University of Illinois
at Chicago



BORDERLINE OVARIAN TUMORS: A WEB-BASED ATLAS
NCI Borderline Ovarian Tumor Workshop, Bethesda, MD, August 27-28, 2003


Introduction

It is said that a picture is worth more than a thousand words. Pathologists believe that a picture with a few descriptive words is …priceless. The purpose of this web page is to offer practicing surgical pathologists and pathology residents didactic samples of ovarian borderline tumors of the ovary (also called atypical proliferative tumors or tumors of low malignant potential) and the tumors that enter into their differential diagnosis.

One of the most difficult areas in gynecological pathology is the spectrum of diseases that fall between the categories of clear cut benign epithelial lesion and clear cut invasive carcinomas. Pathologists sometimes disagree on terminology, even on the definition of apparently self-explanatory terms such as "destructive invasion", "severe nuclear atypia" and "microinvasion". For this reason, the National Institutes of Health convened pathologists, clinical and surgical oncologists, epidemiologists and basic scientists interested in this field for the Borderline Ovarian Tumor Workshop that was held in Bethesda, MD on August 27 and 28, 2003. The major topics of discussion are summarized in a collection of articles published in the August, 2004 issue of Human Pathology. This web page was designed with the intent of supplementing the didactic value of these papers, especially the article by J. D. Seidman et al. entitled "Ovarian borderline tumors: Diverse contemporary viewpoints on terminology and diagnostic criteria with illustrative images". - André Kajdacsy-Balla, MD, PhD


Contributors

Contributors to this atlas (in alphabetical order) are:

Jules J. Berman, Ph.D., M.D., National Cancer Institute, Division of Cancer Treatment and Diagnosis, Bethesda, MD
André Kajdacsy-Balla, M.D., Ph.D., Department of Pathology, University of Illinois, Chicago, IL
Esther Oliva, M.D., Department of Pathology, Massachusetts General Hospital, Boston, MA
Brigitte Ronnett, M.D., The Johns Hopkins University School of Medicine, Baltimore, MD
Jeffrey D. Seidman, M.D., Department of Pathology, Washington Hospital Center, Washington, DC
Robert A. Soslow, M.D, Memorial Sloan Kettering Cancer Center, New York, NY
Russell Vang, M.D., Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD


Acknowledgements

The contributors thank Andrea Ariesa R. Samaniego, Program Coordinator, Department of Pathology, University of Illinois, Chicago, IL for the web page design and implementation.

The Borderline Ovarian Tumor Worskhop was sponsored by the NIH Office of Rare Diseases and the NCI Office of Women's Health.



Serous Borderline Tumor: Figures 1-6
Figure 1 depicts a serous borderline tumor composed of large and small papillae with minimal epithelial stratification. These features distinguish serous borderline tumor from serous cystadenofibroma. Figures 2-4 show more extensive tufting and evident hierarchical branching. Glands containing papillae embedded in stroma in Figure 3 are characteristic of serous borderline tumor. The cytologic features of serous borderline tumor are low grade (Figures 5 and 6). Submitted by Robert A. Soslow, MD
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Serous Borderline Tumor with Micropapillary Features (MSBT): Figures 7-11
Serous borderline tumors containing micropapillary growth in an area measuring greater than 5mm are classified as MSBT. Note the contrast between serous borderline tumor at the top of Figure 7 and extensive micropapillary growth at the bottom. More proliferative examples, Figures 8-9, show long, slender micropapillae surrounding large fibrovascular cores without hierarchical branching. Figure 10 shows both micropapillary and cribriform growth patterns. The cytologic grade of MSBTs should not exceed grade 2 of 3; Figure 11 illustrates a MSBT with cytologic atypia at the high end of the spectrum permitted for this diagnosis. Submitted by Robert A. Soslow, MD

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Seromucinous Borderline Tumor: Figures 12-15
The low power appearance resembles serous borderline tumor or MSBT (Figures 12-13). High power examination reveals columnar cells with apical mucin, endocervical-type cells, and cuboidal cells with dense cytoplasm (Figures 14-15). Note associated neutrophils. Submitted by Robert A. Soslow, MD
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Lymph Node Involvement: Figures 16-19
Benign Mullerian serous inclusions (endosalpingiosis) are shown in Figure 16. Figure 17 contrasts serous borderline tumor (upper right) with endosalpingiosis (lower left). Endocervicosis, benign Mullerian endocervical-type inclusions, is depicted in Figure 18. Mesothelial cells in subcapsular sinuses, illustrated in Figure 19, can cause diagnostic confusion with serous borderline tumor and metastatic carcinoma. Submitted by Robert A. Soslow, MD

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Microinvasion: Figures 20-23
The most commonly encountered type of microinvasion is seen in Figures 20-23: isolated cells or small groups of cells, in stroma, with surrounding retraction spaces. Some investigators classify proliferations resembling low grade serous carcinomas, when minute, as microinvasion (Figure 23), but others use the terminology "microinvasive carcinoma". Submitted by Robert A. Soslow, MD
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Mimics of serous borderline tumor: Figures 24-27
High grade serous carcinomas may, on occasion, grow in a non-invasive pattern and therefore mimic serous borderline tumor at low power (Figure 24). Severe cytologic atypia (grade 3 of 3) is shown at high power in Figure 25. This is incompatible with a diagnosis of serous borderline tumor. Figures 26 and 27, both micropapillary tumors, show nuclear atypia that exceeds what many pathologists would accept in a borderline tumor. Submitted by Robert A. Soslow, MD
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Mucinous Borderline Tumor (GI Type), including Intraepithelial Carcinoma and Microinvasion: Figures 1-3

Figure 1. Borderline/ atypical proliferative/ low malignant potential mucinous tumor, gastrointestinal type. Cystic component with stratified epithelium: low-power magnification of one case (1A) and intermediate-power magnification of another case (1B). High-power magnification of Fig. 1A (1C) showing cystic component lined by columnar cells with mucinous cytoplasm and low nuclear-to-cytoplasmic ratio. The nuclei are round to oval, basally situated, and feature only mild atypia. Submitted by Russell Vang, MD

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Figure 2.
Borderline/ atypical proliferative/ low malignant potential mucinous tumor, gastrointestinal type with intraepithelial carcinoma (2A; high-power magnification): The columnar cells show an increased nuclear-to-cytoplasmic ratio with some degree of loss of cytoplasmic mucin. The nuclei are enlarged, round to oval, and show variation in size and shape. The nuclei contain prominent nucleoli and irregularly distributed chromatin. Severe nuclear atypia, shown here, is the criterion recommended by the workshop for a diagnosis of intraepithelial carcinoma, regardless of architecture. The problematic lesion in Fig. 2B (low-power magnification) is from another case and is subject to more than one interpretation. It shows a complex intracystic proliferation with labyrinthine epithelium that might be considered as intraepithelial carcinoma by some gynecologic pathologists; however, architectural complexity would not be considered by the workshop as sufficient for a diagnosis of intraepithelial carcinoma if the nuclear atypia is not severe (high-power magnification not shown). On the other hand, lesions within stroma (rather than intracystic) and having this degree of complexity may represent the confluent/expansile type of invasive mucinous carcinoma if the size measures greater than that allowed for microinvasion. Submitted by Russell Vang, MD

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Figure 3.
Borderline/ atypical proliferative/ low malignant potential mucinous tumor, gastrointestinal type with microinvasion. Intermediate-power magnification (3A): The microinvasive area illustrated here shows complex anastamosing epithelium, irregular nests with a haphazard arrangement within stroma and focal cleft-like spaces around nests, and an associated stromal reaction. Other areas of the tumor showed classic features of mucinous borderline tumor, gastrointestinal-type (not shown). 3B: High-power magnification of a different case showing nests surrounded by clear spaces. The cells have atypical nuclei and abundant, partially mucinous cytoplasm. Submitted by Russell Vang, MD

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Figures 1 and 2: Borderline/atypical proliferative/low malignant potential mucinous tumor, gastrointestinal type. Mucinous epithelium exhibits tufts and intraglandular papillary growth without stromal invasion (1) and displays mild nuclear atypia with goblet cells in the differentiated portions of the epithelial tufts (2). Submitted by Brigitte Ronnett, MD
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Figure 3: Borderline/atypical proliferative/low malignant potential mucinous tumor with intraepithelial carcinoma. Mucinous epithelium exhibits stratification and detached papillae without invasion of the underlying ovarian stroma. Submitted by Brigitte Ronnett, MD
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Figure 4: Borderline/atypical proliferative/low malignant potential mucinous tumor with intraepithelial carcinoma. Higher magnification of the tumor in Figure 3 demonstrates marked nuclear atypia. Submitted by Brigitte Ronnett, MD
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Figure 5: Borderline/atypical proliferative/low malignant potential mucinous tumor. There is a complex intraglandular pattern which is a combination of focal papillary and cribriform-like growth and tangential sectioning. This pattern does not qualify for intraepithelial carcinoma by any of the proposed criteria because there is insufficient nuclear atypia or true cribriform growth. Submitted by Brigitte Ronnett, MD
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Figure 6: Borderline/atypical proliferative/low malignant potential mucinous tumor with microinvasion. Small clusters of mildly atypical cells are present within spaces in the underlying stroma in an area measuring less than 3 mm in greatest dimension. Submitted by Brigitte Ronnett, MD
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Figure 7: Borderline/atypical proliferative/low malignant potential mucinous tumor with microinvasion. Two small glands composed of cells with mildly atypical nuclei and surrounded by spaces are present within reactive stroma adjacent to the borderline tumor component which exhibits intraglandular papillary growth. Submitted by Brigitte Ronnett, MD
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Figure 8: Borderline/atypical proliferative/low malignant potential mucinous tumor with microinvasion. A small focus of infiltrative glands with moderate to marked nuclear atypia is present within the stroma underlying a cystic gland. The remainder of the tumor (not illustrated) was a borderline tumor with intraepithelial carcinoma. Microinvasive tumor with this higher-grade appearance might be considered microinvasive carcinoma by some pathologists. Submitted by Brigitte Ronnett, MD
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Figure 9: Well differentiated mucinous carcinoma, confluent glandular/expansile type. Atypical mucinous glands are arranged back-to-back, with little or no intervening stroma. Submitted by Brigitte Ronnett, MD
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Figure 10: Ovarian mucinous tumor associated with pseudomyxoma peritonei. The tumor simulates a borderline ovarian mucinous tumor. A low-grade appendiceal mucinous tumor was present and both tumors were cytokeratin 7-negative and cytokeratin 20-positive, consistent with secondary involvement of the ovary by the appendiceal tumor (stains not illustrated). Submitted by Brigitte Ronnett, MD
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Figures 11 and 12: Metastatic colonic adenocarcinoma with a deceptive pattern of invasion. This tumor is composed of variably sized cysts, without destructive stromal invasion (11), lined by mucinous epithelium with marked nuclear atypia (12). It simulates a borderline ovarian mucinous tumor with intraepithelial carcinoma. This tumor was diffusely positive for cytokeratin 20 and negative for cytokeratin 7, consistent with a colonic carcinoma (stains not illustrated). Submitted by Brigitte Ronnett, MD

 
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Figure 1. Noninvasive desmoplastic implant.Glands are embedded in a granulation tissue-type stroma. There are a few single cells with abundant eosinophilic cytoplasm isolated in the stroma. Submitted by Jeffrey Seidman, MD

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Figure 2.Noninvasive desmoplastic implant. Glands are branching but have smooth contours. The granulation tissue-type stroma overshadows the epithelial component. Submitted by Jeffrey Seidman, MD
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Figure 3. Noninvasive desmoplastic implant. High magnification shows that the epithelium has hobnail features. The stroma is loose and edematous. Submitted by Jeffrey Seidman, MD
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Figure 4. Invasive implant. The glands have an infiltrative pattern. There is only mild cytological atypia. The stroma is fibrotic and dense. Submitted by Jeffrey Seidman, MD
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Figure 5. Invasive implant. Glands and solid epithelial nests with moderate to severe nuclear atypia are surrounded by a space. Psammoma bodies are present. Submitted by Jeffrey Seidman, MD
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Figure 6. Invasive implant. Infiltrative pattern of small interanastomosing glands with angulated contours. Submitted by Jeffrey Seidman, MD
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Figure 7. Invasive implant. An infiltrative pattern of solid nests each surrounded by a space. Submitted by Jeffrey Seidman, MD
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Figure 8. Invasive implant. This low magnification view shows a subtle pattern of invasion of large glands containing smaller papillary proliferations. A higher power view of one of the glands or a small biopsy showing smaller numbers of these glands would not have diagnostic features of invasion. Submitted by Jeffrey Seidman, MD
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Figure 9. Endosalpingiosis. Glands lined by tubal type epithelium without significant atypia. There are blunt simple papillae but no significant epithelial stratification and no detachment of cell clusters. Submitted by Jeffrey Seidman, MD
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Figure 10. Noninvasive epithelial implant. A papillary proliferation of serous type epithelium on the peritoneal surface. Submitted by Jeffrey Seidman, MD
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Figure 11. Noninvasive epithelial implant. Low magnification. A papillary proliferation of serous type epithelium with psammomatous calcification lies on the peritoneal surface without invasion of underlying tissue. Submitted by Jeffrey Seidman, MD
 
Invasive Implants
Destruction and replacement of the preexistent lobular architecture of the adipose tissue by fibroblastic and/ or desmoplastic stroma and chronic inflammation associated with irregular nests of serous epithelium. The epithelial proliferation is seen as irregular glands, papillary formations or single cells (Figures 1-6) which frequently show nuclear features of malignancy (high nuclear/cytoplasmic ratio, nuclear hyperchromatism, and prominent nucleoli) (Figure 7). Submitted by Esther Oliva, MD
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Non-invasive Implants, Desmoplastic Type
Implants lie on peritoneal surfaces without evidence of infiltration of the underlying tissue, making it possible to draw a line to separate implant tissue from preexistent tissue (Figures 2, 3 and 6). The implants show a prevalence of stroma vs epithelium (Figures 2 and 5). The appearance of the stroma is desmoplastic, fibroblastic or granulation tissue-like, and it is typically associated with inflammatory cells and recent hemorrhage (Figures 1 and 5). The epithelial component appears as irregular glands, papillae or single cells (Figures 1 and 5) and the cytologic features of the epithelial nests are not overtly malignant (Figure 4). Submitted by Esther Oliva, MD
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Non-invasive, Epithelial Implants
Well-defined, frequently rounded proliferations of free floating nests and/or papillary structures that are surrounded by reactive mesothelium (Figures 1-5). There is only mild to moderate cytologic atypia consistent with that seen in a borderline tumor (Figures 2,3 and 5 ). Notice that there is no destruction of the underlying tissue or associated stromal proliferation.
Submitted by Esther Oliva, MD
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Disclaimer: This selection of images is brought to you for educational purposes only. The views are those of the contributors and do not reflect endorsement by the NIH or the University of Illinois at Chicago. This web page contains statements related to rendered diagnostic opinions. In view of the wide range of opinions regarding the tumors under discussion, none of these statements is intended as, or should be interpreted as representing the "standard of care."

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