PLAG1-Rearranged Uterine Sarcomas: A Study of 11 Cases Showing a Wide Phenotypical Spectrum Not Limited to Myxoid Leiomyosarcoma-like Morphology.

PLAG1 gene fusions were recently identified in a subset of uterine myxoid leiomyosarcomas (M-LMS). However, we have encountered cases of PLAG1-rearranged uterine sarcomas (PLAG1-US) lacking M-LMS-like morphology and/or any expression of smooth muscle markers. To better characterize their clinicopathological features, we performed a multi-institutional search which yielded 11 cases. The patients ranged in age from 34-72 years (mean: 57). All tumors arose in the uterine corpus, ranging in size from 6.5-32 cm (mean: 15). The most common stage at presentation was pT1b (n=6), three cases had stage pT1 (unspecified) and one case each presented in stage pT2a and pT3b. Most were treated only by hysterectomy with adnexectomy. The follow-up (range: 7-71 months; median: 39 months) was available for 7 patients. Three cases (7-21 months of follow-up) had no evidence of disease. Three out of 4 remaining patients died of disease within 55-71 months, while the last developed peritoneal spread and was transferred for palliative care at 39 months. Morphologically, the tumors showed a high inter- and intratumoral heterogeneity. M-LMS-like and epithelioid LMS-like morphology was present in 3 and 5 primary tumors, respectively, the rest mostly presented as non-descript ovoid/spindle cell sarcomas. Unusual morphological findings included prominently hyalinized stroma (n=3), adipocytic differentiation with areas mimicking myxoid liposarcoma (n=2), osteosarcomatous differentiation (n=1) and undifferentiated pleomorphic sarcoma-like areas (n=1). The mitotic activity ranged from 3-24 mitoses/10 high-power fields (mean: 9), 3/10 cases showed necrosis. In 3/11 cases, no expression of SMA, h-caldesmon or desmin was noted, whereas 5/5 cases expressed PLAG1. By RNA-sequencing, the following fusion partners were identified: PUM1, CHCHD7 (each n=2), C15orf29, CD44, MYOCD, FRMD6, PTK2 and TRPS1 (each n=1). One case only showed PLAG1 gene break by FISH. Our study documents a much broader morphological spectrum of PLAG1-US than previously reported, encompassing but not limited to M-LMS-like morphology with occasional heterologous (particularly adipocytic) differentiation. Since it is currently difficult to precisely define their line of differentiation, for the time being, we suggest using a descriptive name PLAG1-rearranged uterine sarcoma.

Mutational Profile in Vulvar, Vaginal, and Urethral Melanomas: Review of 37 Cases With Focus on Primary Tumor Site.

Melanomas of female genital tract are rare tumors with poor prognosis. While BRAF-V600E is the most common pathogenic mutation seen in cutaneous sun-exposed melanomas, mucosal and anogenital melanomas usually lack BRAF mutations and instead they harbor KIT alterations. The American Joint Committee on Cancer staging guideline (AJCC eighth edition) recommends using cutaneous melanoma guidelines for vulvar melanoma staging and does not provide any recommendations for vaginal melanoma staging. The aim of this study is to investigate the mutational status of invasive melanomas arising from different anatomic sites in lower female genital tract (vulvar hair-bearing skin, glabrous skin, vagina and urethra) in a group of 37 patients. Tumors were analyzed using a DNA targeted next-generation sequencing panel covering the 21 most common genes and mutation hotspots in melanomas. The most common genetic alterations in invasive melanomas of lower female genital tract are KIT (32%), TP53 (22%), and NF1 (19%). Overall 66% (21/32) of cases showed a pathogenic alteration in at least one of the MAPK pathway genes. No statistical significance seen between different primary tumor sites and the frequency of the oncogenic mutations, nor were any significant differences found by mutation status. Only one case of urethral melanoma showed a BRAF non-V600E mutation (D594G). Our results suggest a similar molecular pathogenesis and overall survival in melanomas arising from lower female genital tract, irrespective of their exact location in the urogenital area. Future classifications of melanoma should consider grouping vulvar melanomas with mucosal rather than cutaneous melanomas.

A data science approach for the classification of low-grade and high-grade ovarian serous carcinomas.

BACKGROUND: Copy Number Alternations (CNAs) is defined as somatic gain or loss of DNA regions. The profiles of CNAs may provide a fingerprint specific to a tumor type or tumor grade. Low-coverage sequencing for reporting CNAs has recently gained interest since successfully translated into clinical applications. Ovarian serous carcinomas can be classified into two largely mutually exclusive grades, low grade and high grade, based on their histologic features. The grade classification based on the genomics may provide valuable clue on how to best manage these patients in clinic. Based on the study of ovarian serous carcinomas, we explore the methodology of combining CNAs reporting from low-coverage sequencing with machine learning techniques to stratify tumor biospecimens of different grades. RESULTS: We have developed a data-driven methodology for tumor classification using the profiles of CNAs reported by low-coverage sequencing. The proposed method called Bag-of-Segments is used to summarize fixed-length CNA features predictive of tumor grades. These features are further processed by machine learning techniques to obtain classification models. High accuracy is obtained for classifying ovarian serous carcinoma into high and low grades based on leave-one-out cross-validation experiments. The models that are weakly influenced by the sequence coverage and the purity of the sample can also be built, which would be of higher relevance for clinical applications. The patterns captured by Bag-of-Segments features correlate with current clinical knowledge: low grade ovarian tumors being related to aneuploidy events associated to mitotic errors while high grade ovarian tumors are induced by DNA repair gene malfunction. CONCLUSIONS: The proposed data-driven method obtains high accuracy with various parametrizations for the ovarian serous carcinoma study, indicating that it has good generalization potential towards other CNA classification problems. This method could be applied to the more difficult task of classifying ovarian serous carcinomas with ambiguous histology or in those with low grade tumor co-existing with high grade tumor. The closer genomic relationship of these tumor samples to low or high grade may provide important clinical value.

TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.

To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC.

Low-grade serous tumors of ovary.

The creation of the category of borderline/atypical proliferative tumors in the World Health Organization Classification of Ovarian Tumors in 1973 prompted extensive investigation of the clinicopathologic and genetic features of low-grade serous ovarian tumors (borderline tumors/atypical proliferative tumors, noninvasive micropapillary tumors, and invasive low-grade serous carcinomas). The clinicopathologic studies of these tumors resulted in clarification of the prognostic significance of several histologic features of the ovarian tumors and their associated peritoneal lesions. The genetic studies resulted in a reassessment of the relationship between low-grade and high-grade serous carcinoma and their differing pathways of origin. This review focuses on several of the morphologic findings, their diagnostic criteria, differential diagnosis and biologic significance, and discusses the dualistic classification of serous carcinomas into high-grade and low-grade tumors.

Democratizing Artificial Intelligence in Anatomic Pathology.

CONTEXT.­: Artificial intelligence is a transforming technology for anatomic pathology. Involvement within the workforce will foster support for algorithm development and implementation. OBJECTIVE.­: To develop a supportive ecosystem that enables pathologists with variable expertise in artificial intelligence to create algorithms in a development environment with seamless transition to a production environment. RESULTS.­: The development team considered internal development and vended solutions. Because of the extended timeline and resource requirements for internal development, a decision was made to use a vended solution. Vendor proposals were solicited and reviewed by pathologists, IT, and security groups. A vendor was selected and pipelines for development and production were established. Proposals for development were solicited from the pathology department. Eighty-four investigators were selected for the initial cohort, receiving training and access to dedicated subject matter experts. A total of 30 of 31 projects progressed through the model development process of annotating, training, and validation. Based on these projects, 15 abstracts were submitted to national meetings. CONCLUSIONS.­: Democratizing artificial intelligence by creating an ecosystem to support pathologists with varying levels of expertise can break down entry barriers, reduce overall cost of algorithm development, improve algorithm quality, and enhance the speed of adoption.

Phenotypic Profiling and Molecular Mechanisms in Hyperparathyroidism-jaw Tumor Syndrome.

CONTEXT: Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease. OBJECTIVE: (1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss. DESIGN: Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73). RESULTS: We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion. CONCLUSIONS: Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors. CLINICAL TRIAL NUMBER: NCT04969926.

HMGA1 and HMGA2 rearrangements in mass-forming endometriosis.

Endometriosis is a common gynecologic disorder characterized by ectopic endometrium associated with pelvic pain and infertility. The pathogenesis of endometriosis is unclear, and several genetic, endocrine, immune, and environmental agents have been studied as putative causative factors. However, consistent somatic genetic alterations have not been identified. Rarely, endometriosis presents as a mass lesion with an infiltrative pattern reminiscent of malignancy. We describe cytogenetic and molecular cytogenetic findings of mass-forming endometriosis. The index case of pulmonary endometriosis underwent conventional and molecular cytogenetics analysis. In addition, 16 cases of mass-forming endometriosis, 11 cases of usual endometriosis, and six endometriomas were investigated by fluorescence in situ hybridization (FISH) for HMGA1 and HMGA2 loci, performed on paraffin-embedded thin tissue sections with custom-designed probes. The index patient had an endometriotic lung nodule, with a 46,XX, t(5;6)(q13;p21) karyotype and HMGA1 rearrangement by FISH. A second patient had decidualized endometriosis forming a large abdominal mass and HMGA1 rearrangement by FISH. Of the 15 other cases of mass-forming endometriosis, one had HMGA1 rearrangement and two had HMGA2 rearrangement. The rearrangements were found in the stromal component exclusively. None of the usual endometriosis cases or endometriomas had HMGA1 or HMGA2 rearrangements. In conclusion, mass-forming endometriosis is an uncommon subset of endometriosis that harbors HMGA1 or HMGA2 rearrangements in up to 29% of cases. The present findings support the concept that endometriosis is clonal and that rearrangement of HMGA genes likely contributes to its pathogenesis.

Clinicopathologic, Immunohistochemical, and Molecular Characteristics of Ovarian Serous Carcinoma With Mixed Morphologic Features of High-grade and Low-grade Serous Carcinoma.

Despite the current classification of high-grade serous carcinoma (HGSCA) and low-grade serous carcinoma (LGSCA) as mutually exclusive diseases based on morphology and molecular pathogenesis, cases with mixed morphologic features of HGSCA and LGSCA have been reported. Herein we assess the clinicopathologic, immunohistochemical (IHC), and molecular genetic characteristics of a group of these cases, which we termed indeterminate grade serous carcinoma (IGSCA) in comparison with groups of HGSCA and LGSCA. Using the World Health Organization (WHO) classification criteria, we selected 27 LGSCA and 19 IGSCA for detailed morphologic study. Thirteen classic HGSCA, 19 classic LGSCA, and 19 IGSCA were selected for p53 and BRAF V600E IHC and molecular genetic testing by next-generation sequencing. IGSCA showed the architectural patterns of invasion of LGSCA, but with higher grade nuclear features focally and a mitotic index intermediate between LGSCA and HGSCA. Few cases in the IGSCA group showed mutant TP53 by IHC or sequencing (4/18, 22.2%), 1 case had mutant BRAF non-V600E by sequencing, and 1 had an NRAS mutation. When present, the mutations were identical in the low-grade and high-grade areas. The IGSCA group had a long-term survival similar to the classic HGSCA group. IGSCA with mixed morphologic features of HGSCA and LGSCA is a rare and potentially clinically aggressive variant of serous carcinoma. Their distinct morphologic, but heterogenous molecular features, including low frequency of TP53 and BRAF mutations suggest that these rare tumors may have a different pathogenesis pathway compared with classic HGSCA and classic LGSCA.

Analysis of gene expression in stage I serous tumors identifies critical pathways altered in ovarian cancer.

OBJECTIVE: Despite recent advances in the conceptual understanding of the pathogenesis of ovarian cancer, it remains the foremost cause of death from gynecologic malignancies in developed countries. The main reason for such a high rate of mortality is the lack of sensitive and specific biomarkers and imaging techniques for early detection of ovarian cancer. Additional biological insights into early-stage ovarian carcinogenesis are needed to help speed the development of markers for early detection of ovarian cancer. The objective of this study was to characterize differentially expressed genes in high-grade stage I serous carcinoma of the ovary. METHODS: We analyzed gene expression in macrodissected formalin-fixed, paraffin-embedded samples from 5 high-grade stage I serous carcinomas and 5 stage I borderline tumors of the ovary using the Illumina Whole Genome DASL assay (cDNA-mediated annealing, selection, extension, and ligation) corresponding to 24,000 genes. Significance Analysis of Microarrays was performed to determine differentially expressed genes in stage I serous carcinoma, and class prediction analysis was performed to determine the predictive value of differentially expressed gene sets to correctly classify serous carcinoma from borderline tumors in 3 independent data sets. Altered transcription factor pathways and biological pathways unique to stage I serous carcinoma were identified through class comparison of differentially expressed genes. RESULTS: Unsupervised cluster analysis of gene expression correctly classified stage I serous carcinomas from serous borderline tumors. Supervised analysis identified several known, as well as novel, genes differentially expressed in stage I ovarian cancer. Using a differentially expressed gene set, class comparison prediction analysis correctly identified serous carcinomas from serous borderline tumors in 3 independent data sets at over 80% accuracy, sensitivity, and specificity. Pathway analysis demonstrated the significance of p53 and E2F pathways in serous carcinogenesis and significant involvements of cell cycle and immune response pathways in stage I serous epithelial ovarian cancer. CONCLUSION: We have identified differentially expressed genes associated with the carcinogenesis of high-grade stage I serous EOC. Furthermore, integrative analysis of biological and transcription pathway data contributed to the confirmation of important biological pathways and discovery of additional unique genes and pathways that may have potential importance in ovarian pathogenesis and biomarker development.

Ciliated adenocarcinoma of the ovary with evidence of serous differentiation: report of a case.

A patient with bilateral ovarian adenocarcinomas composed predominantly of ciliated cells incidentally found at autopsy is reported. Although obviously malignant, a majority of the cells expressed well-differentiated cilia with terminal bar formation. In one of the masses, the neoplastic cells seemed to arise from a serous adenofibroma. The tumor was confined to the ovaries without evidence of metastatic spread. Although morphologically resembling an endometrioid-type neoplasm, immunohistochemical and molecular studies were more consistent with a serous phenotype, especially in light of its apparent origination from a serous adenofibroma. We agree with previous observations suggesting that although the neoplasm seems morphologically worrisome, it may actually portend a more benign clinical course.

Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes.

PURPOSE: Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort. EXPERIMENTAL DESIGN: Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n = 50), copy-number variation (CNV, n = 40), cell morphometry (n = 39), and protein expression (n = 22). Gene ontology and network enrichment analysis were used to relate over- and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings. RESULTS: Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multivariable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm2 could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup. CONCLUSIONS: Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.

Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer.

PURPOSE: One of the major obstacles in the treatment of ovarian cancer is the development of multidrug resistance. Recent evidence shows that high-grade ovarian cancer often shows activation of the signal transducers and activators of transcription 3 (Stat3) pathway with subsequent transcription of genes that support tumor growth and survival. Less studied is the role of the Stat3 pathway in acquired drug resistance. There is no information on Stat3 expression in chemotherapy naïve ovarian cancer as compared with tumors collected later in the natural history of the disease. To further clarify the significance of Stat3 activation in ovarian cancer, here we investigated the Stat3 expression and activation in ovarian cancer and ovarian cancer multidrug resistance cell lines. EXPERIMENTAL DESIGN: Western blotting, electrophoretic mobility shift assay, luciferase assays, ELISA assay, and real-time reverse transcription-PCR determined interleukin-6 and Stat3 pathway expression and activation in cell lines. Stat3 expression in ovarian cancer tissue microarray was evaluated by immunohistochemistry. RESULTS: Activated (phosphorylated) Stat3 is overexpressed in most paclitaxel-resistant ovarian cancer cells. Inhibition of Stat3 activation results in significant decreases in paclitaxel resistance and enhanced apoptosis. Drug-resistant recurrent tumors have significantly greater phosphorylated Stat3 (pStat3) expression as compared with matched primary tumors. Tumors with associated inflammatory cell infiltrates also have a higher proportion of cells staining intensely for nuclear phosphorylated Stat3 as compared with tumors without inflammatory infiltrates, consistent with paracrine activation of the Stat3 pathway by immune-mediated cytokines. CONCLUSIONS: These data support the hypothesis that interruption of Stat3 signaling could reverse resistance to paclitaxel and perhaps other chemotherapy agents in human cancer.

Autoimplants in serous borderline tumors of the ovary: a clinicopathologic study of 30 cases of a process to be distinguished from serous adenocarcinoma.

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.

Whole-genome allelotyping identified distinct loss-of-heterozygosity patterns in mucinous ovarian and appendiceal carcinomas.

PURPOSE: Mucinous adenocarcinoma of the ovary is one of the common histologic types of ovarian cancer. Its pathogenesis is largely unknown. In addition, the differential diagnosis of metastatic mucinous carcinomas to the ovaries, particularly those originating from the appendix, remains challenging. The purpose of this study is to identify molecular biomarkers for mucinous ovarian adenocarcinoma and compare them with those of appendiceal origin. EXPERIMENTAL DESIGN: Genome-wide loss-of-heterozygosity (LOH) analysis was done on DNA isolated from 28 microdissected primary mucinous ovarian carcinomas and five appendiceal adenocarcinomas. Markers from high-loss regions were selected for further analysis on a total of 32 ovarian and 14 appendiceal cancers. RESULTS: High levels of LOH rates (>40%) were detected on chromosome arms 9p, 17p, and 21q in mucinous ovarian carcinoma cases. The frequency of allelic loss was similar between high-grade and low-grade mucinous ovarian carcinoma cases but was significantly higher in ovarian versus appendiceal cases. In addition, LOH rates on five chromosomal loci were statistically different between ovarian and appendiceal carcinomas. CONCLUSION: A high frequency of LOH can be found in mucinous ovarian adenocarcinomas independent of grade. Despite histologic similarities between mucinous ovarian carcinomas and metastatic appendiceal carcinomas, they have distinct LOH profiles, which may be used for distinguishing the two diseases.

Fine needle aspiration cytology of cervical lymph node involvement by ovarian serous borderline tumor.

Serous borderline tumor (SBT) involving a cervical lymph node is extremely rare. In addition, fine needle aspiration (FNA) cytology of the involved cervical lymph node shares tremendous morphologic similarity with other low-grade papillary carcinomas. Thus, it can be easily misdiagnosed as metastatic carcinoma. A 42-year-old female had a history of bilateral SBT and postbilateral salpingo-oophorectomy. She presented with left cervical lymphadenopathy 6 months later. FNA cytology showed a low-grade papillary neoplasm with psammoma bodies. Needle core biopsy along with immunostains was diagnostic of cervical lymph node involvement (LNI) of SBT. although extremely rare, cervical LNI can be found in patients with SBTs. FNA cytology, sometimes, is indistinguishable from metastatic papillary adenocarcinoma. Cell block or needle core biopsy is essential to make the correct diagnosis.

Current issues in the pathology of ovarian cancer.

The majority of primary ovarian tumors are histologically classified as surface epithelial-stromal neoplasms. The malignant potential of such neoplasms may be categorized, on the basis of the extent of epithelial proliferation and stromal invasion, as benign, borderline or malignant. Recent efforts to further classify the malignant potential of such neoplasms have produced a new system for the histologic grading of ovarian carcinoma as well as new potential histologic predictors of behavior, including micropapillary morphology and stromal microinvasion in serous tumors. Among mucinous ovarian neoplasms, new criteria have been proposed to distinguish primary ovarian from metastatic carcinomas; the distinction may be difficult but has great clinical significance. The origin of ovarian mucinous tumors associated with pseudomyxoma peritonei has been reassessed. Finally, recent pathologic findings from prophylactic salpingo-oophorectomy specimens in patients with hereditary risks for ovarian carcinoma have highlighted the additional risk for fallopian tube carcinoma and primary peritoneal carcinoma. Special processing of the pathologic specimens is required to detect early and minimal neoplasia in this setting. These current issues in the pathology of ovarian carcinoma and their clinical significance form the basis of this review.

Serous borderline (low malignant potential, atypical proliferative) ovarian tumors: workshop perspectives.

Although the category of serous borderline ovarian tumor (S-BOT) was established more than 30 years ago, the nomenclature and prognostic significance of various histological features of these neoplasms continues to engender controversy. The Borderline Ovarian Tumor Workshop was held in Bethesda, MD, in August 2003 in an attempt to examine the existing data, establish areas of agreement, and identify areas needing further investigation. This report addresses 6 areas of controversy regarding S-BOT: (1) tumors with and without a micropapillary architecture (typical vs micropapillary type), (2) peritoneal implants, (3) stromal microinvasion, (4) ovarian surface involvement, (5) lymph node involvement, and (6) recurrent tumors. Each of these issues is addressed by summarizing the data in the literature on which the discussions were based, areas of agreement that emerged, divergent opinions and the reasoning behind them, and the conclusions of the participants with recommended nomenclature.

Borderline ovarian tumors: key points and workshop summary.

This article documents major points of agreement and disagreement among experts invited to participate in a Borderline Ovarian Tumor Workshop held in Bethesda, MD, on August 27-28, 2003. It is suggested that controversies related to the diagnosis and management of these tumors are often related to lack of data in the literature (small numbers of cases, unreported or unclear criteria for diagnosis and follow-up, insufficient length of follow-up, etc), and specific recommendations are made for further investigation and for reporting of data in future studies.