Uterine serous carcinomas (USC) are characterized by aggressive and bulky disease. Unlike most other uterine carcinoma cases, these tumors usually arise from endometrium which is atrophic rather than hyperplastic.
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EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Serous papillary adenocarcinoma of the endometrium, uterine serous carcinoma INCIDENCE 10% of endometrial carcinomas AGE-RANGE AND MEDIAN 39-93 years Median 68 years GEOGRAPHIC DISTRIBUTION Worldwide though may be lesser incidence in Norway and Australia
DISEASE ASSOCIATIONS CHARACTERIZATION ENDOMETRIAL POLYPS
- Serous papillary carcinoma of the endometrium arising from endometrial polyps: a clinical, histological, and immunohistochemical study of 13 cases.
Trahan S, Tetu B, Raymond PE.
Department of Pathology, L'Hotel-Dieu de Quebec, Centre Hospitalier Universitaire de Quebec, Laval University, Quebec City, Quebec, Canada G1R 2J6.
Hum Pathol. 2005 Dec;36(12):1316-21. Abstract quote
Serous papillary carcinoma is an aggressive tumor. Point mutations in the p53 suppressor gene might explain in part the rapid growth of this malignant tumor and its unfavorable outcome.
The aims of this study were to evaluate the behavior of serous papillary carcinoma developing in endometrial polyps and to assess the p53 protein overexpression. Patients included in this study were treated in our institution between 1982 and 2003. All clinical and pathological materials were examined. A p53 protein immunohistochemical analysis was performed on paraffin-embedded tissues.
Thirteen serous papillary carcinomas arising from benign polyps of the endometrium were identified. The patients' age averaged 73 years. All patients were treated surgically. After an average follow-up of 22 months, 54% of the patients were dead or alive with disease. Of 10 serous papillary carcinomas, 8 (80%) for which paraffin blocks were available overexpressed the p53 protein. A serous papillary carcinoma arising from benign polyps of the endometrium remains a malignant neoplasia with an unfavorable outcome even if the primary tumor is limited to the polyp.
The high rate of protein p53 overexpression suggests that a p53 gene mutation occurs early in the disease and might explain the rapid growth of the tumor.
Most tumors are small and atrophic but have a papillary exophytic appearance
Occasionally, the tumor may be confined to the polyp
HISTOLOGICAL TYPES CHARACTERIZATION Precursor lesions Precursor lesions have been sought and have been classified as minimal uterine serous carcinoma (MUSC). This term has been applied to cases of endometrial intraepithelial carcinoma (EIC) and superficial serous carcinoma (SSC).
EIC is defined as replacement of the uterine surface epithelium and/or underlying glands by high grade malignant cells which represent the in situ phase of USC. SSC is defined as USC without myometrial or lymphovascular invasion.
In a study of 21 cases of MUSC, 13 of 14 cases (93%) of MUSC confined to the uterus were disease free and one died from unrelated causes. The other 7 women all presented with extrauterine disease, including microscopic deposits, and were dead or alive with recurrences.
Classic Complex papillary architecture with cuboidal to hobnailed shaped cells having marked cytologic atypia
High mitotic activity
Psammoma bodies in 1/3 of cases
In almost all cases, the adjacent endometrium is atrophic and may show the precursor lesions
Tend to invade deeply into myometrium with extensive lymphatic invasion
- Serous Endometrial Cancers That Mimic Endometrioid Adenocarcinomas: A Clinicopathologic and Immunohistochemical Study of a Group of Problematic Cases.
Darvishian F, Hummer AJ, Thaler HT, Bhargava R, Linkov I, Asher M, Soslow RA.
From the *Department of Pathology, Memorial Sloan-Kettering Cancer Center; and daggerDepartment of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.
Am J Surg Pathol. 2004 Dec;28(12):1568-1578. Abstract quote
BACKGROUND:: Uterine serous carcinomas (USCs) can exhibit an architecturally well-differentiated tubuloglandular morphology with or without an accompanying papillary growth pattern. These features make it difficult to distinguish USCs from endometrial endometrioid carcinomas (EECs). Given the aggressive behavior of USC, compared with EEC, and differences in management, it is important to correctly classify endometrial carcinomas that exhibit a tubuloglandular architecture with high nuclear grade. We sought an immunohistochemical panel to minimize subjectivity in the distinction of USC from EEC.
MATERIALS AND METHODS:: We identified 8 problematic endometrial cancers, exhibiting a tubuloglandular growth pattern and high nuclear grade, whose classification as EEC or USC was debated or resulted in disagreement. We selected 13 cases of International Federation of Gynecology and Obstetrics (FIGO) grade 2 EEC and 16 cases of USC as controls. An immunohistochemical panel, including p53, beta-catenin, cyclin D1, estrogen receptor (ER), progesterone receptor (PR), and PTEN, was evaluated.
RESULTS:: As a group, the clinical features and immunoprofile of the study cases resembled those of the serous controls. The study cases expressed p53, beta-catenin, cyclin D1, and ER and PR, and showed loss of PTEN in 75%, 12.5%, 0%, 37.5%, 37.5%, and 12.5% of cases, respectively. p53, beta-catenin, cyclin D1, ER and PR expression, and PTEN loss were seen in 87.5%, 0%, 19%, 31%, 12%, and 0% of the serous controls and in 7%, 70%, 54%, 92%, 92%, and 61.5% of the endometrioid controls, respectively. The combination of lack of p53 expression, positive PR expression, and loss of PTEN best distinguished between EEC and USC using discriminant analysis (multivariate P = 0.008, <0.001, and 0.05, respectively).
CONCLUSION:: In endometrial carcinomas exhibiting high nuclear grade and low architectural grade, using a panel of immunohistochemical stains may facilitate the distinction of USC from EEC. Our clinical and immunohistochemical data also support the concept that there is a group of endometrial adenocarcinomas composed of tubular glands that are indeed serous carcinomas.
MINMAL UTERINE SEROUS CARCINOMA/
ENDOMETRIAL INTRAEPITHELIAL CARCINOMA
- Lack of PTEN expression in endometrial intraepithelial neoplasia is correlated with cancer progression.
Baak JP, Van Diermen B, Steinbakk A, Janssen E, Skaland I, Mutter GL, Fiane B, Lovslett K.
Hum Pathol. 2005 May;36(5):555-61. Abstract quote
Summary We tested the hypothesis that PTEN inactivation may stratify cancer progression risk among putative endometrial hyperplasias, classified prognostically by means of the morphometric D score (DS). The DS, calculated from 3 morphometric variables measured in routine hematoxylin-eosin-stained endometrial biopsy slides, is the most sensitive and specific method of endometrial cancer risk prediction currently available.
Clinical outcomes of 103 women with endometrial hyperplasia on biopsy were tallied according to the DS. Seven (7/103; 7%) patients with carcinoma during follow-up were all distributed within the high-risk prognostic group (ie, DS <1 = endometrial intraepithelial neoplasia [EIN]) (7/21; 33% progression). None of the 82 cases with a DS higher than 1 progressed. All cases that progressed were PTEN null, indicating that this genotype is capable of further stratifying cancer progression risk in hyperplasias irrespective of histological categorization. However, only 16% of the PTEN-null cases progressed. When PTEN expression pattern was combined with EIN, the prognostic power was greatly increased (specificity from 63% for PTEN and 85% for EIN to 93% when combined; positive predictive value from 16% and 33% to 50%).
We conclude that loss of PTEN expression is the first biomarker in EIN that increases the accuracy of the prognostic DS to predict cancer progression risk. Unless endometrial hyperplasias are stratified by histological morphometric D-Score, PTEN has a low positive predictive value.
- Minimal uterine serous carcinoma: a clinicopathological study of 40 cases.
Hui P, Kelly M, O'malley DM, Tavassoli F, Schwartz PE.
1Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
Mod Pathol. 2005 Jan;18(1):75-82 Abstract quote.
The term 'minimal uterine serous carcinoma' has been proposed to include serous carcinomas with invasion limited to the endometrium (superficial serous carcinoma), and those without stromal invasion (intraepithelial serous carcinoma or endometrial intraepithelial carcinoma). Both lesions display similar cytological and immunohistochemical profiles of a typical invasive serous carcinoma with a high nuclear grade and an overexpression of mutant p53 protein.
We studied the clinicopathologic features of 40 cases of minimal uterine serous carcinoma. All patients were postmenopausal and underwent hysterectomy and surgical staging procedures. There were nine cases of intraepithelial serous carcinoma and 31 cases of superficial serous carcinoma. Five intraepithelial serous carcinomas and 16 superficial serous carcinomas exclusively involved an endometrial polyp. A total of 18 minimal uterine serous carcinomas also involved, in addition to a polyp, the endometrium proper in the form of intraepithelial serous carcinoma (13 cases) and superficial serous carcinoma (five cases).
Overall, minimal uterine serous carcinomas were found to involve an endometrial polyp in 88% of the cases (35/40) and were confined to the polyp in 53% (21/40). Extrauterine tumors were present in 45% of the cases (18/40). In all, 22 patients with tumor limited to their uteri demonstrated an overall survival of 94% (2-73 months of follow-up). Eight of 18 patients with extrauterine tumors died of their malignancy (1.5-62 months of follow-up).
In conclusion, a significant majority of minimal uterine serous carcinomas involve an endometrial polyp. Complete surgical staging is important to predict the prognosis. When the lesion is confined to an endometrial polyp and/or the endometrium proper, the clinical outcome is excellent.
- Endometrial glandular dysplasia: a newly defined precursor lesion of uterine papillary serous carcinoma. Part I: morphologic features.
Zheng W, Liang SX, Yu H, Rutherford T, Chambers SK, Schwartz PE.
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8070, USA.
Int J Surg Pathol. 2004 Jul;12(3):207-23. Abstract quote
Dysplastic epithelium frequently bridges the changes between normal epithelium and noninvasive carcinoma. However, such a dysplastic lesion has not been previously described in the development of uterine papillary serous carcinoma (UPSC) or between resting endometrium and serous endometrial intraepithelial carcinoma (EIC), which is composed of indisputably malignant noninvasive cancer cells.
In this study, we hypothesize that there is a lesion bridging benign endometrium and serous EIC. Based on current understanding of carcinogenesis in general, the lesion should exhibit dysplastic features that are more atypical than "resting endometrium" but fall short of serous EIC. If the putative dysplastic endometrial lesion exists, it should be highly associated with UPSC rather than uterine endometrioid carcinoma (UEC).
We examined the morphologic appearance of the endometrium from 32 uteri with UPSC, 16 with serous EIC, and 60 with UEC. The endometrial dysplastic lesions were identified and their pathologic features were characterized. Immunohistochemical staining with p53 and MIB-1 were performed in all sections containing endometrial dysplastic lesions, serous EICs, and benign areas. In addition, 25 postmenopausal endometrial biopsies including 6 benign resting endometria, 8 dysplastic lesions, and 11 serous EICs were also compared for the level of p53 overexpression and cellular proliferative activity. We found that endometrial dysplastic lesions do exist in the endometrial specimens we speculated and examined.
We designate it as endometrial glandular dysplasia (EmGD). EmGD was present in 17 (53%) uteri with UPSC compared with 1 (1.7%) uterus removed for UEC (p = 0.001). EmGD was identified in 12 (75%) of 16 serous EIC uteri. Areas of both EmGD and serous EIC were found in 15 (47%) of the 32 UPSC uteri. Transitions from either EmGD to serous EIC or serous EIC to UPSC were present in 8 (25%) of the UPSC cases. No transitions from EmGD to UPSC were identified in any hysterectomy specimen. EmGD was frequently found in endometrial polyps. There was no statistically significant difference between EmGD in a polyp (48%) and EmGD in nonpolypoid endometrium (52%). The majority of EmGDs were multifocal and involved superficial endometrial glands. However, single glandular involvement and endometrial surface epithelial involvement were also seen. Immunohistochemically, EmGD lesions mostly showed intermediate scores/indices of p53 and MIB-1 in comparison with serous EIC and resting endometrium. EmGD is a morphologically distinct entity, which is commonly and specifically associated with uterine tumors with serous differentiation.
EmGD may represent the earliest identifiable morphologic change in the development of UPSC. Characteristics of p53 and MIB-1 immunostains of EmGD may be of diagnostic usage in surgical pathology practice. Recognition of EmGD may provide an opportunity to improve the management of UPSC.
- Minimal uterine serous carcinoma: diagnosis and clinicopathologic correlation.
Wheeler DT, Bell KA, Kurman RJ, Sherman ME.
Johns Hopkins Hospital and the Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Am J Surg Pathol. 2000 Jun;24(6):797-806. Abstract quote
The clinicopathologic features of uterine serous carcinoma (USC) lacking myometrial invasion, including its putative precursor lesion endometrial intraepithelial carcinoma (EIC), have not been studied extensively. Some USCs may prove fatal even when myometrial invasion is apparently absent, whereas others may be cured with surgery alone. Accordingly, the authors studied eight cases of pure EIC (no invasion identified) and 13 superficial serous carcinomas (SSCs) in which invasion was limited to the endometrial stroma to clarify the behavior of these lesions.
The review demonstrated that the most important feature in assessing prognosis is the presence or absence of extrauterine disease at presentation. Thirteen of 14 patients (93%) with EIC or SSC confined to the uterus (stage I or IIA) were disease free and one was dead of unrelated causes at 52 months, whereas seven women who presented with extrauterine disease, even if only microscopic, were either dead of disease or alive with recurrences. Accordingly, patients with EIC or SSC must undergo meticulous surgical staging at the time of hysterectomy.
Because the distinction between EIC and SSC based on the identification of stromal invasion is difficult and these lesions share a unique pattern of clinical behavior, the authors regard EIC and SSC measuring 1 cm or less as "minimal uterine serous carcinoma."
- Endometrial intraepithelial carcinoma with associated peritoneal carcinomatosis.
Soslow RA, Pirog E, Isacson C.
Department of Pathology, New York Presbyterian Hospital-Weill Medical College of Cornell University, NY 10021, USA.
Am J Surg Pathol. 2000 May;24(5):726-32. Abstract quote
Endometrial intraepithelial carcinoma (EIC) is a recently described entity, defined as a noninvasive, cytologically malignant lesion that replaces the endometrial surface epithelium. EIC frequently coexists with uterine serous carcinoma (USC) and is hypothesized to be its precursor lesion. However, the clinical significance and biologic potential of finding EIC without USC is not known.
We report three postmenopausal women with EIC alone who were found to have multiple, synchronous foci of extrauterine serous carcinoma at presentation. Because the clinical findings in these patients simulated primary peritoneal serous carcinoma (PSC), we compared the clinicopathologic features of these cases with a group of nine bona fide PSCs for which exhaustively sectioned endometria, fallopian tubes, and ovaries were available for review. The average age of the EIC patients was 73 years. Two patients presented with abdominal distention and one with vaginal bleeding. Hysterectomy in each case showed endometrial polyps with EIC, but without invasive USC, in a background of atrophic endometrium. Bilateral salpingo-oophorectomy and staging showed serous carcinoma involving the ovarian hilum, the surfaces of the fallopian tubes and ovaries, in addition to peritoneal carcinomatosis. p53 overexpression was observed in both EIC and the extrauterine deposits of serous carcinoma in each case. The average age of the PSC patients was 66 years. All nine patients presented with abdominal distention. EIC was not identified in any of the hysterectomy specimens.
Bilateral salpingo-oophorectomies, omentectomies, and peritoneal biopsies showed peritoneal carcinomatosis, including bulky peritoneal tumor deposits, but only minimal ovarian surface involvement. p53 overexpression was observed in seven cases. These findings indicate that EIC without coincident USC can be associated with invasive, extrauterine serous carcinomatosis. We did not, however, find any significant differences between the clinicopathologic features of primary extrauterine serous carcinomas (PSCs) and those associated with EIC.
We conclude that the finding of EIC in an endometrial curettage specimen should prompt a thorough search for an invasive uterine and/or extrauterine serous carcinoma. Conversely, an endometrial origin should be excluded in patients with peritoneal carcinomatosis.
- Endometrial intraepithelial carcinoma: a distinctive lesion specifically associated with tumors displaying serous differentiation.
Ambros RA, Sherman ME, Zahn CM, Bitterman P, Kurman RJ.
Department of Pathology, Albany Medical College, New York, NY, USA.
Hum Pathol. 1995 Nov;26(11):1260-7. Abstract quote
Endometrial intraepithelial carcinoma (EIC) is a recently described lesion characterized by replacement of endometrial surface epithelium or glands by malignant cells resembling high-grade invasive endometrial carcinoma. EIC has been identified in a high proportion of uteri containing serous carcinoma, but its association with other endometrial tumors is unknown.
To determine the strength and specificity of the association of EIC with tumors displaying serous differentiation, the appearance of the endometrium in 38 uteri with serous carcinoma, 113 with endometrioid carcinoma, and 34 with malignant mixed mesodermal tumor (MMMT) were compared. EIC was present in 34 (98%) uteri with serous carcinoma compared with 7 (6%) uteri removed for endometrioid carcinoma (P = .0001). Hyperplasia without atypia was found in only 2 (5%) of 38 serous carcinomas compared with 38 (34%) of 113 endometrioid carcinomas. Similarly, atypical hyperplasia was not found in any uterus with serous carcinoma, but was present in 14 (12%) uteri with endometrioid carcinoma (P = .02). The endometrium was inactive or atrophic in 29 (76%) patients with serous carcinoma compared with 33 (29%) with endometrioid carcinoma (P = .0001). EIC was found in five (56%) of nine MMMTs with a serous epithelial component (serous-MMMT) compared with one (4%) of 25 MMMTs woth an endometrioid epithelial component (endometrioid-MMMT).
As with endometrioid and serous carcinomas, hyperplasia with and without atypia was more common with endometrioid-MMMTs as compared with serous-MMMTs. Hyperplasia was found in 25 (100%) and atypical hyperplasia in 8 (32%) of 25 endometrioid-MMMTs, but in none of the nine serous-MMMTs. This study shows that EIC is frequently and specifically associated with uterine tumors displaying serous differentiation.
The findings suggest that EIC represents a form of intraepithelial tumor growth characteristic of serous carcinoma and serous MMMT and that EIC is the likely precursor of these neoplasms. In addition, the findings provide further evidence supporting the view that MMMTs represent variants of carcinoma not sarcoma.
CHARACTERIZATION p53 Overexpression in 71% of cases Ki-67 High proliferation rate 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 Prognostic Factors Most important feature which determines prognosis is the presence or absence of extrauterine disease at initial presentation
The surgeon must do a careful staging and the pathologist must do a diligent search for microscopic deposits of disease.
5 Year Survival 36% for all stages Metastasis May extensively involve the lymphatics of the myometrium, cervix, broad ligament, fallopian tube, and ovaries
Extends over the peritoneal surfaces of the pelvis and abdomen
Treatment Surgery with chemotherapy
Uterine papillary serous carcinoma: a study on 108 cases with emphasis on the prognostic significance of associated endometrioid carcinoma, absence of invasion, and concomitant ovarian carcinoma.
Carcangiu ML, Chambers JT.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510.
Gynecol Oncol 1992 Dec;47(3):298-305 Abstract quote
One hundred eight cases of uterine papillary serous carcinoma (UPSC) were analyzed to characterize its histologic features and biologic behavior. Special situations that could conceivably modify the behavior and therapeutic approaches were considered: (1) the occurrence of areas of endometrioid carcinoma in otherwise typical UPSC; (2) the confinement of UPSC to an otherwise benign endometrial polyp or the endometrial mucosa or absence of residual tumor at the time of hysterectomy; and (3) the coexistence of a superficial UPSC and a serous ovarian carcinoma.
There was coexistence of endometrioid and UPSC in 22 cases, and tumor was confined to an endometrial polyp or endometrium in 19 cases. There was simultaneous pathologic stage I UPSC and papillary serous ovarian carcinoma in 10 cases. In patients with pathologic stages I and II UPSC the presence of areas of endometrioid carcinoma intermixed with the UPSC did not improve survival. Patients with stage I disease and no residual tumor or tumor confined to an endometrial polyp/endometrial mucosa and without vascular invasion had a survival not statistically different from those with stage I disease but with myometrial and/or vascular invasion.
Patients with stage I UPSC with concomitant ovarian serous surface papillary carcinoma had survival not statistically different from patients with stage IV UPSC.
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