin, elongated micropapillae emanate. Both types generally show only moderate cytologic atypia. The prognostic significance of the micropapillary pattern in a noninvasive tumor is controversial; however, most studies have shown an increased frequency of surface involvement, bilaterality, and peritoneal involvement in micropapillary-type tumors, as compared with those of the typical type.2,3,4,5,6,7,8,9,10 An increase in frequency of stromal invasion in ovarian tumors has been reported, and some authors have suggested an association with an increased frequency of invasive peritoneal implants.2,7,11
The presence of a moderately differentiated or a poorly differentiated carcinoma arising within a tumor that shows a spectrum of epithelial differentiation from benign through borderline raises the issue of the role of benign and borderline tumors as precursors of serous carcinoma of the ovary. Well-differentiated serous carcinomas almost always arise within an existing serous neoplasm, which is usually a serous borderline tumor or adenofibroma — often one with micropapillary architecture.2,12 This known feature and the results of genetic alterations suggest that well-differentiated serous carcinomas arise by way of an adenoma-to-carcinoma sequence (from a benign serous cystadenoma to a typical borderline tumor to a micropapillary borderline tumor to an invasive, well-differentiated carcinoma).13,14,15 In contrast, several studies have shown that even the smallest high-grade serous carcinomas rarely arise within preexisting serous neoplasms16 and that such tumors have features, such as TP53 mutations, that are typical of advanced-stage, high-grade serous carcinoma.15,17 These data have led to the suggestion that poorly differentiated serous carcinomas arise without a preceding benign or premalignant lesion from ovarian surface epithelium or from serous epithelial inclusion cysts.
Discussion of Management
Dr. Penson: After careful staging, it was determined that this patient had ovarian cancer, confined to the ovary, with a poorly differentiated component. The cancer was stage IA of IV, in accordance with the classification system of the International Federation of Gynecology and Obstetrics (in which stage I is confined to the ovaries and stage IV involves metastases to the liver or lung). Although the tumor was completely resected with negative margins, the question of adjuvant therapy had to be decided.
Ovarian cancer is typically considered advanced when there are intraabdominal transcoelomic metastases (stage III disease) (Table 1), with subtle symptoms that commonly result in a delayed diagnosis.18,19 Although early-stage disease may be identified by strategies such as proteomics analysis and CA-125 algorithms, screening with the use of tumor markers or ultrasonography is not recommended at this time.20,21 In high-risk populations, such as women with BRCA mutations or with strong family histories of breast cancer or ovarian cancer, the disease is more successfully prevented by prophylactic oophorectomy than by relying on screening. In the case of this patient, the diagnosis was made at an early stage because of the coincidental development of endometrial polyps with postmenopausal bleeding.
Surgical resection has been the mainstay of treatment for ovarian carcinoma, and a recent randomized, controlled trial showed that the amount of disease left at the completion of surgery (with <1 cm considered optimal and 1 cm suboptimal) was one of the most important prognostic factors for ovarian cancer.22 However, since the majority of patients do not have disease that can be resected completely, the development of effective chemotherapy has been a priority.
A series of randomized, controlled trials has defined the standard of care for chemotherapy in advanced ovarian cancer. Several recent studies have shown that cisplatin and paclitaxel have greater efficacy than cyclophosphamide and cisplatin.23,24,25
The most recent randomized trial finally confirmed the adoption of carboplatin plus paclitaxel, with an improved toxicity profile as compared with that of cisplatin and paclitaxel, as the standard of care for advanced ovarian cancer.26 Docetaxel, a less neurotoxic alternative to paclitaxel, is used more often in Europe than in the United States.27 The five-year overall survival rate for women with ovarian cancer has increased incrementally from 37 percent in the 1970s to 39 percent in the 1980s. In the most recent data from the 1990s,28 the five-year overall survival rate stands at 43 percent. A study in this issue of the Journal found that additional surgical debulking offered no survival advantage for patients with stage III ovarian cancer receiving chemotherapy.29
This patient had early ovarian cancer, defined as cancer confined to the ovaries, and she had an anticipated probability of survival at five years of 70 to 90 percent. Stage IA or IB (unilateral or bilateral disease confined to the ovaries) with well-differentiated or possibly moderately differentiated tumor is defined as posing a low risk.30 All other tumors, including high-grade carcinoma and stage IC disease (defined by surface involvement, rupture of tumor, or the presence of cytologically positive peritoneal washings), are considered high-risk, early-stage ovarian cancer. Until 2003, no study had shown a survival advantage with any form of postoperative therapy for patients such as this woman. Most randomized trials have compared two treatments without a control group receiving no chemotherapy. Several studies have shown an advantage with platinum-based therapy, which appears to offer freedom from relapse for a longer duration than melphalan or intraperitoneal radioactive phosphorus (32P) therapy, but without a significant survival benefit.31,32
In 2003, two studies comparing chemotherapy and observation in early-stage ovarian cancer were reported.33,34 A meta-analysis published at the same time suggested a marked improvement in survival with adjuvant chemotherapy.35 A further meta-analysis of data from four studies suggested that even patients with well-differentiated stage IA tumors may gain a possible advantage with chemotherapy, with a similar degree of benefit in every subgroup — although the results of subgroup analyses did not reach statistical significance.32,34,35,36
Even though these results may be interpreted to suggest that every patient with invasive epithelial ovarian cancer should receive adjuvant chemotherapy, there is evidence that careful staging remains the most important predictor of outcome and should determine the therapy.35 In a study in which formal staging was required as part of the eligibility criteria, the stage was optimally determined at surgery in only 34 percent of patients. These patients had an estimated eight-year survival rate of approximately 80 percent, as compared with 50 percent for patients for whom staging was limited. Although chemotherapy appeared to improve overall survival, this benefit was not statistically significant and in the optimally staged group, chemotherapy had no advantage. This study therefore suggests that in patients who have undergone comprehensive and complete staging at laparotomy, early-stage disease can be managed with observation and that the benefit from chemotherapy is seen in treating more advanced disease, if present but not detected, in patients whose cancer was poorly staged.
A separate multivariate analysis has identified the degree of differentiation as the most powerful prognostic indicator of the likelihood of disease-free survival, and some experts believe that observation should be restricted to patients with well-differentiated tumors.37 However, this issue remains controversial. Finally, a recent study comparing three cycles of paclitaxel and carboplatin with six cycles found that the disease-free and overall survival estimates at five years in the two treatment groups were not significantly different.38 Since there was more toxicity with six cycles of chemotherapy, many oncologists have taken this study as support for limited treatment for patients with early-stage ovarian cancer that has a relatively good prognosis. However, the number of events (recurrences and deaths) in this group of patients with a good prognosis limits statistical power to show the significance of an apparently better outcome with six cycles of chemotherapy.
Clinically, the most common quandary for patients with apparently early-stage ovarian cancer in whom staging has been inadequate is the choice between repeated surgery with a staging laparotomy and adjuvant chemotherapy. For patients who do not wish to receive chemotherapy, staging is mandatory. Although we know little about patients' preferences with respect to this trade-off, clinicians often favor chemotherapy over a second surgery, particularly when recurrent disease is so devastating, and they often also favor six cycles of carboplatin and paclitaxel.
Recommendations for This Patient
Although this patient had undergone optimal staging and had stage IA disease, the presence of poorly differentiated serous carcinoma prompted a recommendation for adjuvant chemotherapy with carboplatin and paclitaxel. There is a developing consensus that, above a certain threshold, there is no advantage to increasing the dose intensity of platinum. Therefore, many patients are treated with the lowest reasonable dose of carboplatin, equivalent to an area under the concentration–time curve of 5, which this patient received.39 The patient had considerable hematologic toxic effects, fatigue, alopecia, and peripheral neuropathy, so chemotherapy was discontinued after five cycles.
We recommended follow-up every three months in the first year, with clinical examination, pelvic examination, and surveillance with the tumor marker CA-125. It is not our practice to conduct surveillance with CT scans, since there is no proven survival advantage to treating patients with asymptomatic recurrence of ovarian cancer, and a longer time to clinical confirmation of disease recurrence is a significant predictor of a better response to further treatment. Currently, 15 months after completion of chemotherapy, the patient's tumor remains in complete remission.
Dr. Robert E. Scully (Pathology): As a pathologist, I have difficulty accepting the results of the two studies published in 2003 that showed a survival advantage associated with chemotherapy among patients with early-stage cancer because there was no central review of the pathological features of the epithelial tumors by an expert committee, or by a single expert in the field of gynecologic pathology, or even a review by the local pathologist as the cases were analyzed. The epithelial tumors of the ovary are a category of tumors in which there is very poor interobserver and intraobserver reproducibility, not only in terms of separating borderline tumors from carcinomas, but also in the grading of tumors and differentiation of cell types. I think this is a defect of many, if not most, of the published randomized studies.
Dr. Penson: I agree that for clinical studies the patient groups should be as homogeneous as possible, and this should include making sure the tumors are correctly classified and graded.
Dr. Bell: Which patients with early ovarian cancer should be referred for staging and which should not?
Dr. Penson: I think that only patients with well-differentiated tumors can avoid chemotherapy, and they will require comprehensive staging to ensure a good chance of cure.
Anatomical Diagnosis
Right ovary: papillary serous cystadenocarcinoma, grade 2 to 3 of 3, arising as a polypoid intracystic mass in a serous tumor containing benign, typical borderline, and micropapillary borderline areas.
Left ovary: serous borderline tumor, typical type, small.
Uterus, omentum, and lymph nodes: no evidence of cancer.
Source Information
From the Cancer Center, Department of Medicine, Division of Hematology–Oncology (R.T.P.), and the Departments of Radiology (D.S.) and Pathology (D.A.B.), Massachusetts General Hospital; and the Departments of Medicine (R.T.P.), Radiology (D.S.), and Pathology (D.A.B.), Harvard Medical School.
References
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A 52-year-old woman visited her gynecologist because of a single episode of painless postmenopausal bleeding. Her last menstrual period had been more than one year previously. A pelvic ultrasonogram showed the endometrial stripe to be thickened, at 8 mm, and revealed a complex cystic mass, 12 cm in diameter, with a mural nodule in the right adnexa (Figure 1A). This finding was confirmed by computed tomographic (CT) scanning (Figure 1B). An endometrial-biopsy specimen revealed that the endometrium was normal.
Figure 1. Radiologic Studies.
A pelvic ultrasonogram (Panel A) shows a large cystic mass in the right ovary with a mural nodule (arrow). The contrast-enhanced CT scan (Panel B) confirms the finding of a unilocular cystic mass in the right ovary and shows the enhancement in the mural nodule (arrow).
The patient had no gastrointestinal or urinary symptoms. Her weight was stable, and she reported no symptoms other than shortness of breath attributed to obesity. She had had normal Papanicolaou smears on a regular basis and two normal pregnancies 27 and 29 years previously. She had hypertension, which was controlled with metoprolol tartrate, and hypercholesterolemia, which was managed by diet. She had smoked in the distant past and she drank alcohol in moderation. Her 27-year-old daughter had been treated with radioactive iodine for thyroid cancer. Her father had died of renal-cell carcinoma at 72 years of age.
On physical examination, the patient's weight was 108.9 kg and the temperature 37.11°C. The blood pressure was 148/84 mm Hg and the heart rate 103 beats per minute with a regular rhythm. The results of an examination of the head, eyes, ears, nose, and throat were normal. Examination of the chest and heart revealed no abnormalities. The breasts appeared normal, and there was no axillary or supraclavicular lymphadenopathy. The abdomen was not distended. There was suprapubic fullness on palpation at the pelvic inlet, but no discrete mass, organomegaly, or inguinal lymphadenopathy. There was no tenderness, fluid wave, or shifting dullness. The bowel sounds were normal. There was no edema or calf tenderness, and the distal pulses were normal. A pelvic examination revealed normal external genitalia with minimal atrophy and good support. The cervix appeared normal, with no mucosal lesion. The uterus was normal in size and contour, nontender, but was deviated posteriorly by a prominent smooth anterior mass. There was no nodularity in the cul-de-sac on rectovaginal examination. The pelvic sidewalls were smooth and unremarkable. A rectal examination disclosed small hemorrhoids.
The hemoglobin level was 11.8 g per deciliter and the hematocrit 33.6 percent. Laboratory measurements of the levels of blood chemicals yielded the following results: alanine aminotransferase, 58 U per liter; aspartate aminotransferase, 38 U per liter; and alkaline phosphatase, 118 U per liter. The level of CA-125 was 49.6 U per milliliter. The results of other laboratory tests were within normal ranges.
A surgical procedure was planned to begin with laparoscopy, followed, if the findings were benign, by hysteroscopy to rule out an occult endometrial tumor and therapeutic endometrial ablation. The patient consented to undergo laparotomy, hysterectomy, and oophorectomy, if these procedures were required.
During an examination performed while the patient was under anesthesia, the uterus was found moved posteriorly and to the left by a mass that was fixed to the uterine fundus on the right side. The diameter of the mass was approximately 18 cm, and it was palpable above the umbilicus on abdominal examination. Because of the large size of the mass, its fixation to the uterus, and the elevated level of CA-125, an exploratory laparotomy was performed, rather than the planned laparoscopy.
On exploration, there was a right adnexal mass that originated from the right infundibulopelvic ligament. It was adherent to the superior aspect of the uterus with no evidence of other surface involvement. The left ovary and the remainder of the abdomen appeared normal.
The mass and uterus were removed en bloc. Microscopic examination of an intraoperative frozen section disclosed a serous papillary cystic tumor, which was thought probably to be a low-grade cystadenocarcinoma. A total abdominal hysterectomy, bilateral oophorectomy, gastrocolic omentectomy, appendectomy, and a full staging procedure were performed, including examination and palpation of all peritoneal surfaces. Multiple random biopsy specimens were obtained from the diaphragms, the pericolic gutters, and the pelvis. Enlarged lymph nodes that appeared to be hyperplastic rather than containing metastatic carcinoma were present in both obturator fossae. Therefore, lymph nodes were removed up to the bifurcation of the aorta.
The patient's postoperative recovery was uneventful, and she was discharged on the sixth hospital day.
Differential Diagnosis
Dr. Richard T. Penson: May we review the imaging studies?
Dr. Dushyant Sahani: Imaging studies included transabdominal and transvaginal pelvic ultrasonography. A large, unilocular cystic mass with a mural nodule was identified in the right adnexa, involving the right ovary (Figure 1A). The left ovary could not be identified. The uterus was normal, and the endometrial stripe measured approximately 10 mm. The differential diagnosis includes a primary cystic ovarian neoplasm, which could be benign, malignant, or borderline. Metastases to the ovary are usually bilateral and solid. Endometriosis was considered unlikely because of the large size of the mass.
An abdominal pelvic CT scan was obtained, and again showed a large cystic mass with a posterior mural nodule (Figure 1B). There was no evidence of metastasis to the peritoneum, to the lymphatics, or to other abdominal or pelvic organs. Again, the left ovary was not identified.
Pathological Discussion
Dr. Debra A. Bell: The specimens received in the pathology department were the uterus with attached left fallopian tube and ovary, the right fallopian tube and ovary, the omentum, and dissections of both the right and left pelvic lymph nodes. An examination of the right ovary revealed a cystic ovary, 13 by 12 by 9 cm, with a smooth surface and an attached and unremarkable fallopian tube. The opened specimen revealed that ovarian tissue had been replaced by a unilocular cyst that contained cloudy yellow fluid. The wall of the cyst was predominantly smooth and ranged from 0.2 to 1.5 cm in thickness. Protruding into this large cyst was a single polypoid mass measuring 1.5 by 1.0 cm. Two centimeters from this intracystic mass, the cyst wall was thickened and contained a smaller 1.5-cm cyst filled with a 1.3-cm papillary excrescence. The left ovary measured 3.0 by 2.2 by 1.7 cm and had a bosselated unremarkable surface. The cut surface of the ovary revealed several smooth-walled cysts measuring from 0.8 to 1 cm in diameter. The attached fallopian tube was unremarkable. The uterine cavity contained an endometrial polyp measuring 3.8 by 3.5 by 0.3 cm, and several grossly typical leiomyomas ranging from 0.8 to 2.8 cm in diameter were present in the myometrium. The omentum was unremarkable.
Microscopical examination (Figure 2) revealed that the large unilocular cyst in the right ovary was lined by a single layer of ciliated cells that ranged in shape from cuboidal to columnar. The polypoid mass that extended into the cyst was composed of sheets of cells and closely apposed glands and cysts. The cells were cuboidal to polygonal and contained highly pleomorphic nuclei with prominent and irregular nucleoli. The presence of solid masses of cells with a marked degree of nuclear atypia was sufficient for a diagnosis of serous carcinoma, grade 2 to 3 of 3. The 1.5-cm intramural cyst contained a papillary proliferation.
Figure 2. Histopathological Features of the Tumor (Hematoxylin and Eosin).
Panel A shows a typical area in a serous borderline tumor. There are irregular, branching papillae that progressively decrease in size (hierarchical branching). At higher magnification (Panel B), the papillae are lined with mildly to moderately atypical columnar and cuboidal cells. Detached clusters of similar cells are present. Panel C shows a micropapillary area in the serous borderline tumor. Smoothly contoured papillae are lined with fine micropapillae. At higher magnification (Panel D), the micropapillae are five times as long as they are wide, and they are lined with polygonal cells with an elevated nuclear-to-cytoplasmic ratio. Panel E shows an area of serous carcinoma. Sheets of cells and closely apposed glands are present. At higher magnification (Panel F), the cells have irregular pleomorphic, highly atypical nuclei with prominent nucleoli.
In some areas, hierarchically branching fibrous papillae with irregular contours were present. These papillae were lined with moderately atypical cuboidal and columnar cells. Detached clusters of similar atypical cells were present as well. These histologic features are those of a serous borderline tumor, typical type. In other areas, the papillae were broader and had smooth contours. These were lined by elongated micropapillae that emanated directly from the broad fibrous papillae. The micropapillae were five times as long as they were wide and did not contain fibrovascular cores. The cells lining the papillae and also present in the micropapillae were polygonal, with a high nuclear-to-cytoplasmic ratio and moderate cytologic atypia. These features are those of a serous borderline tumor, micropapillary type. Microscopical examination of the left ovary revealed a small serous borderline tumor, typical type.
Tumors of the epithelium of the ovary are categorized by the World Health Organization according to epithelial type and degree of epithelial differentiation.1 The classification according to epithelial type is based on the resemblance of the epithelium in the tumor to normal epithelium. Thus, serous tumors have epithelium that resembles the fallopian-tube type of epithelium, endometrioid tumors resemble endometrium, mucinous tumors resemble either endocervical or gastrointestinal mucinous epithelium, clear-cell tumors resemble renal-cell carcinoma or hypersecretory endometrium or endometrium associated with pregnancy, transitional-cell tumors resemble urothelium, and squamous-cell carcinomas resemble squamous epithelium (Table 1). These tumors are also classified on the basis of their degree of differentiation as benign, borderline, or malignant tumors (Table 1). Benign serous tumors of the ovary are characterized by a single layer of cuboidal or columnar cells that often contain cilia. Borderline tumors are defined as tumors that show a degree of epithelial proliferation that is intermediate between obviously benign tumors and malignant tumors. These tumors are characterized by the presence of epithelial atypia and tufting, and they contain detached clusters of atypical epithelial cells, without stromal invasion. Serous carcinomas of the ovary are characterized by the confluence or close approximation of glands and cysts that are lined with cells that have a high degree of nuclear atypia; they usually have irregular nests of highly pleomorphic and atypical cells infiltrating a desmoplastic, fibrous, or edematous stroma.1
Table 1. Classification of Ovarian Epithelial Tumors.
The morphologic features of particular interest in this case are, first, the presence of both typical and micropapillary variants in the borderline areas of the tumor and, second, the presence of a moderately differentiated or a poorly differentiated carcinoma arising in a neoplasm that shows a spectrum of abnormalities that range from benign to typical borderline to micropapillary borderline tumors.
Serous borderline tumors of the ovary, which are also referred to as tumors of low malignant potential or atypical proliferative tumors, have two distinct histologic patterns that may be present either in isolation or, more commonly, admixed with the other histologic types.2,3,4,5,6,7,8,9,10 The typical pattern is characterized by hierarchically branching, fibrous papillae with irregular contours that end in detached clusters of atypical cells. The architectural pattern of a micropapillary tumor is that of smoothly contoured, large, fibrous papillae from which thin, elongated micropapillae emanate. Both types generally show only moderate cytologic atypia. The prognostic significance of the micropapillary pattern in a noninvasive tumor is controversial; however, most studies have shown an increased frequency of surface involvement, bilaterality, and peritoneal involvement in micropapillary-type tumors, as compared with those of the typical type.2,3,4,5,6,7,8,9,10 An increase in frequency of stromal invasion in ovarian tumors has been reported, and some authors have suggested an association with an increased frequency of invasive peritoneal implants.2,7,11
The presence of a moderately differentiated or a poorly differentiated carcinoma arising within a tumor that shows a spectrum of epithelial differentiation from benign through borderline raises the issue of the role of benign and borderline tumors as precursors of serous carcinoma of the ovary. Well-differentiated serous carcinomas almost always arise within an existing serous neoplasm, which is usually a serous borderline tumor or adenofibroma — often one with micropapillary architecture.2,12 This known feature and the results of genetic alterations suggest that well-differentiated serous carcinomas arise by way of an adenoma-to-carcinoma sequence (from a benign serous cystadenoma to a typical borderline tumor to a micropapillary borderline tumor to an invasive, well-differentiated carcinoma).13,14,15 In contrast, several studies have shown that even the smallest high-grade serous carcinomas rarely arise within preexisting serous neoplasms16 and that such tumors have features, such as TP53 mutations, that are typical of advanced-stage, high-grade serous carcinoma.15,17 These data have led to the suggestion that poorly differentiated serous carcinomas arise without a preceding benign or premalignant lesion from ovarian surface epithelium or from serous epithelial inclusion cysts.
Discussion of Management
Dr. Penson: After careful staging, it was determined that this patient had ovarian cancer, confined to the ovary, with a poorly differentiated component. The cancer was stage IA of IV, in accordance with the classification system of the International Federation of Gynecology and Obstetrics (in which stage I is confined to the ovaries and stage IV involves metastases to the liver or lung). Although the tumor was completely resected with negative margins, the question of adjuvant therapy had to be decided.
Ovarian cancer is typically considered advanced when there are intraabdominal transcoelomic metastases (stage III disease) (Table 1), with subtle symptoms that commonly result in a delayed diagnosis.18,19 Although early-stage disease may be identified by strategies such as proteomics analysis and CA-125 algorithms, screening with the use of tumor markers or ultrasonography is not recommended at this time.20,21 In high-risk populations, such as women with BRCA mutations or with strong family histories of breast cancer or ovarian cancer, the disease is more successfully prevented by prophylactic oophorectomy than by relying on screening. In the case of this patient, the diagnosis was made at an early stage because of the coincidental development of endometrial polyps with postmenopausal bleeding.
Surgical resection has been the mainstay of treatment for ovarian carcinoma, and a recent randomized, controlled trial showed that the amount of disease left at the completion of surgery (with <1 cm considered optimal and 1 cm suboptimal) was one of the most important prognostic factors for ovarian cancer.22 However, since the majority of patients do not have disease that can be resected completely, the development of effective chemotherapy has been a priority.
A series of randomized, controlled trials has defined the standard of care for chemotherapy in advanced ovarian cancer. Several recent studies have shown that cisplatin and paclitaxel have greater efficacy than cyclophosphamide and cisplatin.23,24,25
The most recent randomized trial finally confirmed the adoption of carboplatin plus paclitaxel, with an improved toxicity profile as compared with that of cisplatin and paclitaxel, as the standard of care for advanced ovarian cancer.26 Docetaxel, a less neurotoxic alternative to paclitaxel, is used more often in Europe than in the United States.27 The five-year overall survival rate for women with ovarian cancer has increased incrementally from 37 percent in the 1970s to 39 percent in the 1980s. In the most recent data from the 1990s,28 the five-year overall survival rate stands at 43 percent. A study in this issue of the Journal found that additional surgical debulking offered no survival advantage for patients with stage III ovarian cancer receiving chemotherapy.29
This patient had early ovarian cancer, defined as cancer confined to the ovaries, and she had an anticipated probability of survival at five years of 70 to 90 percent. Stage IA or IB (unilateral or bilateral disease confined to the ovaries) with well-differentiated or possibly moderately differentiated tumor is defined as posing a low risk.30 All other tumors, including high-grade carcinoma and stage IC disease (defined by surface involvement, rupture of tumor, or the presence of cytologically positive peritoneal washings), are considered high-risk, early-stage ovarian cancer. Until 2003, no study had shown a survival advantage with any form of postoperative therapy for patients such as this woman. Most randomized trials have compared two treatments without a control group receiving no chemotherapy. Several studies have shown an advantage with platinum-based therapy, which appears to offer freedom from relapse for a longer duration than melphalan or intraperitoneal radioactive phosphorus (32P) therapy, but without a significant survival benefit.31,32
In 2003, two studies comparing chemotherapy and observation in early-stage ovarian cancer were reported.33,34 A meta-analysis published at the same time suggested a marked improvement in survival with adjuvant chemotherapy.35 A further meta-analysis of data from four studies suggested that even patients with well-differentiated stage IA tumors may gain a possible advantage with chemotherapy, with a similar degree of benefit in every subgroup — although the results of subgroup analyses did not reach statistical significance.32,34,35,36
Even though these results may be interpreted to suggest that every patient with invasive epithelial ovarian cancer should receive adjuvant chemotherapy, there is evidence that careful staging remains the most important predictor of outcome and should determine the therapy.35 In a study in which formal staging was required as part of the eligibility criteria, the stage was optimally determined at surgery in only 34 percent of patients. These patients had an estimated eight-year survival rate of approximately 80 percent, as compared with 50 percent for patients for whom staging was limited. Although chemotherapy appeared to improve overall survival, this benefit was not statistically significant and in the optimally staged group, chemotherapy had no advantage. This study therefore suggests that in patients who have undergone comprehensive and complete staging at laparotomy, early-stage disease can be managed with observation and that the benefit from chemotherapy is seen in treating more advanced disease, if present but not detected, in patients whose cancer was poorly staged.
A separate multivariate analysis has identified the degree of differentiation as the most powerful prognostic indicator of the likelihood of disease-free survival, and some experts believe that observation should be restricted to patients with well-differentiated tumors.37 However, this issue remains controversial. Finally, a recent study comparing three cycles of paclitaxel and carboplatin with six cycles found that the disease-free and overall survival estimates at five years in the two treatment groups were not significantly different.38 Since there was more toxicity with six cycles of chemotherapy, many oncologists have taken this study as support for limited treatment for patients with early-stage ovarian cancer that has a relatively good prognosis. However, the number of events (recurrences and deaths) in this group of patients with a good prognosis limits statistical power to show the significance of an apparently better outcome with six cycles of chemotherapy.
Clinically, the most common quandary for patients with apparently early-stage ovarian cancer in whom staging has been inadequate is the choice between repeated surgery with a staging laparotomy and adjuvant chemotherapy. For patients who do not wish to receive chemotherapy, staging is mandatory. Although we know little about patients' preferences with respect to this trade-off, clinicians often favor chemotherapy over a second surgery, particularly when recurrent disease is so devastating, and they often also favor six cycles of carboplatin and paclitaxel.
Recommendations for This Patient
Although this patient had undergone optimal staging and had stage IA disease, the presence of poorly differentiated serous carcinoma prompted a recommendation for adjuvant chemotherapy with carboplatin and paclitaxel. There is a developing consensus that, above a certain threshold, there is no advantage to increasing the dose intensity of platinum. Therefore, many patients are treated with the lowest reasonable dose of carboplatin, equivalent to an area under the concentration–time curve of 5, which this patient received.39 The patient had considerable hematologic toxic effects, fatigue, alopecia, and peripheral neuropathy, so chemotherapy was discontinued after five cycles.
We recommended follow-up every three months in the first year, with clinical examination, pelvic examination, and surveillance with the tumor marker CA-125. It is not our practice to conduct surveillance with CT scans, since there is no proven survival advantage to treating patients with asymptomatic recurrence of ovarian cancer, and a longer time to clinical confirmation of disease recurrence is a significant predictor of a better response to further treatment. Currently, 15 months after completion of chemotherapy, the patient's tumor remains in complete remission.
Dr. Robert E. Scully (Pathology): As a pathologist, I have difficulty accepting the results of the two studies published in 2003 that showed a survival advantage associated with chemotherapy among patients with early-stage cancer because there was no central review of the pathological features of the epithelial tumors by an expert committee, or by a single expert in the field of gynecologic pathology, or even a review by the local pathologist as the cases were analyzed. The epithelial tumors of the ovary are a category of tumors in which there is very poor interobserver and intraobserver reproducibility, not only in terms of separating borderline tumors from carcinomas, but also in the grading of tumors and differentiation of cell types. I think this is a defect of many, if not most, of the published randomized studies.
Dr. Penson: I agree that for clinical studies the patient groups should be as homogeneous as possible, and this should include making sure the tumors are correctly classified and graded.
Dr. Bell: Which patients with early ovarian cancer should be referred for staging and which should not?
Dr. Penson: I think that only patients with well-differentiated tumors can avoid chemotherapy, and they will require comprehensive staging to ensure a good chance of cure.
Anatomical Diagnosis
Right ovary: papillary serous cystadenocarcinoma, grade 2 to 3 of 3, arising as a polypoid intracystic mass in a serous tumor containing benign, typical borderline, and micropapillary borderline areas.
Left ovary: serous borderline tumor, typical type, small.
Uterus, omentum, and lymph nodes: no evidence of cancer.
Source Information
From the Cancer Center, Department of Medicine, Division of Hematology–Oncology (R.T.P.), and the Departments of Radiology (D.S.) and Pathology (D.A.B.), Massachusetts General Hospital; and the Departments of Medicine (R.T.P.), Radiology (D.S.), and Pathology (D.A.B.), Harvard Medical School.
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