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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.
OUTLINE
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 bodiesOccasionally, 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. Lined by nonciliated cuboidal to columnar epithelium with bland cytology 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 stromaLining cells have high nuclear:cytoplasmic ratio with varying nuclear atypia
Ciliated cells common
Psammoma bodies present in 25%
Invasion into the underlying stroma
Department of Pathology, Stanford University School of Medicine, CA.
Stromal-epithelial patterns of invasion in serous tumors of the ovary have been subclassified as destructive and nondestructive. By definition, well-differentiated serous tumors featuring destructive stromal invasion are classified as low-grade serous carcinomas whereas those with either no stromal invasion or stromal microinvasion are classified as serous tumors of low malignant potential (S-LMP). The histologic features of stromal microinvasion in ovarian S-LMP have been addressed in a variety of studies, but controversy persists regarding diagnostic criteria and prognostic significance, particularly in patients with high-stage disease. In addition, a subset of otherwise typical S-LMP has patterns of invasion that are not classic destructive invasion and do not meet the current diagnostic criteria for stromal microinvasion because of either qualitative features or size restrictions.
To further evaluate the full histologic spectrum of stromal-epithelial patterns of invasion in otherwise typical S-LMP, we examined a series of 60 ovarian S-LMP (34 FIGO stage I; 26 FIGO stages II, III, and IV) with stromal-epithelial alterations not meeting criteria for classic destructive invasion. This group of cases included those meeting the definition of microinvasion and a subset that would be excluded based on size measurements or unusual qualitative features, but did not exhibit significant stromal reaction. Five patterns of invasion were identified: individual eosinophilic cells and cell clusters, cribriform, simple and noncomplex branching papillae, inverted macropapillae, and micropapillae.
Individual, discrete aggregates of invasive epithelium ranged from 1 to 12 mm (mean, 1.4 mm) in greatest linear dimension as measured by conventional methods. The number of discrete foci ranged from 1 to greater than 10; in 7 tumors (12%), the invasive foci were diffusely scattered throughout the stroma without discrete aggregates. These stromal-epithelial alterations were associated with disease progression and/or death due to disease in 9 of 50 (18%) patients with follow-up (mean, 92.5 mo) and were covariant with other adverse prognostic features (invasive implants, nodular lymph node aggregates, high stage, and unresectable disease). Disease progression was most strongly linked to the presence of micropapillae, but the majority of patients with adverse outcome had the more common, classic stromal-epithelial patterns associated with microinvasion (ie, individual cells, cell clusters, and simple papillae). Neither size of the largest contiguous aggregate nor extent of stromal involvement correlated with outcome. Classic microinvasion disproportionately occurred in patients presenting during pregnancy (P<0.0001), and was not associated with adverse outcome in that setting, but follow-up was limited. Based on the cumulative outcome data, the presence of stromal-epithelial patterns of invasion distinct from classic destructive invasion in otherwise typical S-LMP stratifies patients at long-term risk for disease progression, but does not warrant a diagnosis of carcinoma or a change in current management schemes. Maintaining classification as a serous tumor of low malignant potential (serous borderline tumor) with stromal invasion seems appropriate even in the presence of diffuse stromal involvement or discrete aggregates measuring greater than 3 (or 5) mm.
As the stromal-epithelial alteration featuring micropapillae may represent a comparatively higher-risk lesion with a clinical course analogous to that of low-grade serous carcinoma, pathologists should identify this specific stromal-epithelial pattern in the diagnostic report until sufficient data is acquired to form more definitive conclusions regarding its prognosis.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 bodiesINVASIVE 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 tumorsWilliam 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 prognosisReactive 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 AUTOIMPLANTS
- Autoimplants in Serous Borderline Tumors of the Ovary: A Clinicopathologic Study of 30 Cases of a Process to Be Distinguished From Serous Adenocarcinoma.
Rollins SE, Young RH, Bell DA.
*James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Boston, MA daggerHarvard Medical School, Boston, MA.
Am J Surg Pathol. 2006 Apr;30(4):457-462. Abstract quote
The clinical and pathologic features of serous borderline tumors (SBTs) with autoimplants (AIs) were studied with emphasis on their relation to survival, ovarian SBT with a micropapillary pattern, and their distinction from serous adenocarcinoma. The 30 patients ranged in age from 17 to 70 years (mean, 35.8 years). Two had stage I disease, 10 had stage II disease, and 18 had stage III disease. Twenty-five patients had bilateral ovarian tumors. In 28 cases, AIs were present on the surface of the neoplasm or between exophytic surface tumor papillae; in 2 cases, AIs were between papillae within intracystic tumor.
The AIs consisted of single cells or glands and clusters of cells with mild to moderate nuclear atypia within a fibroblastic stroma; the stroma dominated over the epithelium in extent within the AI. In many cases, the epithelial cells in the AI had abundant eosinophilic cytoplasm. All but 2 of the patients had coexisting noninvasive peritoneal implants; 3 of them also had invasive peritoneal implants. Six of the SBTs had a micropapillary pattern; 3 of these were stage III and 3 stage II tumors.
Clinical follow-up was available for 11 patients. Eight were alive and well after 4 to 7 years (mean, 5 years); 3 of these patients had stage II disease and 5 had stage III disease. Three were dead of disease after 7 to 12 years (mean, 9 years). Two patients who died of disease had stage III disease, and 1 of them had invasive implants. The third patient had stage II disease, invasive implants, and the tumor was of the micropapillary type. Our study indicates that the majority of patients with SBT with AI have stage II or III disease and abundant exophytic tumor. SBTs with AI had a micropapillary pattern in 20% of the cases. AIs do not appear to have an adverse impact on survival when controlled for peritoneal implant type and for this reason must be distinguished from true stromal invasion in serous carcinoma, a misdiagnosis sometimes made, or seriously entertained, initially in these cases.
Features that favor AI over carcinoma arising in an SBT are 1) a location between tumor papillae or on the ovarian surface 2) a predominance of stroma over epithelial cells, and 3) the "borderline" cytologic appearance of epithelial cells.MICROPAPILLARY
Noninvasive and invasive micropapillary (low-grade) serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases.Smith Sehdev AE, Sehdev PS, Kurman RJ.
Am J Surg Pathol. 2003 Jun;27(6):725-36. Abstract quote Reports describing the behavior of micropapillary serous carcinomas (MPSCs) of the ovary have focused on those that are noninvasive. There are only very limited data on the behavior of those that are invasive.
To further characterize the behavior of MPSCs, invasive versus noninvasive primary tumors were distinguished based on the presence or absence of destructive infiltrative growth. To qualify for inclusion, invasive MPSCs, like the noninvasive tumors, were required to display a micropapillary architecture and low-grade nuclei.
A total of 135 cases of MPSC were identified: 96 noninvasive and 39 invasive. On follow-up, survival for 10 patients with stage I noninvasive and invasive MPSCs was 100%, and survival for women with stage II and III noninvasive and invasive MPSCs with noninvasive implants was 80%. In contrast, the 5-year and 10-year survival for patients with stage II and III noninvasive MPSCs with invasive implants was 85% and 55%, respectively. The 5-year and 10-year survival for women with invasive MPSCs and invasive implants was 55% and 45%, respectively. The median time from diagnosis to death for women with noninvasive and invasive MPSCs with invasive implants was 60 months (range 33-240 months). The indolent behavior of these low-grade carcinomas distinguishes them from conventional serous carcinomas, which are high-grade aggressive neoplasms. Five of six patients with small (<5 mm) MPSCs in whom follow-up was available presented with high stage disease. Of these five women, three are alive and well and two are alive with disease (one with invasive and one with noninvasive implants). Nearly three fourths of noninvasive MPSCs were associated with atypical proliferative serous tumors, adenofibromas, or both, and 62% of invasive MPSCs were associated with noninvasive MPSCs, atypical proliferative serous tumors, and adenofibromas, alone or in combination. In addition to the frequent mixtures of these tumor components, transitions between them were common.
These data in conjunction with recent molecular genetic studies strongly suggest that MPSCs (low-grade carcinomas) arise from atypical proliferative serous tumors unlike conventional serous carcinomas (high-grade carcinomas), which appear to develop de novo. The findings provide further support for the hypothesis that there are distinct pathways of carcinogenesis for low-grade and high-grade serous carcinoma of the ovary.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.
MIXED-EPITHELIAL PAPILLARY CYSTADENOMA OF BORDERLINE MALIGNANCY OF MULLERIAN TYPE
Squamous predominance in mixed-epithelial papillary cystadenomas of borderline malignancy of mullerian type arising in endometriotic cysts: a study of four cases.Nagai Y, Kishimoto T, Nikaido T, Nishihara K, Matsumoto T, Suzuki C, Ogishima T, Kuwahara Y, Hurukata Y, Mizunuma M, Nakata Y, Ishikura H.
Am J Surg Pathol 2003 Feb;27(2):242-7 Abstract quote Mixed-epithelial papillary cystadenoma of borderline malignancy of mullerian type (MEBMM) is composed of a mixture of mullerian epithelial types, such as mucinous, serous, endometrioid, and squamous.
Four cases of MEBMM with squamous overgrowth (MEBMMSO) were reviewed. The patients' median age was 56 years, and all cases were unilateral. The clinical stages were Ia (two cases), Ic (one case), and IV based on the presence of tumor cells in pleural fluid (one case). No recurrence was seen in three of the cases. In one of those three cases, there was no recurrence after undergoing surgery only; in the other two of those three cases, there was no recurrence after undergoing surgery and receiving postoperative chemotherapy. In the single case that was at stage IV at initial presentation, a recurrent MEBMMSO nodule was found at a second look 17 months after the initial surgery.
In terms of gross findings, all of the tumors were cystic with intracystic papillary fronds. In addition, old endometriotic lesions lined the cysts. The tumors were mainly composed of a proliferation of squamous-type epithelium, with minor foci containing a mixture of other mullerian-type epithelia, especially mucinous. Intraepithelial infiltration by neutrophilic leukocytes was prominent. The differential diagnosis of MEBMMSO includes proliferating Brenner tumors.
PSAMMOMA-CARCINOMA 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 nestsSEROMUCINOUS
Diagnostic criteria and behavior of ovarian seromucinous (endocervical-type mucinous and mixed cell-type) tumors: atypical proliferative (borderline) tumors, intraepithelial, microinvasive, and invasive carcinomas.Shappell HW, Riopel MA, Smith Sehdev AE, Ronnett BM, Kurman RJ.
Am J Surg Pathol 2002 Dec;26(12):1529-41 Abstract quote Ovarian endocervical-type (mullerian) mucinous tumors and tumors composed of a mixture of endocervical-type mucinous, serous, endometrioid, squamous, and indifferent cells with abundant eosinophilic cytoplasm reported to date have been primarily limited to borderline and microinvasive types, with only one report of a disease-related death.
The clinicopathologic features of 54 endocervical-type and mixed cell-type mucinous tumors, defined as tumors with papillary architecture resembling serous tumors but containing endocervical-type mucinous epithelium, were evaluated. Thirty-four tumors (64%) were classified as atypical proliferative (borderline) tumors based on the absence of stromal invasion and the absence of micropapillary architecture measuring >5 mm. Five tumors (9%) qualified as intraepithelial carcinoma based on the presence of marked cytologic atypia or a complex cribriform growth pattern involving the epithelium covering the surface of papillae or lining cystic spaces. Eight tumors (15%) with stromal invasion </=5 mm were classified as microinvasive carcinoma. Seven tumors (13%) with either stromal invasion (five tumors) or micropapillary architecture measuring >5 mm (two tumors) were classified as carcinoma. Sixteen tumors (30%) were bilateral, and endosalpingiosis was identified in 41% of cases. Serous-type differentiation was present in all cases.
Of the 29 patients with atypical proliferative tumors, intraepithelial carcinomas, and microinvasive carcinomas for whom follow-up was available, there were no disease-related deaths. In contrast, of the seven patients whose tumors had either stromal invasion or micropapillary architecture >5 mm, two stage III patients died of disease (one with frank invasion and one with a micropapillary tumor that lacked stromal invasion). One other stage III patient with a noninvasive micropapillary carcinoma was alive with disease at 84 months. The remaining four patients (three stage I and one stage III) were alive with no evidence of disease.
In summary, most endocervical-type atypical proliferative tumors are stage I and benign. The presence of either intraepithelial carcinoma or microinvasion has no adverse effect on behavior. Rare endocervical-type mucinous tumors demonstrate histologically malignant features and aggressive behavior that warrant designation as carcinoma.
As with serous tumors, micropapillary architecture without frank invasion in endocervical-type mucinous tumors is associated with disease recurrence and death when presenting as advanced-stage disease. All the tumors in this study were composed of a heterogeneous population of cells, consisting mainly of serous (ciliated) and endocervical-type mucinous cells. In addition, they all contained endometrioid-type cells, hobnail cells, and indifferent cells with abundant eosinophilic cytoplasm to a varying degree. Accordingly, it appears that tumors that feature endocervical-type mucinous cells are rarely if ever pure but almost invariably of mixed cell type.
Despite containing mucinous epithelium, the papillary architecture, serous-type differentiation, association with endosalpingiosis, frequent bilaterality, size, and clinical behavior of endocervical-type mucinous tumors closely resemble serous tumors. We therefore recommend the term "seromucinous" for these tumors, which acknowledges both their serous and mucinous features.
SPECIAL STAINS/
IMMUNO-HISTOCHEMISTRYCHARACTERIZATION GENERAL
Mod Pathol. 2006 Mar;19(3):364-72 Abstract quote.
The correct identification of invasive implants in the peritoneum in serous borderline tumors (SBTs) of the ovary is an important determinant of diagnosis, treatment, and prognosis. Although the histologic criteria to distinguish noninvasive from invasive implants have been defined, the distinction can still be difficult.
We examined the presence and distribution of mesothelial cells, stromal fibrocytes, and myofibroblasts in invasive and noninvasive peritoneal implants in 100 noninvasive, 100 invasive, and 100 metastatic nests/foci from 20 cases of SBTs with peritoneal implants, 10 serous carcinomas with peritoneal metastasis, and 10 cases of endosalpingiosis by immunostaining for calretinin, CD34, and alpha-SMA. All 100 invasive nests from seven SBTs and all 100 metastatic nests from the cases of serous carcinoma showed loss of calretinin+ mesothelial cells and stromal CD34+ fibrocytes around the nests.
In contrast, 72/100 noninvasive nests displayed the presence of mesothelial cells around the nests and 68 displayed preservation of surrounding stromal fibrocytes. alpha-smooth muscle actin positive myofibroblasts were present as a stromal response in 100/100 metastatic nests, 100/100 invasive nests and 54/100 noninvasive nests. The loss of mesothelial cells and stromal fibrocytes surrounding invasive nests together with a proliferation of myofibroblasts as demonstrated by immunostaining proved to be a sensitive and specific tool to separate invasive from noninvasive implants and represents an important adjunct to morphologic diagnosis.
Combined sensitivity and specificity of the three antibodies was 100 and 81%, respectively. These methods, however, may not be helpful for small biopsies of noninvasive desmoplastic implants. The distribution of these cells provides some insights into the histogenesis of invasive and noninvasive implants in SBTs.
- An Immunohistochemical Comparison Between Low-Grade and High-Grade Ovarian Serous Carcinomas: Significantly Higher Expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in High-Grade Neoplasms.
O'neill CJ, Deavers MT, Malpica A, Foster H, McCluggage WG.
From the *Department of Pathology, Royal Group of Hospitals Trust, Belfast, Northern Ireland; daggerDepartment of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX; and double daggerDepartment of Pathology, Belfast City Hospital Trust, Belfast, Northern Ireland.
Am J Surg Pathol. 2005 Aug;29(8):1034-1041. Abstract quote
Ovarian serous carcinoma (OSC) is the most common ovarian epithelial malignancy. Recently, a dualistic pathway of ovarian serous carcinogenesis has been proposed based on morphologic observations and molecular genetic analysis.
In this scheme, low-grade OSC arises in a stepwise fashion from a benign serous cystadenoma through a usual serous borderline tumor through a micropapillary variant of serous borderline tumor. In contrast, the more common high-grade OSC arises de novo from the ovarian surface epithelium or the epithelium of cortical inclusion cysts with an as yet unrecognized precursor lesion. Although the division of OSC into low- and high-grade variants is gaining greater acceptance, and although there is accumulating molecular genetic evidence for this, there is little published information regarding a comparison of protein expression between these two types of OSC.
In this study, we have investigated the immunohistochemical expression of a wide range of proteins in cases of low-grade (n = 22) and high-grade (n = 47) OSC. Antibodies used were p53, MIB1, BCL2, WT1, HER-2/neu, C-KIT, osteopontin, and survivin. For all antibodies, except MIB1, cases were scored as 0 (negative or occasional positive cells), 1+ (<10% cells positive), 2+ (10%-25% cells positive), 3+ (26%-50% cells positive), 4+ (51%-75% cells positive) or 5+ (>75% cells positive). For MIB1, the percentage of positive nuclei was calculated. There was a statistically significant higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade compared with low-grade OSC (P < 0.05). Thirty of 47 (64%) cases of high-grade OSC exhibited 5+ staining with p53 compared with 4 of 22 (18%) low-grade neoplasms. Twelve of 47 (26%) high-grade OSCs exhibited 5+ staining with BCL2 compared with 1 of 22 (5%) low-grade OSCs. The mean MIB1 proliferative index in high-grade OSCs was 55.4% compared with 23.0% in low-grade OSCs.
Virtually all cases of both low-grade and high-grade OSCs exhibited diffuse nuclear positivity with WT1 and diffuse cytoplasmic positivity with survivin. Osteopontin expression was variable with no significant difference in expression between low-grade and high-grade OSC. Although expression of both HER-2/neu and C-KIT was significantly higher in high-grade compared with low-grade OSC, only rare cases exhibited strong positivity with these antibodies, which could be of therapeutic value in individual cases, although this would require additional molecular investigations.
The significant differences in protein expression between low-grade and high-grade OSC provides further support for a different underlying pathogenesis. In particular, the differences in p53 immunoreactivity are in keeping with the observation that p53 gene mutation is more common in high-grade than low-grade OSC.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.
p53
- Patterns of p53 Mutations Separate Ovarian Serous Borderline Tumors and Low- and High-grade Carcinomas and Provide Support for a New Model of Ovarian Carcinogenesis: A Mutational Analysis With Immunohistochemical Correlation.
Singer G, Stohr R, Cope L, Dehari R, Hartmann A, Cao DF, Wang TL, Kurman RJ, Shih IM.
From the Departments of *Pathology and daggerOncology and Gyencology/Obstetrics, Johns Hopkins University School of Medicine, Baltimore MD; double daggerInstitute of Pathology, University Hospital Basel, Basel, Switzerland; and section signInstitute of Pathology and ||Department of Urology, University of Regensburg, Regensburg, Germany.
Am J Surg Pathol. 2005 Feb;29(2):218-224. Abstract quote
The infrequent association of serous borderline tumors (SBTs) with invasive serous carcinoma has led to the view that SBTs are unrelated to invasive serous carcinoma. Nonetheless, mortality associated with SBTs is generally attributed to malignant transformation, and traditionally these tumors have been designated as "carcinomas of low malignant potential." Previous immunohistochemical studies evaluating p53 expression and molecular genetic studies evaluating mutational status have reported that p53 overexpression and mutations are infrequent in SBTs and occur in as many as 50% to 80% of invasive serous carcinomas. The different methodologies for determining p53 status and the failure to correlate the findings with tumor grade make these studies difficult to interpret.
The current study was undertaken to overcome these deficiencies and to reconcile the relationship of SBTs to invasive serous carcinoma by performing a morphologic, immunohistochemical, and molecular genetic analysis comparing SBTs with low- and high-grade serous carcinoma. The molecular genetic analysis used a highly stringent, carefully designed nucleotide-sequencing method. A total of 96 sporadic serous tumors including 25 SBTs (11 atypical proliferative serous tumors and 14 intraepithelial low-grade serous carcinomas [noninvasive micropapillary serous carcinomas, MPSCs]), 12 low-grade serous carcinomas (invasive MPSCs), and 59 high-grade serous carcinomas were analyzed for their p53 mutational status of exons 5 to 9. Functional mutations, defined as mutations resulting in the alteration of the structure of the encoded protein, were detected in 30 of 59 (50.8%) high-grade serous carcinomas and 1 (8.3%) of 12 low-grade invasive serous carcinomas compared with 2 (8%) of 25 SBTs, both of these in intraepithelial low-grade serous carcinomas (noninvasive MPSCs). The similar frequency of p53 mutations in SBTs and low-grade invasive serous carcinomas in contrast to the significantly higher frequency of p53 mutations in high-grade serous carcinomas (P < 0.0005) suggests a common lineage for SBTs and low-grade invasive serous carcinomas and supports the view that SBTs are unrelated to the usual type of invasive serous carcinoma, which is a high-grade neoplasm. Mutational status was also correlated with p53 immunoreactivity. Although p53 immunoreactivity is generally higher in those specimens containing mutant p53, immunostaining is neither sufficiently specific nor sensitive enough to predict p53 mutations. The molecular genetic findings confirm our hypothesis of dual pathways of serous carcinogenesis based on previous analyses of KRAS and BRAF mutations on the same set of cases in which KRAS and BRAF mutations were found in 60% of SBTs and low-grade serous carcinoma but not in high-grade serous carcinomas.
Based on these studies, we have proposed a model of serous carcinogenesis in which SBTs are the precursors of low-grade serous carcinomas whereas the usual type of invasive serous carcinoma is a high-grade neoplasm that develops "de novo" from in situ alterations in epithelial inclusion cysts.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 ENDOSALPINGIOSIS
Mullerian papilloma-like proliferation arising in cystic pelvic endosalpingiosis.McCluggage WG, O'Rourke D, McElhenney C, Crooks M.
Department of Pathology, Royal Group of Hospitals Trust, and the Department of Pathology, Belfast City Hospital, Belfast; and the Department of Obstetrics and Gynaecology, Lagan Valley Hospital, Lisburn, Ireland.
Hum Pathol 2002 Sep;33(9):944-6 Abstract quote This report describes an unusual epithelial proliferation occurring in pelvic cystic endosalpingiosis. A cyst mass lined by a layer of ciliated epithelial cells involved the posterior surface of the cervix and vagina.
The epithelial proliferation within the wall resembled a mullerian papilloma with fibrous and fibrovascular cores lined by bland cuboidal epithelial cells. Other areas had a microglandular growth pattern resembling cervical microglandular hyperplasia, and focally there was a solid growth pattern. Foci of typical endosalpingiosis involved the surface of both ovaries and pelvic soft tissues. The cystic lesion recurred after partial cystectomy and drainage and was followed up radiologically and with periodic fine-needle aspiration.
Part of the wall of the cyst removed 11 years after the original surgery showed an identical epithelial proliferation. MIB1 staining showed a proliferation index of less than 5%, contrasting with the higher proliferation index of a typical serous borderline tumor. The differential diagnosis is discussed.
As far as we are aware, this is the first report of such a benign epithelial proliferation involving cystic endosalpingiosis.
PERITONEAL MESOTHELIOMA
*Department of Human Pathology and Oncology, University of Florence, Florence †Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Center, (CSPO), Scientific Institute of Tuscany, Florence, Italy.
Distinguishing between epithelioid peritoneal mesothelioma and papillary serous carcinomas involving the peritoneum may be very difficult, owing to overlapping morphologic features. Immunohistochemistry may facilitate establishing a correct diagnosis, but, as no single antibody has demonstrated absolute sensitivity and specificity for either mesothelioma or serous carcinoma, the differential diagnosis is based mainly on the combined use of several markers.
The purpose of this study was to ascertain the sensitivity and specificity of a series of mesothelial markers [including more recently investigated antigens such as h-caldesmon (h-CD) and D2-40] and, using receiver operating characteristic curve analysis, to identify a selected appropriate panel of antibodies for differentiating between epithelioid peritoneal mesothelioma and serous papillary carcinoma of the ovary. Fifteen cases of epithelioid peritoneal mesothelioma and 40 cases of papillary serous carcinoma of the ovary (25 primary and 15 metastatic to the peritoneum) were immunostained for h-CD, D2-40, calretinin, cytokeratin 5/6, thrombomodulin, estrogen and progesterone receptors (ER and PR), Ber-EP4, B72.3, CA19-9, and CD15. h-CD and calretinin showed the highest sensitivity (100%), followed by D2-40 (93.3%) and cytokeratin 5/6 (93.3%); thrombomodulin had the lowest sensitivity (60%). h-CD and thrombomodulin had the best specificity (95%) for mesothelioma, followed by calretinin (87.5%), D2-40 (80%), and cytokeratin 5/6 (72.5%). Among carcinoma markers, ER and Ber-EP4 demonstrated the highest sensitivity (95%) followed by B72.3 (72.5%), PR (65%), CA19.9 (60%), and CD15 (45%).
The specificity of the nonmesothelial markers was 100%, except for Ber-EP4 (93.3%). The relationship between the values of sensitivity and specificity of each marker using receiver operating characteristic analysis permitted the identification of h-CD, calretinin, ER, and Ber-EP4 as the markers with the best performance in differentiating epithelioid peritoneal mesothelioma from serous papillary carcinoma of the ovary.
- Value of immunohistochemistry in distinguishing peritoneal mesothelioma from serous carcinoma of the ovary and peritoneum: a review and update.
Ordonez NG.
From The University of Texas M. D. Anderson Cancer Center, Houston.
Adv Anat Pathol. 2006 Jan;13(1):16-25. Abstract quote
At present, a large number of immunohistochemical markers that can be used in the differential diagnosis between epithelioid peritoneal mesotheliomas and serous carcinomas are available. However, great differences of opinion exist regarding the individual value of some of these markers.
This article provides a critical review of all of the information that is currently available on those markers that have the greatest potential for assisting in distinguishing between peritoneal mesotheliomas and serous carcinomas. The conclusion of this review indicates that the positive serous carcinoma markers, by and large, have a higher degree of sensitivity and specificity in assisting in discriminating between these malignancies than the positive mesothelioma markers.
From a practical point of view, a combination of MOC-31 (or Ber-EP4), estrogen receptors, and calretinin immunostaining should allow a clear distinction to be made between epithelioid peritoneal mesotheliomas and serous carcinomas in most cases.
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.
PRIMARY PERITONEAL SEROUS CARCINOMA
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS
Departments of *Pathology ∥Biostatistics and Applied Mathematics, The University of Texas M.D. Anderson Cancer Center, Houston, TX †Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY ‡The Johns Hopkins University, Baltimore, MD §Washington Hospital Center, Washington, DC ¶Sarasota Pathology, Sarasota, FL ♯Cedars Sinai Hospital, Los Angeles, CA.
Although grading has been demonstrated to be an important prognostic factor in ovarian serous carcinoma, there is no system universally used to perform this task. A few years ago, we proposed a two-tier system for grading ovarian serous carcinoma that is based primarily on the assessment of nuclear atypia (uniformity vs. pleomorphism) in the worst area of the tumor. Tumor grade in this two-tier system is correlated with survival.
After being used by numerous pathologists and trainees at The University of Texas M.D. Anderson Cancer Center (MDACC) for 15 years, we have observed that this system is user-friendly and reproducible.
We undertook this study to evaluate the interobserver and intraobserver variability among a group of 7 gynecologic pathologists and 2 general surgical pathologists using this grading system. A total of 80 cases of ovarian serous carcinoma, 40 low-grade and 40 high-grade, were circulated twice among these pathologists. Slides with examples of low-grade and high-grade serous carcinoma were sent with the unknowns. A website was used to provide diagnostic criteria, images of examples of ovarian low-grade and high-grade carcinoma, and a log form to facilitate data entry. Statistical analysis demonstrated an overall kappa statistic among the different observers of 0.909. The intergrader kappa's ranged from 0.717 to 1.000 in the first round of the review and from 0.701 to 1.000 in the second round. Eight of the participants had an intragrader kappa ranging from 0.775 to 1.000 (excellent agreement), whereas a single participant had an intragrader kappa of 0.725 (good agreement).
This study demonstrates that the two-tier grading system (the MDACC grading system) for ovarian serous carcinoma on the basis of the assessment of nuclear atypia is easy to learn and is highly reproducible.
These findings would support its universal use, which would be beneficial for the standardization of clinical trials and protocols, thus facilitating the understanding of this disease and investigation into the treatment of patients affected by these tumors.
- Ovarian Serous Tumors of Low Malignant Potential (Borderline Tumors): Outcome-Based Study of 276 Patients With Long-Term (>/=5-Year) Follow-Up.
Longacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR.
From the Department of Pathology, Stanford University, Stanford, CA. The current address for Dr. McKenney is University of Arkansas for Medical Sciences, Little Rock, AR. The current address for Dr. Tazelaar is Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ.
Am J Surg Pathol. 2005 Jun;29(6):707-723. Abstract quote
The natural history, classification, and nomenclature of ovarian serous tumors of low malignant potential (S-LMP) (serous tumors of borderline malignancy, atypical proliferating tumors) are controversial.
To determine long-term outcome for patients with S-LMP and further evaluate whether S-LMP can be stratified into clinically benign and malignant groups, the clinicopathologic features of 276 patients with S-LMP and >/=5 year follow-up were studied. The histology of the ovarian primary, extraovarian implants, and recurrent tumor(s) were characterized using World Health Organization criteria and correlated with FIGO stage and clinical follow-up. After censoring nontumor deaths, overall survival and disease-free survival for the 276 patients was 95% (98% FIGO stage I; 91% FIGO II-IV) and 78% (87% FIGO stage I; 65% FIGO stage II-IV), respectively. Unresectable disease (P < 0.001) and invasive implants (P < 0.001) were associated with decreased survival.
When compared with typical S-LMP, S-LMP with micropapillary features were more strongly associated with invasive implants (P < 0.008) and decreased overall survival (P = 0.004), but patient outcome with micropapillary S-LMP was not independent of implant type. Stromal microinvasion in the primary tumor was also correlated with adverse outcome, independent of stage of disease, micropapillary architecture, and implant type (P = 0.03). There was no association between outcome and lymph node status. Transformation to low-grade serous carcinoma occurred in 6.8% of patients at intervals of 7 to 288 months (58% >/= 60 months) and was strongly associated with increased tempo of disease and decreased survival (P < 0.001). S-LMP forms a heterogeneous group, morphologically and clinically distinct from benign serous tumors and serous carcinoma.
The majority of S-LMP are clinically benign, but recurrences are not uncommon, and persistent disease as well as deaths occur. Progression to low-grade serous carcinoma is highly predictive of more aggressive disease. Other features associated with recurrent and/or progressive disease include FIGO stage, invasive implants, microinvasion in the primary tumor, and micropapillary architecture. These predictors tend to co-occur, and no single clinical or pathologic feature or combination of features identify all adverse outcomes.
The small, but significant risk of progression over time to low-grade serous carcinoma emphasizes the need for prolonged follow-up in patients with S-LMP.Serous Carcinoma of the Ovary, Fallopian Tube, or Peritoneum Presenting as Lymphadenopathy.
Euscher ED, Silva EG, Deavers MT, Elishaev E, Gershenson DM, Malpica A.
Departments of *Pathology and daggerGynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX.
Am J Surg Pathol. 2004 Sep;28(9):1217-1223. Abstract quote
The clinicopathologic features of 35 cases of serous carcinoma of the ovary, fallopian tube, or peritoneum presenting as lymphadenopathy are described. The cases were retrieved from the files of the Department of Pathology at the University of Texas M. D. Anderson Cancer Center from a 20-year period (1982-2002).
The following parameters were evaluated: patient age at diagnosis, lymph node involved, primary tumor site, tumor histology, peritoneal disease status, and survival. The patients ranged in age from 30 to 85 years (mean, 59 years). The lymph nodes involved were inguinal, 20 cases; supraclavicular, 11 cases; axillary, 2 cases; cervical, 1 case; and retroperitoneal, 1 case. Primary tumor sites included 20 ovarian, 10 peritoneal, and 2 fallopian tube. In 2 patients, total abdominal hysterectomy/bilateral salpingo-oophorectomy and complete staging showed no additional tumor, and in 1 patient with a previous history of total abdominal hysterectomy/bilateral salpingo-oophorectomy for a benign condition, imaging studies did not identify a primary site. The carcinoma was high grade in 30 cases and low grade in 4 cases. In one case, the diagnosis was made on cytology material and the tumor could not be graded. Peritoneal disease status was known in 33 patients and was as follows: omentum with gross disease, 16 cases; and omentum without gross disease, 17 cases.
Follow-up was available in 33 patients and ranged from 4 to 204 months, with a median survival of 36 months for stage III patients and 29 months for stage IV patients. Patients with adenopathy and minimal peritoneal disease (grossly negative omentum) had a median survival of 120 months compared with 24 months for those with bulky peritoneal disease (grossly positive omentum).
Serous carcinoma of the ovary, fallopian tube, or peritoneum presenting as a lymph node metastasis is uncommon. In rare cases, a primary site may not be found. The median survival of the patients for stage is not appreciably different from those patients presenting in the usual fashion, suggesting that this atypical presentation does not adversely affect survival. Patients with minimal peritoneal disease and extra-abdominal lymph node metastases survive longer than those with bulky peritoneal disease
Grading ovarian serous carcinoma using a two-tier system.
Malpica A, Deavers MT, Lu K, Bodurka DC, Atkinson EN, Gershenson DM, Silva EG.
Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Am J Surg Pathol. 2004 Apr;28(4):496-504. Abstract quote
In this study, we evaluate a two-tier system for grading ovarian serous carcinoma. This system is based primarily on the assessment of nuclear atypia with the mitotic rate used as a secondary feature.
The study included 50 cases of low-grade ovarian serous carcinoma and 50 cases of high-grade ovarian serous carcinoma retrieved from the files of the Department of Pathology at the University of Texas M. D. Anderson Cancer Center from a 28-year period. Cases assigned to the low-grade category were characterized by the presence of mild to moderate nuclear atypia. As a secondary feature, they tended to show up to 12 mitoses per 10 high power fields (HPFs), whereas those in the high-grade category had marked nuclear atypia and as a secondary feature more than 12 mitoses per 10 HPFs. For comparison, the tumors were also graded using the Shimizu/Silverberg and the FIGO grading systems. Patients in the low-grade ovarian serous carcinoma group ranged in age from 19 to 75 years (mean 41.7 years) while patients in the high-grade ovarian serous carcinoma group ranged in age from 27 to 76 years (mean 55 years). All of the cases except one were advanced FIGO stage. Using the Shimizu/Silverberg system, the low-grade ovarian serous carcinoma cases were distributed as follows: grade 1, 47 cases; grade 2, 3 cases. Using the FIGO grading system, 35 cases were grade 1 and 15 cases were grade 2. Regarding the high-grade ovarian serous carcinoma group using the Shimizu/Silverberg system, 14 of the cases were grade 2 and 36 cases were grade 3. Using the FIGO grading system, 1 case was grade 1, 38 cases were grade 2, and 11 cases were grade 3. Most of the patients in both groups were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy and also received cisplatinum-based chemotherapy.
On follow-up, 37 patients in the low-grade ovarian serous carcinoma group had died of disease at a median 4.2 years after diagnosis compared with 46 patients in the high-grade ovarian serous carcinoma group who died of disease at a median of 1.7 years. Eight patients in the low-grade ovarian serous carcinoma group and 4 patients in the high-grade ovarian serous carcinoma group were alive with disease at median follow-ups of 4.3 and 3.85 years, respectively. Four patients with low-grade serous carcinoma were alive without evidence of disease after a follow-up that ranged from 4.4 to 22.6 years (median 6.85 years), and one died of other causes 14 years after the diagnosis of her ovarian tumor. On multivariate analysis, residual tumor and tumor grade based on the M. D. Anderson two-tier system for grading ovarian serous carcinoma were found to be significant independent prognostic factors (P = 0.003 and 0.04, respectively). Of interest, 60% of the low-grade ovarian serous carcinomas in this study were associated with a serous neoplasm of low malignant potential, whereas this association was present in only 2% of the high-grade ovarian serous carcinomas.
This finding could reflect a difference in the pathogenesis of ovarian serous carcinomas of different grades. In summary, there is usually a good correlation between the two-tier grading system herein presented and the Shimizu/Silverberg and the FIGO grading systems.
Because this system is based on defined criteria that are easy to follow and because it involves only two diagnostic categories, it should provide better reproducibility in the grading of ovarian serous carcinoma. However, additional studies are required to validate these statements.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.
Serous borderline tumors of the ovary: a long-term follow-up study of 137 cases, including 18 with a micropapillary pattern and 20 with microinvasion.Prat J, De Nictolis M.
Am J Surg Pathol 2002 Sep;26(9):1111-28 Abstract quote The natural history of serous borderline tumors (SBTs) of the ovary varies considerably. A group of investigators have proposed that a small subset of SBTs with a micropapillary architecture and an allegedly higher incidence of invasive peritoneal implants should be designated "micropapillary serous carcinomas." Based on the overall favorable prognosis of the nonmicropapillary SBTs, these investigators have recommended abandoning the borderline category of serous tumors, restricting them to benign (benign and typical SBTs) and malignant types; other investigators, however, are in favor of retaining the original grouping, designating borderline tumors with a micropapillary pattern as such instead of designating them carcinomas.
We have reviewed the clinicopathologic records of 137 patients with ovarian SBTs and obtained follow-up information on 106 of them ranging from 1 to 18 years (mean 7 years). Of the 21 patients with stage I tumors who had conservative surgical treatment, only two (9.5%) were subsequently found to have tumor in the contralateral ovary. Both were successfully managed by reoperation alone. Forty-five stage I patients had procedures that included bilateral oophorectomy, and two of them (4.4%) had a pelvic recurrence, which was fatal in one patient (whose tumor had been understaged) and occurred on multiple occasions in the other patient, finally transforming into invasive carcinoma; that patient survived. Of the 45 stage II-IV patients, only the six (13%) with invasive implants had an unfavorable outcome: three died of tumor (from 7 to 9.3 years), and the other three were alive with progressive disease from 5 to 10 years. Solid epithelial nests or small papillae surrounded by clefts and micropapillary architecture were found more often in invasive than in noninvasive implants. However, the only feature specifically associated with a poor outcome was obvious destructive invasion of the underlying tissue. Among the 137 SBTs, we identified 18 cases of serous borderline tumors with a micropapillary pattern (SBT-MP) (so-called "micropapillary carcinoma") and 20 cases of SBT with microinvasion (SBT-Minv) (three of which were also micropapillary). We compared the two groups of tumors with the remaining 102 cases of typical SBTs (which lacked micropapillary pattern and microinvasion). Of the 17 patients with SBT-MP and follow-up data, only the one patient with invasive implants had an unfavorable outcome; similarly, of the two patients with SBT-Minv and an unfavorable outcome, one had invasive implants and the other had been incompletely staged. SBTs have a very favorable prognosis, but complete surgical staging and prolonged follow-up are advised because pelvic recurrence and occasionally transformation to invasive carcinoma may occur.
Designation of SBTs as "atypical proliferative tumors" is not recommended because it discourages complete surgical staging and follow-up. Advanced stage tumors with noninvasive implants are common, characteristically behave in a benign fashion, and can be safely treated conservatively. The rare SBTs associated with invasive implants are almost always fatal. SBT-MP and SBT-Minv are much closer in their biologic behavior to SBTs than to serous carcinomas. The micropapillary pattern alone does not imply an unfavorable prognosis; only micropapillary tumors associated with invasive implants behave aggressively.
Micropapillary and cribriform patterns in ovarian serous tumors of low malignant potential: a study of 99 advanced stage cases.Deavers MT, Gershenson DM, Tortolero-Luna G, Malpica A, Lu KH, Silva EG.
Am J Surg Pathol 2002 Sep;26(9):1129-41 Abstract quote Recently some investigators have proposed abandoning the term ovarian serous tumor of low malignant potential (SLMP) and dividing the tumors in this category into two new groups, micropapillary serous carcinoma and atypical proliferative serous tumor, based on the presence or absence of marked epithelial proliferation with a micropapillary or cribriform pattern (MP/CP).
We reviewed 99 cases of advanced stage SLMP (FIGO stages II and III) to determine whether the presence or absence of MP/CP predicts the clinical course, thus justifying the proposed change in terminology. Eighteen cases of MP/CP and 81 cases of typical SLMP were identified. The patients with MP/CP ranged from 23 to 59 years of age at the time of diagnosis (median 35 years), whereas those with typical SLMP were 17 to 67 years old (median 38 years). Bilateral ovarian involvement by SLMP was more frequent in the MP/CP cases, 13 of 18 (72%), as compared with the cases with typical SLMP, 46 of 81 (57%). There was a trend toward a greater frequency of invasive implants in MP/CP cases, 3 of 18 (17%) MP/CP versus 5 of 81 (6%) typical. The mean follow-up period was 125 months for MP/CP patients and 132 months for the typical group. Differences in the frequency of recurrence and the progression-free survival between the groups were found to be significant. Fourteen (78%) of the MP/CP patients experienced either progression or recurrence of disease, whereas 25 (31%) of the typical SLMP patients had a recurrence (p = 0.001). The progression-free survival ranged from 3 to 208 months for MP/CP patients versus 15 to 233 months for typical SLMP patients (p <0.0001). The majority of the recurrences in both groups were low-grade serous carcinoma, 11 of 14 (79%) patients with progression/recurrence in the MP/CP group and 17 of 25 (68%) patients with recurrence in the typical group. The overall survival of the patients in the two groups, however, was not significantly different. Five (28%) MP/CP patients and 12 (15%) patients with typical SLMP died of disease (p = 0.11). All 17 of these patients developed serous carcinoma and died secondary to tumor progression. Four of eight (50%) patients with invasive implants and 13 of 91 (14%) patients with noninvasive implants died of disease.
Our findings of more frequent bilateral ovarian involvement, more frequent recurrence with a shorter progression-free interval, and the trend toward a more frequent association with invasive implants support the contention that MP/CP SLMP are a distinct subgroup of serous tumors. However, the overall survival of patients with MP/CP SLMP is similar to that of patients with typical SLMP and justifies the retention of tumors with MP/CP within the LMP category. Additionally, our long-term follow-up of patients with typical SLMP indicates that a number of these tumors do not follow a benign course and supports their continued designation as borderline neoplasms.
IMPLANTS 90% with no progression of disease after 4 years 17% with no progression of disease after 4 years
Departments of *Pathology, and daggerGynecologic Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX.
Ovarian serous borderline neoplasm with noninvasive implants traditionally have been considered to be nonaggressive tumors associated with an excellent prognosis. However, in our experience, recurrences commonly develop as patients are followed over many years.
Eighty cases of advanced-stage ovarian serous borderline tumor with noninvasive implants were identified; the minimum follow-up period for these cases was 5 years or until the death of the patient. The following cases were excluded: patients treated by cystectomy, patients who died of other causes, patients who developed other tumors, and patients who had as the only positive material after resection of the primary borderline neoplasm a tumor detected on a second look or third look operation. Hematoxylin and eosin-stained slides from the original ovarian tumor and the staging biopsies were reviewed in all cases. Slides of the recurrent tumor were available in all cases except for 2 in which the diagnosis was established clinically. The presence or absence of a micropapillary/cribriform pattern and microinvasion in the ovarian tumor was recorded. Follow-up was obtained from the patients' charts. Fischer exact test was used for statistical analysis.
The patients' ages ranged from 17 to 67 years (median 36 y). Seventy-three patients were treated by total abdominal hysterectomy and bilateral salpingo-oophorectomy. Seven patients were treated by total abdominal hysterectomy and unilateral salpingo-oophorectomy. The International Federation of Gynecology and Obstetrics stage was as follows: stage II (29 cases), stage III (50 cases), and stage IV (1 case). After surgery, 58 patients were treated with chemotherapy, 7 with radiotherapy, and 1 with hormonal therapy. The follow-up ranged from 5 to 31 years (median 15.7 y). Thirty-five patients (44%) developed recurrences. Only 10% of the patients had a recurrence in less than 5 years, 19% had their recurrences between 5 and 10 years, 10% between 10 and 15 years, and 5% more than 15 years after resection of the primary neoplasm. The only statistically significant feature associated with recurrence was the presence of a micropapillary/cribriform pattern, although this pattern was present in only 26% of the cases that recurred. Of the 35 patients who had a recurrence, 2 were diagnosed clinically, both are alive with progressive disease at 1 and 5 years after the diagnosis of the recurrence; 6 had recurrent serous borderline tumors, all are without evidence of disease with a follow-up ranging from 7 to 18 years after resection of the ovarian borderline tumor (median 14 y); and 27 patients subsequently developed low-grade serous carcinoma, 7 are alive with progressive disease with a follow-up ranging from 10 to 29 years (median 15 y) and 20 died of disease between 3 to 25 years after resection of the ovarian borderline tumor (median 16 y).
In summary, the true recurrence rate of ovarian serous borderline tumors with noninvasive implants can only be obtained through a long follow-up. In this group of patients, 77% and 34% of the subsequent tumors developed 5 years and 10 years after diagnosis of the ovarian tumor, respectively. Histologic examination of the recurrent tumor is important in determining further therapy and prognosis for these patients; all patients who recurred with borderline tumor are without evidence of disease, whereas 74% of the patients who recurred with low-grade serous carcinoma died of disease.
We propose that patients be followed for a minimum of 10 years to evaluate for recurrences and for 20 years to evaluate for survival.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.
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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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