Serous Tumors of the Ovary

Background

Serous tumors are very common tumors of the ovary, arising from the surface epithelium, comprising 20-50% of all ovarian tumors. The demographics of these tumors are presented below.

TUMOR TYPE TUMOR NAME AGE OF PRESENTATION PERCENTAGE OF TUMORS

Benign Serous cystadenoma 60 yrs 70%

Borderline malignancy Atypical proliferative serous tumors, Serous tumor of borderline malignancy 30-60 yrs 5-10%

Carcinoma Serous cystadenocarcinoma 40-70 yrs 20-25%

The clinical appearance of these tumors varies with the histologic type. Under the microscope, serous tumors tend to be uniform throughout the tumor. Thus carcinomas generally lack areas of benign and borderline, merging with malignant histologies.

One of the most confusing and diagnostically challenging areas for the pathologist is the assessment of peritoneal implants. These are not metastatic foci but rather thought of as a field change involving extraovarian mesothelium as well as ovarian mesothelium. These implants occur in 16-59% of serous borderline tumors. The implants are more common in cases where the primary ovarian tumor has a surface component. Implants have been divided into noninvasive and invasive. Noninvasive implants are further divided into epithelial and desmoplastic subtypes.

The striking difference in prognosis is evident by the rates of progression of disease with invasive implants. The story gets even more complicated because serous carcinomas may also be associated with noninvasive desmoplastic implants. As a rule of thumb, these implants in serous carcinomas usually have a greater degree of nuclear atypia and the epithelial component occupies 50% or more of the implant area. The pelvic or para-aortic lymph nodes may also contain atypical serous epithelium.

Serous carcinomas may sometimes be confused with other papillary tumors of the ovary, including endometrioid and clear cell carcinomas. Endometrioid tumors have more uniform papillae which are longer, broader, and more villous. Clear cell carcinomas are lined by hobnail or clear cells and have hyalinized cores.

Finally tumors metastatic to the ovary may simulate serous carcinomas. In particular, metastatic breast carcinoma may be difficult to distinguish. Immunohistochemistry reveals immunopositivity for gross cystic disease fluid protein-15 for breast cancer and CA125 for serous carcinoma.

PATHOGENESIS CHARACTERIZATION

CHROMOSOMAL ABNORMALITIES

Micropapillary serous carcinoma of the ovary has distinct patterns of chromosomal imbalances by comparative genomic hybridization compared with atypical proliferative serous tumors and serous carcinomas

Annette Staebler, MD
Kerstin Heselmeyer-Haddad, PhD
Karen Bell, MD
Maureen Riopel, MD
Elizabeth Perlman, MD
Thomas Ried, MD
Robert J. Kurman, MD

Hum Pathol 2002;33:47-59. Abstract quote

Recent studies have subdivided serous borderline tumors into 2 categories: atypical proliferative serous tumors (APSTs), which have a relatively benign course, and micropapillary serous carcinomas (MPSCs), which behave like low-grade carcinoma.

This study was undertaken to determine, using comparative genomic hybridization (CGH), whether cytogenetic changes support this hypothesis. Nine cases of APST, 10 of MPSC, and 11 of invasive serous carcinoma (SC) were analyzed by CGH. Tumor DNA was extracted from frozen or paraffin-embedded tissue from the primary ovarian tumor, using either sections with at least 70% tumor cells or tissue after relative enrichment by microdissection. Chromosomal imbalances were identified in 3 of 9 APST, 6 of 10 MPSC, and 11 of 11 SC. Three or more chromosomal imbalances were found in 0 of 9 APST, 4 of 10 MPSC, and 9 of 11 SC. Recurrent copy number alterations were grouped into 4 classes correlating with the different tumor types. Class I changes were present in APST and in MPSC or SC and included +8q (7 of 11 SC, 2 of 10 MPSC, 2 of 9 APST), –9p (5 of 11 SC, 0 of 10 MPSC, 1 of 9 APST), and +12 (+12p in 3/11 SC, +12 in 2 of 10 MPSC, +12 in 1 of 9 APST). Class II changes were found only in MPSC and SC, but not in APST. The most frequent examples were +3q (10 of 11 SC, 1 of 10 MPSC), –4q (5 of 11 SC, 1 of 10 MPSC), and –17p (5 of 11 SC, 1 of 10 MPSC). Class III changes were limited to SC, like –16q (7 of 11 SC) and –18q (6 of 11 SC). Class VI changes were unique to MPSC. Gain of 16p (3 of 10 MPSC) was the only aberration in this group. This aberration was not only unique to MPSC but was also the most frequent finding in MPSC.

These data support the hypothesis that noninvasive serous tumors of the ovary can be subdivided into 2 categories: APST and MPSC. The number of imbalances in MPSC is substantially higher than in APST and lower than in SC. Some changes in MPSC are shared with SC and APST and others with SC only, suggesting that a subset of MPSC may represent a stage in progression from APST to SC. Other cases of MPSC with independent genetic alterations may represent another subset of tumors that are a distinct entity from APST and SC.

SALPINGITIS

Salpingitis, Salpingoliths, and Serous Tumors of the Ovaries: Is There a Connection?
Jeffrey D. Seidman, M.D.; Mark E. Sherman, M.D.; Karen A. Bell, M.D.; Hidetaka Katabuchi, M.D.; Timothy J. O'Leary, M.D., Ph.D.; Robert J. Kurman, M.D.

From the Department of Pathology, Washington Hospital Center, Washington, D.C. (J.D.S.); the Departments of Pathology (M.E.S., K.B., H.K., R.J.K.), Gynecology and Obstetrics (R.J.K.), The Johns Hopkins Medical Institution, Baltimore, Maryland; and the Department of Cellular Pathology, Armed Forces Institute of Pathology, Washington, D.C. (T.J.O.).

Int J Gyn Pathol 2002;21:101-107 Abstract quote
We have observed luminal and mucosal calcifications frequently surrounded by a mantle of bland epithelium in the fallopian tubes (“salpingoliths”) of women with serous tumors of the ovaries. These lesions resemble noninvasive peritoneal “implants” in women with advanced stage atypical proliferative serous tumors (APSTs) and micropapillary serous carcinomas (MPSCs).

The presence of salpingitis and salpingoliths was prospectively evaluated in 358 women with a variety of nonneoplastic and neoplastic ovarian conditions and compared with 87 previously reported women with APSTs/MPSCs in an effort to determine whether these lesions were specifically associated with serous tumors. The frequency of chronic salpingitis among women without ovarian pathology was 27%, and the frequency of salpingoliths was 4%. Serous epithelial tumors (cystadenomas, APST/MPSC, and carcinomas) were significantly more often associated with chronic salpingitis (53%) and salpingoliths (32%) than all other cases with or without ovarian neoplasms (p<0.01). APSTs/MPSCs were associated with salpingoliths significantly more frequently than all other groups (p<0.001). For patients with APSTs/MPSCs, salpingoliths were found significantly more often in advanced stage (FIGO II and III) patients (51%) than stage I patients (24%) (p<0.01), but salpingitis, present in 60% of these patients, was not stage-dependent (p>0.05). Chronic salpingitis was identified in 66% of women with endometriosis, which was significantly more frequent than those with normal ovaries (27%) (p<0.001).

In conclusion, fallopian tube abnormalities may be related to both the high frequency of infertility and the noninvasive peritoneal implants in women with APSTs/MPSCs. Whether the fallopian tubes with salpingoliths are the source of the peritoneal “implants,” the recipient of implants, or are independent is unknown. In addition, the high frequency of salpingitis in women with endometriosis may be related to the mechanism of endometriosis-associated infertility.

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION

General

TUMOR TYPE GROSS APPEARANCE

Benign Unilocular to multilocular cysts
Polypoid excrescences
Bilateral in 10%

Borderline malignancy Similar to benign but more extensive papillae
Bilateral in 25%

Carcinoma Predominately cystic and papillary, solid and firm, or solid and cystic
Bilateral in 66%

VARIANTS

HISTOLOGICAL TYPES CHARACTERIZATION

General
The key differentiating histologic feature is the presence of stromal invasion, present only in carcinomas. Invasion is associated with a desmoplastic host response caused by the infiltrating tumor cells. It is defined by one or more of the following characteristics:

Irregular, often slit-like glandular lumens
Small, tight nests of tumor cells and single tumor cells growing in a dense fibrous or hyalinized stroma
Glomeruloid formations
Psammoma bodies

Occasionally, there are small nests of invasive cells with lymphatic invasion. The term microinvasion has been used to designate these tumors and is defined as tumors containing one or more foci not exceeding 3 mm in maximal linear dimension or 10 mm2 in area. From a prognostic standpoint, these tumors have the same prognosis as tumors lacking microinvasion.

Benign
Lined by nonciliated cuboidal to columnar epithelium with bland cytology

Borderline malignancy
Polypoid excrescences and papillae lined by atypical proliferating epithelial cells forming small papillae that appear to be detached from the cyst wall
No invasion into the underlying stroma

Carcinoma
Lining cells have high nuclear:cytoplasmic ratio with varying nuclear atypia
Ciliated cells common
Psammoma bodies present in 25%
Invasion into the underlying stroma

IMPLANTS

NONINVASIVE

Epithelial type Papillary proliferations of atypical serous cells with a minimal stromal component are present on the surface of the peritoneum in smoothly contoured subperitoneal invaginations or in invaginations between lobules of the omentum

Desmoplastic type Reactive stroma layered onto the peritoneal surface and lining invaginations between omental fat lobules
Embedded within the implants are small glands and papillae lined by atypical serous cells, single cells, and psammoma bodies

INVASIVE Irregular infiltration and destruction of the underlying tissue, resembling grade I serous carcinoma

Refined Diagnostic Criteria for Implants Associated With Ovarian Atypical Proliferative Serous Tumors (Borderline) and Micropapillary Serous Carcinomas

Karen A. Bell, M.D.; Ann E. Smith Sehdev, M.D.; Robert J. Kurman, M.D.

Am J Surg Pathol 2001;25:419-432 Abstract quote

Characterization of invasive peritoneal implants from patients with noninvasive serous ovarian tumors has important prognostic and treatment implications, but the criteria for distinguishing invasive and noninvasive implants vary among investigators and can be difficult to apply.

The authors studied 148 implants from 60 patients, 33 with primary atypical proliferative serous tumor, and 27 with primary noninvasive micropapillary serous carcinoma, with a mean follow-up of 62 months (median follow-up, 52 months). Previously reported and newly proposed histologic features for implant classification were evaluated and correlated with clinical outcome.

Three criteria were applied for the diagnosis of ``invasive'' implants: invasion of underlying normal tissue, micropapillary architecture, and solid epithelial nests surrounded by clefts. Implants displaying any one of these three features were classified as ``invasive,'' whereas those lacking all three features were classified as ``noninvasive.'' Sixty-six implants were invasive and 82 were noninvasive.

Of the 31 patients with invasive implants, six were dead of disease (DOD), 13 were alive with progressive disease (AWPD), and 12 were alive with no evidence of disease (NED). Of the 29 patients with noninvasive implants, two were DOD, one was dead of uncertain causes, one was AWPD, and 25 were alive with NED. Eighty-nine percent of invasive implants had a micropapillary architecture and 83% had solid epithelial nests surrounded by clefts. A minority of invasive implants (14% of those with underlying normal tissue) demonstrated invasion of normal underlying tissue. Nuclear atypia, mitoses, calcification, necrosis, and identification of individual cells ``infiltrating'' the stroma did not correlate with implant type. The proposed criteria permitted recognition of implants that correlated strongly with adverse outcome. Sixty-one percent of patients with implants displaying any one of the three features used to diagnose invasive implants were AWPD or DOD compared with 10% of patients whose implants lacked these features (p = 0.00001).

Because implants associated with an adverse outcome can be identified before they invade underlying normal tissue, the term invasive implant to describe them is inaccurate and misleading. These implants resemble patterns of growth in micropapillary serous carcinoma of the ovary and the recurrent tumor that is obvious carcinoma. Accordingly, we propose that these extraovarian lesions be designated ``well-differentiated serous carcinoma.''

TYPES OF NODAL SEROUS EPITHELIUM SIGNIFICANCE

Mullerian inclusion glands or lymph node endosalpingiosis Benign glands located in the lymphoid tissue or capsule of the node
No sinus collections
Present in 30-40% of patients without ovarian tumors

Some Mullerian Inclusion Cysts in Lymph Nodes May Sometimes Be Metastases From Serous Borderline Tumors of the Ovary

William F. Moore, M.D.; Rex C. Bentley, M.D.; Andrew Berchuck, M.D.; Stanley J. Robboy, M.D.

From the Departments of Pathology (W.F., R.C.B., S.J.R.) and Obstetrics and Gynecology (A.B., S.J.R.), Duke University Medical Center, Durham, North Carolina, U.S.A.

Am J Surg Pathol 2000;24:710-718 Abstract quote
Glandular inclusions that appear morphologically benign are occasionally found in lymph nodes as well as in peritoneal and omental biopsies. In patients with gynecologic malignancies, the nature and significance of these mullerian inclusion cysts (MIC) present a diagnostic challenge with regard to whether they are benign and incidental or are related to the coincident tumor for which surgery is being performed.

Sixty-two cases of MIC were prospectively identified during a 6-year period. The frequencies were calculated and stratified by lymph node chain distribution, primary tumor site, and primary tumor type. MIC appeared as small cysts lined by a serous (mullerian)-type, cytologically bland, cuboidal to columnar epithelium with a simple architecture. Among 62 women, MIC was found in lymph nodes (27 cases), pelvic peritoneum (19 cases), omentum (16 cases), bowel serosa (9 cases), uterine serosa (8 cases), and parametrial connective tissues (4 cases). Among a set of 417 consecutive cases in which lymphadenectomy was performed, 46 (11%) women had MIC. The MIC involved multiple sites (26 cases in the peritoneum/omentum and 27 in lymph nodes). The primary tumor was in the ovary in 32 of the 46 women with MIC (70%) and of these, 17 were borderline serous (53%). Sixty-two of 6154 lymph nodes examined contained MIC (1.0%). 3.2% of nodes contained MIC in which the primary tumor arose in the ovary, but only 0.1% with either endometrial or cervical tumors (2, p <0.00001). The lymph nodes most often involved by MIC were from para-aortic sites (40%), which reflect the primary drainage route from the ovary. Not uncommonly, neighboring areas in the same lymph node group with MIC disclosed separate foci of obvious metastatic borderline tumor (4 of 10; 40%).

In summary, the increased frequency of MIC in lymph nodes sampled for primary ovarian malignancies suggests that MIC in some cases, rather than being benign, incidental inclusions, are more likely bland-appearing forms of metastatic tumor. The preponderance of inclusions occurs with serous ovarian tumors of borderline malignancy, and the inclusions are overrepresented in the lymph nodes that primarily receive drainage from the ovary.

Serous epithelium with borderline features This is a true metastasis if the lesion is confined to the lymph node sinuses and is unquestionably composed of epithelial cells
This does not adversely affect prognosis

Reactive peritoneal mesothelial cells These may become dislodged and deposit within lymph node sinuses

Independent borderline tumor of the lymph node Small focus of borderline tumor confined to the lymphoid tissue or capsule of the node and accompanied by uninvolved mullerian inclusion glands elsewhere in the node

VARIANTS

Psammomcarcinoma
Invasion of the ovarian stroma or its vascular space (in extraovarian cases, invasion of any intraperitoneal tissue or vascular spaces)
No more than mild to moderate nuclear atypia
Epithelial nests no more than 15 cells in their largest linear dimension
Psammoma bodies in at least 75% of the papillae or nests

Ovarian micropapillary serous borderline tumors. Clinicopathologic features and outcome of seven surgically staged patients.

Goldstein NS, Ceniza N.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.

Am J Clin Pathol 2000 Sep;114(3):380-6 Abstract quote

We report the clinicopathologic findings for 7 patients with completely staged ovarian micropapillary serous borderline tumors (MSBTs) to further clarify tumor behavior.

None of the MSBTs had microinvasion in the ovarian neoplasm. The MSBT pattern constituted 25% to almost all of the neoplasm. Four were bilateral, and 6 involved the ovarian surface. Five patients had peritoneal implants; 2 were invasive, and 3 were noninvasive MSBTs. Distribution of stages among patients was as follows: IA, 1; IC, 1; IIC, 2; IIIB, 2; and IIIC, 1. Median follow-up was 8.5 years. Four patients were alive and well at the last follow-up visit, including 1 patient with stage IIIC (lymph node metastases) disease who had noninvasive implants (12 years after surgery). One patient who was free of disease died of complications of chemotherapy and abdominal surgery. Two patients died of intra-abdominal neoplastic growth (stages IIC and IIIB) 5 and 9 years after surgery, respectively; both had invasive implants.

Without invasive peritoneal implants, MSBTs seem to behave as similar staged nonmicropapillary serous borderline tumors without invasive peritoneal implants. With invasive peritoneal implants, they seem to behave as low-grade carcinomas. Pathologists should recognize MSBT as a neoplasm that can have adverse prognostic features, including invasive peritoneal implants.

SPECIAL STAINS/IMMUNOHISTOCHEMISTRY CHARACTERIZATION

CAVEOLIN-1

Caveolin-1 Expression in Ovarian Carcinoma Is MDR1 Independent

Ben Davidson, MD, PhD
Iris Goldberg, PhD
Vered Givant-Horwitz, MSc
Jahn M. Nesland, MD, PhD, etal.

Am J Clin Pathol 2002;117:225-234 Abstract quote

We studied the role of caveolin-1 in tumor progression and prognosis in serous ovarian carcinoma and the association between caveolin-1 and MDR1 expression. The study involved immunohistochemical analysis for caveolin-1 and P-glycoprotein (P-gp) expression in 75 effusions and 90 solid lesions from ovarian and primary peritoneal carcinoma; in situ hybridization for MDR1 messenger RNA (mRNA) expression in 62 effusions and all 90 tumors; and reverse transcription–polymerase chain reaction (RT-PCR) for caveolin-1 mRNA expression in 23 effusions.

Immunohistochemical analysis localized caveolin-1 to the cell membrane in 43 effusions and 24 tumors. P-gp membrane expression was detected in 14 effusions and 11 tumors; MDR1 mRNA, in 20 effusions and 30 tumors. Caveolin-1 mRNA was expressed in 19 effusions. Caveolin-1 protein expression showed no association with that of P-gp protein or MDR1 mRNA. The expression of all markers was similar in carcinoma cells in pleural and peritoneal effusions.

Caveolin-1 is a novel diagnostic marker for effusions; expression is moderately elevated in tumor cells in effusions, possibly owing to altered signal transduction and metabolism in cancer cells at this site. Expression seems MDR1 independent.

WT1

WT1 immunoreactivity in uterine papillary serous carcinomas is different from ovarian serous carcinomas.

Goldstein NS, Uzieblo A.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
Am J Clin Pathol 2002 Apr;117(4):541-5 Abstract quote
WT1 diffusely stains most ovarian serous carcinomas; reactivity of uterine papillary serous carcinomas has not been evaluated.

We studied WT1 expression in 13 International Federation of Gynecology and Obstetrics stage 1 and 5 stage 3 or 4 uterine papillary serous carcinomas without ovarian metastases and compared their reactivity with the WT1 staining of 30 ovarian serous carcinomas. WT1 reactivity was evaluated with the C19 and 6F-H2 antibody clones. All 18 uterine papillary serous carcinomas were nonreactive for WT1. The nonovarian metastases of the 5 high-stage uterine papillary serous carcinomas also were nonreactive for WT1. In contrast, 29 (97%) of 30 ovarian serous carcinomas were reactive for WT1. WT1 reactivity in an unknown primary serous carcinoma would suggest it is from a nonuterine site.

The mechanisms underlying these findings are unknown. They raise the possibility of genetic differences between the 2 morphologically similar neoplasms.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

PERITONEAL MESOTHELIOMA

Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum.

Attanoos RL, Webb R, Dojcinov SD, Gibbs AR.

Department of Histopathology, Llandough Hospital, Cardiff & Vale NHS Trust, Penarth, UK.

Histopathology 2002 Mar;40(3):237-44 Abstract quote
Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum

Aims: To evaluate the role of mesothelial markers (calretinin, thrombomodulin, cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal carcinoembryonic antigen, Leu-M1, CA-125 and Ber-EP4) in distinguishing diffuse peritoneal malignant mesothelioma from primary serous papillary adenocarcinoma of the ovary and peritoneum.

Methods and results: Paraffin-embedded formalin-fixed blocks from 32 diffuse peritoneal mesotheliomas of epithelial subtype (all females), 20 serous papillary ovarian carcinomas and three primary peritoneal serous papillary carcinomas were studied. Calretinin and Ber-EP4 appeared to be the best positive mesothelial and carcinoma marker, respectively. Nuclear calretinin expression was identified in 28 of 32 malignant mesotheliomas with no nuclear immunoreactivity in the cohorts of serous papillary ovarian and peritoneal carcinomas, thus yielding 88% sensitivity and 100% specificity. Ber-EP4 showed 95% sensitivity and 91% specificity for serous papillary ovarian carcin- oma. Thrombomodulin, cytokeratin 5/6 and CD44H immunoreactivities were seen in 18 (56%), 17 (53%) and 15 (47%) of peritoneal mesotheliomas, respectively, and in six (30%), five (25%) and five (25%) of the ovarian tumours, respectively. None of the three primary peritoneal serous papillary carcinomas expressed calretinin, thrombomodulin, cytokeratin 5/6 or CD44H. Polyclonal and monoclonal CEA, and Leu-M1 were expressed by two (10%), one (5%) and seven (35%) serous papillary ovarian carcinomas, respectively. None of the serous papillary peritoneal carcinomas expressed polyclonal CEA, monoclonal CEA or Leu-M1. CA-125 was positive in 19 (95%) and two (67%) ovarian and peritoneal carcinomas, respectively, and in eight (25%) peritoneal mesotheliomas.

Conclusions: Calretinin and Ber-EP4 are useful discriminant markers in distinguishing peritoneal mesothelioma in women from serous papillary ovarian and peritoneal carcinoma. The other mesothelial markers (thrombomodulin, cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal CEA, and Leu-M1) yielded a too low sensitivity for practical use.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSIS

Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators.

Seidman JD, Kurman RJ.

Department of Pathology, Washington Hospital Center, DC 20010, USA.

Hum Pathol 2000 May;31(5):539-57 Abstract quote

BACKGROUND: The behavior of ovarian serous borderline tumors (SBTs) and significance of various prognostic factors are unclear and difficult to evaluate because of inconsistencies and confusion in the literature. Recent studies have suggested that the morphological features of the primary tumor (presence or absence of micropapillary features) and the peritoneal "implants" (presence or absence of invasive features) can reliably subclassify SBTs into benign and malignant types. The aim of the current review was to test two hypotheses. First, that the alleged malignant behavior of SBTs is poorly documented, and second, that the morphological features of the primary ovarian tumors and the associated peritoneal implants are sufficient to separate SBTs into benign and malignant types, thereby obviating the need for the category.

METHODS: 245 studies reporting approximately 18,000 patients with borderline ovarian tumors were reviewed. After excluding series that lacked clinical follow-up or were not analyzable for other reasons, there remained 97 reports that included 4,129 patients. In addition to recurrences and survival, we evaluated the type of peritoneal implants, microinvasion, lymph node involvement, late recurrences, and progression to carcinoma, as these features have served as the underpinning of the concept of "borderline malignancy" or "low malignant potential."

RESULTS: Among 4,129 patients with SBTs reviewed, the recurrence rate after a mean follow-up of 6.7 years was 0.27% per year for stage I tumors, the disease-free survival was 98.2%, and the overall disease-specific survival rate was 99.5%. For patients with advanced-stage tumors, the recurrence rate was 2.4% per year. However, the majority (69%) of reported recurrences were not pathologically documented, and only 26 cases (8.4% of all recurrences) were documented to have recurred from an adequately sampled ovarian tumor. The most reliable prognostic indicator for advanced stage tumors was the type of peritoneal implant. After 7.4 years of follow-up, the survival of patients with noninvasive peritoneal inplants was 95.3%, as compared with 66% for invasive implants (P < .0001). Microinvasion in the primary ovarian tumor was associated with a 100% survival rate at 6.7 years, and lymph node involvement was associated with a 98% survival rate at 6.5 years. The few reported cases of stage IV disease, progression to invasive carcinoma, and very late (>20 years) recurrences were poorly documented. The survival for all stages among approximately 373 patients in 6 prospective randomized trials followed for a mean of 6.7 years was 100%.

CONCLUSION: Surgical pathological stage and subclassification of extraovarian disease into invasive and noninvasive implants are the most important prognostic indicators for SBTs. Survival for stage I tumors is virtually 100%. Survival for advanced stage tumors with noninvasive implants is 95.3%, whereas survival for tumors with invasive implants is 66%. Invasive implants behave as carcinomas and are most likely metastatic. The precise nature of so-called noninvasive implants is not clear, but they behave in a benign fashion. The presence of a micropapillary architecture in the primary ovarian tumor is a strong predictor of invasive implants. These data support the recommendation that ovarian tumors with a micropapillary architecture be designated "micropapillary serous carcinomas," and those lacking these features, "atypical proliferative serous tumors."

A comparative analysis of 57 serous borderline tumors with and without a noninvasive micropapillary component.

Slomovitz BM, Caputo TA, Gretz HF 3rd, Economos K, Tortoriello DV, Schlosshauer PW, Baergen RN, Isacson C, Soslow RA.

Department of Obstetrics and Gynecology, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, New York, USA.

Am J Surg Pathol 2002 May;26(5):592-600 Abstract quote
The literature concerning serous borderline tumors with a noninvasive micropapillary component suggests an association with invasive implants.

We compared the clinicopathologic features of micropapillary serous borderline tumors (MSBTs) with typical SBTs to determine the following: 1) the importance of focal micropapillary architecture in an otherwise typical SBT, 2) the behavior of low-stage MSBTs, 3) whether high-stage MSBTs are inherently more aggressive than high-stage SBTs, and 4) whether invasive implants are prevalent in an MSBT cohort without referral selection bias. The 57 borderline tumors studied were diagnosed at a university hospital between 1981 and 1998; they included 14 MSBTs, 35 SBTs, and 8 SBTs with focal micropapillary features. None of the specimens were referrals for expert pathologic consultation, thus distinguishing our study group from most of those previously reported.

Neither MSBTs nor SBTs were associated with invasive implants at diagnosis (0 of 14 and 0 of 43, respectively). They also did not differ with respect to overall stage at diagnosis, but MSBTs were more frequently bilateral than SBTs (71% versus 23%, p = 0.001). There was an increased risk of recurrence in MSBT versus SBT (3 of 14 versus 1 of 43, p = 0.035), but this was stage related; there was no difference between groups when evaluating recurrence in stage I disease (0 of 8 versus 0 of 27). There was no difference in recurrence or stage at diagnosis between SBTs with focal micropapillary features and other SBTs. There was 100% survival in all groups.

We conclude that high-stage MSBTs with noninvasive implants should be considered a subtype of SBTs with an increased risk of recurrence. Stage I MSBTs demonstrate clinical features that are similar to low-stage SBTs. Focal micropapillary architecture (<5 mm) has no bearing on outcome. MSBTs in the general population are not strongly associated with invasive implants.

IMPLANTS

NONINVASIVE
90% with no progression of disease after 4 years

Epithelial type

Desmoplastic type

INVASIVE
17% with no progression of disease after 4 years

Ets-1 mRNA Expression in Effusions of Serous Ovarian Carcinoma Patients Is a Marker of Poor Outcome

Ben Davidson, M.D. , Ph.D. ; Bjørn Risberg, M.D. , Ph.D. ; Iris Goldberg, Ph.D. ; Jahn M. Nesland, M.D. , Ph.D. ; Aasmund Berner, M.D. , Ph.D. ; Claes G. Tropé, M.D. , Ph.D. ; Gunnar B. Kristensen, M.D. , Ph.D. ; Magne Bryne, D.D.S. , Ph.D. ; Reuven Reich, Ph.D.

From the Department of Pathology (B.D., B.R., J.M.N., A.B.), the Norwegian Radium Hospital, affiliated with the University of Oslo, Oslo, Norway; the Department of Pathology (I.G.), Sheba Medical Center, Tel-Hashomer, Israel, affiliated with Sackler School of Medicine, Tel-Aviv University; the Departments of Gynecologic Oncology (C.G.T., G.B.K.) and Oral Biology (M.B.), University of Oslo, Oslo, Norway; and the Department of Pharmacology (R.R.), Faculty of Medicine and the David R. Bloom Center for Pharmacy, Hebrew University, Jerusalem, Israel. T

Am J Surg Pathol 2001;25:1493-1500 Abstract quote

Ets-1 proto-oncogene is a transcription factor with a role in the activation of metastasis-associated molecules. We recently found that Ets-1 mRNA expression in solid tumors is a marker of poor prognosis in ovarian carcinoma.

The objective of this study was to compare the expression of Ets-1 mRNA in effusions and primary and metastatic tumors of serous ovarian carcinoma patients and to evaluate its prognostic role in effusions. Sections from 67 malignant effusions and 90 primary and metastatic lesions were evaluated for expression of Ets-1 using mRNA in situ hybridization.

Expression of Ets-1 mRNA was detected in carcinoma cells in 24 of 67 (36%) effusions. Expression in cancer cells was similar in peritoneal and pleural effusions. In solid lesions Ets-1 expression was detected in both tumor cells and stromal cells in 34 of 90 (38%) lesions. Ets-1 expression in tumor cells showed a strong association with that of stromal cells (p <0.001). Ets-1 expression in effusions showed an association with mRNA expression of basic fibroblast growth factor, previously studied in this patient cohort (p = 0.019). Ets-1 expression in solid lesions showed an association with mRNA expression of vascular endothelial growth factor (p <0.001 for both carcinoma and stromal cells), basic fibroblast growth factor (p = 0.007 for carcinoma cells, p = 0.006 for stromal cells), and interleukin-8 (IL-8) (p = 0.001 for tumor cells). Ets-1 mRNA showed upregulation in metastases when compared with effusion specimens (p = 0.028). In univariate survival analysis Ets-1 expression in carcinoma cells in effusions correlated with poor survival (p = 0.003).

Our findings confirm the role of Ets-1 as a novel prognostic marker in advanced-stage ovarian carcinoma and extend it to effusion specimens. The elevated expression in solid metastases supports a central role in tumor progression as well. The association between Ets-1 mRNA expression and the expression of angiogenic genes, documented also in our previous study, points to the close link between these molecules, in agreement with the role of angiogenic genes in the transcriptional activation of Ets-1. The identical phenotype of carcinoma cells in pleural and peritoneal effusions provides further evidence for our theory that cells at these sites share similar genotypic and phenotypic profiles.

Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.

Commonly Used Terms

Immunohistochemistry
Ovaries

Internet Links

Last Updated 5/15/2002

TUMOR TYPE	TUMOR NAME	AGE OF PRESENTATION	PERCENTAGE OF TUMORS
Benign	Serous cystadenoma	60 yrs	70%
Borderline malignancy	Atypical proliferative serous tumors, Serous tumor of borderline malignancy	30-60 yrs	5-10%
Carcinoma	Serous cystadenocarcinoma	40-70 yrs	20-25%

PATHOGENESIS	CHARACTERIZATION
CHROMOSOMAL ABNORMALITIES
Micropapillary serous carcinoma of the ovary has distinct patterns of chromosomal imbalances by comparative genomic hybridization compared with atypical proliferative serous tumors and serous carcinomas Annette Staebler, MD Kerstin Heselmeyer-Haddad, PhD Karen Bell, MD Maureen Riopel, MD Elizabeth Perlman, MD Thomas Ried, MD Robert J. Kurman, MD	Hum Pathol 2002;33:47-59. Abstract quote Recent studies have subdivided serous borderline tumors into 2 categories: atypical proliferative serous tumors (APSTs), which have a relatively benign course, and micropapillary serous carcinomas (MPSCs), which behave like low-grade carcinoma. This study was undertaken to determine, using comparative genomic hybridization (CGH), whether cytogenetic changes support this hypothesis. Nine cases of APST, 10 of MPSC, and 11 of invasive serous carcinoma (SC) were analyzed by CGH. Tumor DNA was extracted from frozen or paraffin-embedded tissue from the primary ovarian tumor, using either sections with at least 70% tumor cells or tissue after relative enrichment by microdissection. Chromosomal imbalances were identified in 3 of 9 APST, 6 of 10 MPSC, and 11 of 11 SC. Three or more chromosomal imbalances were found in 0 of 9 APST, 4 of 10 MPSC, and 9 of 11 SC. Recurrent copy number alterations were grouped into 4 classes correlating with the different tumor types. Class I changes were present in APST and in MPSC or SC and included +8q (7 of 11 SC, 2 of 10 MPSC, 2 of 9 APST), –9p (5 of 11 SC, 0 of 10 MPSC, 1 of 9 APST), and +12 (+12p in 3/11 SC, +12 in 2 of 10 MPSC, +12 in 1 of 9 APST). Class II changes were found only in MPSC and SC, but not in APST. The most frequent examples were +3q (10 of 11 SC, 1 of 10 MPSC), –4q (5 of 11 SC, 1 of 10 MPSC), and –17p (5 of 11 SC, 1 of 10 MPSC). Class III changes were limited to SC, like –16q (7 of 11 SC) and –18q (6 of 11 SC). Class VI changes were unique to MPSC. Gain of 16p (3 of 10 MPSC) was the only aberration in this group. This aberration was not only unique to MPSC but was also the most frequent finding in MPSC. These data support the hypothesis that noninvasive serous tumors of the ovary can be subdivided into 2 categories: APST and MPSC. The number of imbalances in MPSC is substantially higher than in APST and lower than in SC. Some changes in MPSC are shared with SC and APST and others with SC only, suggesting that a subset of MPSC may represent a stage in progression from APST to SC. Other cases of MPSC with independent genetic alterations may represent another subset of tumors that are a distinct entity from APST and SC.
SALPINGITIS
Salpingitis, Salpingoliths, and Serous Tumors of the Ovaries: Is There a Connection? Jeffrey D. Seidman, M.D.; Mark E. Sherman, M.D.; Karen A. Bell, M.D.; Hidetaka Katabuchi, M.D.; Timothy J. O'Leary, M.D., Ph.D.; Robert J. Kurman, M.D. From the Department of Pathology, Washington Hospital Center, Washington, D.C. (J.D.S.); the Departments of Pathology (M.E.S., K.B., H.K., R.J.K.), Gynecology and Obstetrics (R.J.K.), The Johns Hopkins Medical Institution, Baltimore, Maryland; and the Department of Cellular Pathology, Armed Forces Institute of Pathology, Washington, D.C. (T.J.O.).	Int J Gyn Pathol 2002;21:101-107 Abstract quote We have observed luminal and mucosal calcifications frequently surrounded by a mantle of bland epithelium in the fallopian tubes (“salpingoliths”) of women with serous tumors of the ovaries. These lesions resemble noninvasive peritoneal “implants” in women with advanced stage atypical proliferative serous tumors (APSTs) and micropapillary serous carcinomas (MPSCs). The presence of salpingitis and salpingoliths was prospectively evaluated in 358 women with a variety of nonneoplastic and neoplastic ovarian conditions and compared with 87 previously reported women with APSTs/MPSCs in an effort to determine whether these lesions were specifically associated with serous tumors. The frequency of chronic salpingitis among women without ovarian pathology was 27%, and the frequency of salpingoliths was 4%. Serous epithelial tumors (cystadenomas, APST/MPSC, and carcinomas) were significantly more often associated with chronic salpingitis (53%) and salpingoliths (32%) than all other cases with or without ovarian neoplasms (p<0.01). APSTs/MPSCs were associated with salpingoliths significantly more frequently than all other groups (p<0.001). For patients with APSTs/MPSCs, salpingoliths were found significantly more often in advanced stage (FIGO II and III) patients (51%) than stage I patients (24%) (p<0.01), but salpingitis, present in 60% of these patients, was not stage-dependent (p>0.05). Chronic salpingitis was identified in 66% of women with endometriosis, which was significantly more frequent than those with normal ovaries (27%) (p<0.001). In conclusion, fallopian tube abnormalities may be related to both the high frequency of infertility and the noninvasive peritoneal implants in women with APSTs/MPSCs. Whether the fallopian tubes with salpingoliths are the source of the peritoneal “implants,” the recipient of implants, or are independent is unknown. In addition, the high frequency of salpingitis in women with endometriosis may be related to the mechanism of endometriosis-associated infertility.

GROSS APPEARANCE/CLINICAL VARIANTS	CHARACTERIZATION
General
TUMOR TYPE	GROSS APPEARANCE
Benign	Unilocular to multilocular cysts Polypoid excrescences Bilateral in 10%
Borderline malignancy	Similar to benign but more extensive papillae Bilateral in 25%
Carcinoma	Predominately cystic and papillary, solid and firm, or solid and cystic Bilateral in 66%
VARIANTS

HISTOLOGICAL TYPES	CHARACTERIZATION
General	The key differentiating histologic feature is the presence of stromal invasion, present only in carcinomas. Invasion is associated with a desmoplastic host response caused by the infiltrating tumor cells. It is defined by one or more of the following characteristics: Irregular, often slit-like glandular lumens Small, tight nests of tumor cells and single tumor cells growing in a dense fibrous or hyalinized stroma Glomeruloid formations Psammoma bodies
	Occasionally, there are small nests of invasive cells with lymphatic invasion. The term microinvasion has been used to designate these tumors and is defined as tumors containing one or more foci not exceeding 3 mm in maximal linear dimension or 10 mm2 in area. From a prognostic standpoint, these tumors have the same prognosis as tumors lacking microinvasion.
Benign	Lined by nonciliated cuboidal to columnar epithelium with bland cytology
Borderline malignancy	Polypoid excrescences and papillae lined by atypical proliferating epithelial cells forming small papillae that appear to be detached from the cyst wall No invasion into the underlying stroma
Carcinoma	Lining cells have high nuclear:cytoplasmic ratio with varying nuclear atypia Ciliated cells common Psammoma bodies present in 25% Invasion into the underlying stroma
IMPLANTS
*NONINVASIVE*
Epithelial type	Papillary proliferations of atypical serous cells with a minimal stromal component are present on the surface of the peritoneum in smoothly contoured subperitoneal invaginations or in invaginations between lobules of the omentum
Desmoplastic type	Reactive stroma layered onto the peritoneal surface and lining invaginations between omental fat lobules Embedded within the implants are small glands and papillae lined by atypical serous cells, single cells, and psammoma bodies
*INVASIVE*	Irregular infiltration and destruction of the underlying tissue, resembling grade I serous carcinoma
Refined Diagnostic Criteria for Implants Associated With Ovarian Atypical Proliferative Serous Tumors (Borderline) and Micropapillary Serous Carcinomas Karen A. Bell, M.D.; Ann E. Smith Sehdev, M.D.; Robert J. Kurman, M.D.	Am J Surg Pathol 2001;25:419-432 Abstract quote Characterization of invasive peritoneal implants from patients with noninvasive serous ovarian tumors has important prognostic and treatment implications, but the criteria for distinguishing invasive and noninvasive implants vary among investigators and can be difficult to apply. The authors studied 148 implants from 60 patients, 33 with primary atypical proliferative serous tumor, and 27 with primary noninvasive micropapillary serous carcinoma, with a mean follow-up of 62 months (median follow-up, 52 months). Previously reported and newly proposed histologic features for implant classification were evaluated and correlated with clinical outcome. Three criteria were applied for the diagnosis of ``invasive'' implants: invasion of underlying normal tissue, micropapillary architecture, and solid epithelial nests surrounded by clefts. Implants displaying any one of these three features were classified as ``invasive,'' whereas those lacking all three features were classified as ``noninvasive.'' Sixty-six implants were invasive and 82 were noninvasive. Of the 31 patients with invasive implants, six were dead of disease (DOD), 13 were alive with progressive disease (AWPD), and 12 were alive with no evidence of disease (NED). Of the 29 patients with noninvasive implants, two were DOD, one was dead of uncertain causes, one was AWPD, and 25 were alive with NED. Eighty-nine percent of invasive implants had a micropapillary architecture and 83% had solid epithelial nests surrounded by clefts. A minority of invasive implants (14% of those with underlying normal tissue) demonstrated invasion of normal underlying tissue. Nuclear atypia, mitoses, calcification, necrosis, and identification of individual cells ``infiltrating'' the stroma did not correlate with implant type. The proposed criteria permitted recognition of implants that correlated strongly with adverse outcome. Sixty-one percent of patients with implants displaying any one of the three features used to diagnose invasive implants were AWPD or DOD compared with 10% of patients whose implants lacked these features (p = 0.00001). Because implants associated with an adverse outcome can be identified before they invade underlying normal tissue, the term invasive implant to describe them is inaccurate and misleading. These implants resemble patterns of growth in micropapillary serous carcinoma of the ovary and the recurrent tumor that is obvious carcinoma. Accordingly, we propose that these extraovarian lesions be designated ``well-differentiated serous carcinoma.''
TYPES OF NODAL SEROUS EPITHELIUM	SIGNIFICANCE
Mullerian inclusion glands or lymph node endosalpingiosis	Benign glands located in the lymphoid tissue or capsule of the node No sinus collections Present in 30-40% of patients without ovarian tumors
Some Mullerian Inclusion Cysts in Lymph Nodes May Sometimes Be Metastases From Serous Borderline Tumors of the Ovary William F. Moore, M.D.; Rex C. Bentley, M.D.; Andrew Berchuck, M.D.; Stanley J. Robboy, M.D. From the Departments of Pathology (W.F., R.C.B., S.J.R.) and Obstetrics and Gynecology (A.B., S.J.R.), Duke University Medical Center, Durham, North Carolina, U.S.A.	Am J Surg Pathol 2000;24:710-718 Abstract quote Glandular inclusions that appear morphologically benign are occasionally found in lymph nodes as well as in peritoneal and omental biopsies. In patients with gynecologic malignancies, the nature and significance of these mullerian inclusion cysts (MIC) present a diagnostic challenge with regard to whether they are benign and incidental or are related to the coincident tumor for which surgery is being performed. Sixty-two cases of MIC were prospectively identified during a 6-year period. The frequencies were calculated and stratified by lymph node chain distribution, primary tumor site, and primary tumor type. MIC appeared as small cysts lined by a serous (mullerian)-type, cytologically bland, cuboidal to columnar epithelium with a simple architecture. Among 62 women, MIC was found in lymph nodes (27 cases), pelvic peritoneum (19 cases), omentum (16 cases), bowel serosa (9 cases), uterine serosa (8 cases), and parametrial connective tissues (4 cases). Among a set of 417 consecutive cases in which lymphadenectomy was performed, 46 (11%) women had MIC. The MIC involved multiple sites (26 cases in the peritoneum/omentum and 27 in lymph nodes). The primary tumor was in the ovary in 32 of the 46 women with MIC (70%) and of these, 17 were borderline serous (53%). Sixty-two of 6154 lymph nodes examined contained MIC (1.0%). 3.2% of nodes contained MIC in which the primary tumor arose in the ovary, but only 0.1% with either endometrial or cervical tumors (2, p <0.00001). The lymph nodes most often involved by MIC were from para-aortic sites (40%), which reflect the primary drainage route from the ovary. Not uncommonly, neighboring areas in the same lymph node group with MIC disclosed separate foci of obvious metastatic borderline tumor (4 of 10; 40%). In summary, the increased frequency of MIC in lymph nodes sampled for primary ovarian malignancies suggests that MIC in some cases, rather than being benign, incidental inclusions, are more likely bland-appearing forms of metastatic tumor. The preponderance of inclusions occurs with serous ovarian tumors of borderline malignancy, and the inclusions are overrepresented in the lymph nodes that primarily receive drainage from the ovary.
Serous epithelium with borderline features	This is a true metastasis if the lesion is confined to the lymph node sinuses and is unquestionably composed of epithelial cells This does not adversely affect prognosis
Reactive peritoneal mesothelial cells	These may become dislodged and deposit within lymph node sinuses
Independent borderline tumor of the lymph node	Small focus of borderline tumor confined to the lymphoid tissue or capsule of the node and accompanied by uninvolved mullerian inclusion glands elsewhere in the node
VARIANTS
Psammomcarcinoma	Invasion of the ovarian stroma or its vascular space (in extraovarian cases, invasion of any intraperitoneal tissue or vascular spaces) No more than mild to moderate nuclear atypia Epithelial nests no more than 15 cells in their largest linear dimension Psammoma bodies in at least 75% of the papillae or nests
Ovarian micropapillary serous borderline tumors. Clinicopathologic features and outcome of seven surgically staged patients. Goldstein NS, Ceniza N. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.	Am J Clin Pathol 2000 Sep;114(3):380-6 Abstract quote We report the clinicopathologic findings for 7 patients with completely staged ovarian micropapillary serous borderline tumors (MSBTs) to further clarify tumor behavior. None of the MSBTs had microinvasion in the ovarian neoplasm. The MSBT pattern constituted 25% to almost all of the neoplasm. Four were bilateral, and 6 involved the ovarian surface. Five patients had peritoneal implants; 2 were invasive, and 3 were noninvasive MSBTs. Distribution of stages among patients was as follows: IA, 1; IC, 1; IIC, 2; IIIB, 2; and IIIC, 1. Median follow-up was 8.5 years. Four patients were alive and well at the last follow-up visit, including 1 patient with stage IIIC (lymph node metastases) disease who had noninvasive implants (12 years after surgery). One patient who was free of disease died of complications of chemotherapy and abdominal surgery. Two patients died of intra-abdominal neoplastic growth (stages IIC and IIIB) 5 and 9 years after surgery, respectively; both had invasive implants. Without invasive peritoneal implants, MSBTs seem to behave as similar staged nonmicropapillary serous borderline tumors without invasive peritoneal implants. With invasive peritoneal implants, they seem to behave as low-grade carcinomas. Pathologists should recognize MSBT as a neoplasm that can have adverse prognostic features, including invasive peritoneal implants.

SPECIAL STAINS/IMMUNOHISTOCHEMISTRY	CHARACTERIZATION
CAVEOLIN-1
Caveolin-1 Expression in Ovarian Carcinoma Is MDR1 Independent Ben Davidson, MD, PhD Iris Goldberg, PhD Vered Givant-Horwitz, MSc Jahn M. Nesland, MD, PhD, etal.	Am J Clin Pathol 2002;117:225-234 Abstract quote We studied the role of caveolin-1 in tumor progression and prognosis in serous ovarian carcinoma and the association between caveolin-1 and MDR1 expression. The study involved immunohistochemical analysis for caveolin-1 and P-glycoprotein (P-gp) expression in 75 effusions and 90 solid lesions from ovarian and primary peritoneal carcinoma; in situ hybridization for MDR1 messenger RNA (mRNA) expression in 62 effusions and all 90 tumors; and reverse transcription–polymerase chain reaction (RT-PCR) for caveolin-1 mRNA expression in 23 effusions. Immunohistochemical analysis localized caveolin-1 to the cell membrane in 43 effusions and 24 tumors. P-gp membrane expression was detected in 14 effusions and 11 tumors; MDR1 mRNA, in 20 effusions and 30 tumors. Caveolin-1 mRNA was expressed in 19 effusions. Caveolin-1 protein expression showed no association with that of P-gp protein or MDR1 mRNA. The expression of all markers was similar in carcinoma cells in pleural and peritoneal effusions. Caveolin-1 is a novel diagnostic marker for effusions; expression is moderately elevated in tumor cells in effusions, possibly owing to altered signal transduction and metabolism in cancer cells at this site. Expression seems MDR1 independent.
WT1
WT1 immunoreactivity in uterine papillary serous carcinomas is different from ovarian serous carcinomas. Goldstein NS, Uzieblo A. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.	Am J Clin Pathol 2002 Apr;117(4):541-5 Abstract quote WT1 diffusely stains most ovarian serous carcinomas; reactivity of uterine papillary serous carcinomas has not been evaluated. We studied WT1 expression in 13 International Federation of Gynecology and Obstetrics stage 1 and 5 stage 3 or 4 uterine papillary serous carcinomas without ovarian metastases and compared their reactivity with the WT1 staining of 30 ovarian serous carcinomas. WT1 reactivity was evaluated with the C19 and 6F-H2 antibody clones. All 18 uterine papillary serous carcinomas were nonreactive for WT1. The nonovarian metastases of the 5 high-stage uterine papillary serous carcinomas also were nonreactive for WT1. In contrast, 29 (97%) of 30 ovarian serous carcinomas were reactive for WT1. WT1 reactivity in an unknown primary serous carcinoma would suggest it is from a nonuterine site. The mechanisms underlying these findings are unknown. They raise the possibility of genetic differences between the 2 morphologically similar neoplasms.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSIS
Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators. Seidman JD, Kurman RJ. Department of Pathology, Washington Hospital Center, DC 20010, USA.	Hum Pathol 2000 May;31(5):539-57 Abstract quote BACKGROUND: The behavior of ovarian serous borderline tumors (SBTs) and significance of various prognostic factors are unclear and difficult to evaluate because of inconsistencies and confusion in the literature. Recent studies have suggested that the morphological features of the primary tumor (presence or absence of micropapillary features) and the peritoneal "implants" (presence or absence of invasive features) can reliably subclassify SBTs into benign and malignant types. The aim of the current review was to test two hypotheses. First, that the alleged malignant behavior of SBTs is poorly documented, and second, that the morphological features of the primary ovarian tumors and the associated peritoneal implants are sufficient to separate SBTs into benign and malignant types, thereby obviating the need for the category. METHODS: 245 studies reporting approximately 18,000 patients with borderline ovarian tumors were reviewed. After excluding series that lacked clinical follow-up or were not analyzable for other reasons, there remained 97 reports that included 4,129 patients. In addition to recurrences and survival, we evaluated the type of peritoneal implants, microinvasion, lymph node involvement, late recurrences, and progression to carcinoma, as these features have served as the underpinning of the concept of "borderline malignancy" or "low malignant potential." RESULTS: Among 4,129 patients with SBTs reviewed, the recurrence rate after a mean follow-up of 6.7 years was 0.27% per year for stage I tumors, the disease-free survival was 98.2%, and the overall disease-specific survival rate was 99.5%. For patients with advanced-stage tumors, the recurrence rate was 2.4% per year. However, the majority (69%) of reported recurrences were not pathologically documented, and only 26 cases (8.4% of all recurrences) were documented to have recurred from an adequately sampled ovarian tumor. The most reliable prognostic indicator for advanced stage tumors was the type of peritoneal implant. After 7.4 years of follow-up, the survival of patients with noninvasive peritoneal inplants was 95.3%, as compared with 66% for invasive implants (P < .0001). Microinvasion in the primary ovarian tumor was associated with a 100% survival rate at 6.7 years, and lymph node involvement was associated with a 98% survival rate at 6.5 years. The few reported cases of stage IV disease, progression to invasive carcinoma, and very late (>20 years) recurrences were poorly documented. The survival for all stages among approximately 373 patients in 6 prospective randomized trials followed for a mean of 6.7 years was 100%. CONCLUSION: Surgical pathological stage and subclassification of extraovarian disease into invasive and noninvasive implants are the most important prognostic indicators for SBTs. Survival for stage I tumors is virtually 100%. Survival for advanced stage tumors with noninvasive implants is 95.3%, whereas survival for tumors with invasive implants is 66%. Invasive implants behave as carcinomas and are most likely metastatic. The precise nature of so-called noninvasive implants is not clear, but they behave in a benign fashion. The presence of a micropapillary architecture in the primary ovarian tumor is a strong predictor of invasive implants. These data support the recommendation that ovarian tumors with a micropapillary architecture be designated "micropapillary serous carcinomas," and those lacking these features, "atypical proliferative serous tumors."
A comparative analysis of 57 serous borderline tumors with and without a noninvasive micropapillary component. Slomovitz BM, Caputo TA, Gretz HF 3rd, Economos K, Tortoriello DV, Schlosshauer PW, Baergen RN, Isacson C, Soslow RA. Department of Obstetrics and Gynecology, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, New York, USA.	Am J Surg Pathol 2002 May;26(5):592-600 Abstract quote The literature concerning serous borderline tumors with a noninvasive micropapillary component suggests an association with invasive implants. We compared the clinicopathologic features of micropapillary serous borderline tumors (MSBTs) with typical SBTs to determine the following: 1) the importance of focal micropapillary architecture in an otherwise typical SBT, 2) the behavior of low-stage MSBTs, 3) whether high-stage MSBTs are inherently more aggressive than high-stage SBTs, and 4) whether invasive implants are prevalent in an MSBT cohort without referral selection bias. The 57 borderline tumors studied were diagnosed at a university hospital between 1981 and 1998; they included 14 MSBTs, 35 SBTs, and 8 SBTs with focal micropapillary features. None of the specimens were referrals for expert pathologic consultation, thus distinguishing our study group from most of those previously reported. Neither MSBTs nor SBTs were associated with invasive implants at diagnosis (0 of 14 and 0 of 43, respectively). They also did not differ with respect to overall stage at diagnosis, but MSBTs were more frequently bilateral than SBTs (71% versus 23%, p = 0.001). There was an increased risk of recurrence in MSBT versus SBT (3 of 14 versus 1 of 43, p = 0.035), but this was stage related; there was no difference between groups when evaluating recurrence in stage I disease (0 of 8 versus 0 of 27). There was no difference in recurrence or stage at diagnosis between SBTs with focal micropapillary features and other SBTs. There was 100% survival in all groups. We conclude that high-stage MSBTs with noninvasive implants should be considered a subtype of SBTs with an increased risk of recurrence. Stage I MSBTs demonstrate clinical features that are similar to low-stage SBTs. Focal micropapillary architecture (<5 mm) has no bearing on outcome. MSBTs in the general population are not strongly associated with invasive implants.
IMPLANTS
*NONINVASIVE*	90% with no progression of disease after 4 years
Epithelial type
Desmoplastic type
*INVASIVE*	17% with no progression of disease after 4 years
Ets-1 mRNA Expression in Effusions of Serous Ovarian Carcinoma Patients Is a Marker of Poor Outcome Ben Davidson, M.D. , Ph.D. ; Bjørn Risberg, M.D. , Ph.D. ; Iris Goldberg, Ph.D. ; Jahn M. Nesland, M.D. , Ph.D. ; Aasmund Berner, M.D. , Ph.D. ; Claes G. Tropé, M.D. , Ph.D. ; Gunnar B. Kristensen, M.D. , Ph.D. ; Magne Bryne, D.D.S. , Ph.D. ; Reuven Reich, Ph.D. From the Department of Pathology (B.D., B.R., J.M.N., A.B.), the Norwegian Radium Hospital, affiliated with the University of Oslo, Oslo, Norway; the Department of Pathology (I.G.), Sheba Medical Center, Tel-Hashomer, Israel, affiliated with Sackler School of Medicine, Tel-Aviv University; the Departments of Gynecologic Oncology (C.G.T., G.B.K.) and Oral Biology (M.B.), University of Oslo, Oslo, Norway; and the Department of Pharmacology (R.R.), Faculty of Medicine and the David R. Bloom Center for Pharmacy, Hebrew University, Jerusalem, Israel. T	Am J Surg Pathol 2001;25:1493-1500 Abstract quote Ets-1 proto-oncogene is a transcription factor with a role in the activation of metastasis-associated molecules. We recently found that Ets-1 mRNA expression in solid tumors is a marker of poor prognosis in ovarian carcinoma. The objective of this study was to compare the expression of Ets-1 mRNA in effusions and primary and metastatic tumors of serous ovarian carcinoma patients and to evaluate its prognostic role in effusions. Sections from 67 malignant effusions and 90 primary and metastatic lesions were evaluated for expression of Ets-1 using mRNA in situ hybridization. Expression of Ets-1 mRNA was detected in carcinoma cells in 24 of 67 (36%) effusions. Expression in cancer cells was similar in peritoneal and pleural effusions. In solid lesions Ets-1 expression was detected in both tumor cells and stromal cells in 34 of 90 (38%) lesions. Ets-1 expression in tumor cells showed a strong association with that of stromal cells (p <0.001). Ets-1 expression in effusions showed an association with mRNA expression of basic fibroblast growth factor, previously studied in this patient cohort (p = 0.019). Ets-1 expression in solid lesions showed an association with mRNA expression of vascular endothelial growth factor (p <0.001 for both carcinoma and stromal cells), basic fibroblast growth factor (p = 0.007 for carcinoma cells, p = 0.006 for stromal cells), and interleukin-8 (IL-8) (p = 0.001 for tumor cells). Ets-1 mRNA showed upregulation in metastases when compared with effusion specimens (p = 0.028). In univariate survival analysis Ets-1 expression in carcinoma cells in effusions correlated with poor survival (p = 0.003). Our findings confirm the role of Ets-1 as a novel prognostic marker in advanced-stage ovarian carcinoma and extend it to effusion specimens. The elevated expression in solid metastases supports a central role in tumor progression as well. The association between Ets-1 mRNA expression and the expression of angiogenic genes, documented also in our previous study, points to the close link between these molecules, in agreement with the role of angiogenic genes in the transcriptional activation of Ets-1. The identical phenotype of carcinoma cells in pleural and peritoneal effusions provides further evidence for our theory that cells at these sites share similar genotypic and phenotypic profiles.