SOX6 Expression Is Sensitive for Peritoneal Epithelioid Malignant Mesothelioma, But Not Specific in the Differential Diagnosis With Tubo-ovarian Serous Neoplasia.

Primary peritoneal malignant mesothelioma (MM) can demonstrate morphologic overlap with low-grade and high-grade tubo-ovarian serous neoplasms; it is also biologically and prognostically distinct from benign mesothelial proliferations. Currently, there is no single biomarker that can definitively distinguish these neoplasms. Sex-determining region Y box 6 (SOX6) immunohistochemistry has been recently described to differentiate pleural epithelioid MM from lung adenocarcinoma, but it has not been evaluated in the peritoneum. SOX6 immunohistochemistry was performed on 43 peritoneal epithelioid MM, 7 peritoneal biphasic MM, 5 well-differentiated papillary mesotheliomas, 5 serous borderline tumors, 29 low-grade serous carcinomas (LGSCs), 20 high-grade serous carcinomas (HGSCs), and 25 cases of peritoneal reactive mesothelial hyperplasia. Quantitative SOX6 expression in epithelioid MM (median, 100% of tumor cells) was significantly greater than in LGSC/serous borderline tumor (median, 90%; P=0.004) and HGSC (median, 45%; P=0.0001). However, when SOX6 is expression is defined as ≥10% of tumor cells, there was no significant difference in the rate of SOX6 positivity between epithelioid MM (41/43, 95%), LGSC (28/29, 97%; P=1.0), and HGSC (17/20, 85%; P=0.16). Quantitative extent of SOX6 expression in epithelioid MM was significantly greater than in biphasic MM (median, 0%; P=0.0001), well-differentiated papillary mesothelioma (median, 20%; P=0.001), and reactive mesothelial hyperplasia (median, 20%; P=0.0001), but not significantly different from flat quiescent mesothelium (median, 90%; P=0.82). SOX6 immunohistochemistry is 95% sensitive for peritoneal epithelioid MM, but is also consistently expressed in LGSC and HGSC, negating its usefulness in this common differential diagnosis. SOX6 also shows variable expression across the spectrum of reactive, benign neoplastic, and malignant mesothelial lesions of the peritoneum, and does not appear to be diagnostically useful in distinguishing benign from malignant mesothelial proliferations.

Classification of serous ovarian carcinoma based on immunogenomic profiling.

Treatment of serous ovarian cancer (SOC) remains a clinical challenge. Classification of SOC based on immunogenomic profiling is important for establishing immunotherapy strategies. We extracted RNA-seq data of SOC from TCGA-OV. The samples were ultimately classified into high immune (Immunity_H) group and low immune (Immunity_L) group based on the immunogenomic profiling of 29 immune signatures by using unsupervised machine learning methods and modified by multifaceted characterization of immune response. High immune group showed the lower tumor purity and higher anti-tumor immune activity, and the higher expressions of PDCD1, CD274 and CTLA4. Furthermore, the overall survival time and the progression-free interval were significantly longer in high-immun group. The differentially expressed genes were mainly enriched in some immune response related functional terms and PI3K-AKT signaling pathway. According to ImmuCellAI, the abundance of various T cell subtypes in high immune group were significantly higher than those in low immune group. This novel immunotyping shows promise for prognostic and immunotherapeutic stratification in SOC patients.

Nomenclature of appendiceal mucinous lesions according to the 2019 WHO Classification of Tumors of the Digestive System.

BACKGROUND/AIMS: To analysis the appendiceal mucinous lesions according to the World Health Organization (WHO) 2019 classification of tumors of the digestive system (non-neuroendocrine tumors of the appendix vermiformis) MATERIALS AND METHODS: Clinical and histopathological data of 37 patients with histopathologically proven appendiceal mucinous lesion from January 2010 to May 2019 were evaluated retrospectively. Pathology slides were re-evaluated by two pathologists according to the WHO 2019 classification of tumors of the digestive system. RESULTS: Totally 37 patients (male:19 female: 18) aged 23 to 93 years were analyzed. Majority of the patients (75.7 %) had underwent appendectomy due to preliminary diagnosis of acute appendicitis (n=22) or periappendiceal tumoral lesions (n=9), the others (n=9) underwent incidental appendectomy. Whereas acute appendicitis was histopathologically diagnosed in 16 (43.2%) patients, perforation was diagnosed in 12 (32.4%) patients (perforation without appendicitis=3, perforation with appendicitis=6). According to the initial, pathology reports were prepared as follows: mucocele (n=10), mucinous cystadenoma (n=9), low-grade mucinous neoplasm (n=6), mucinous adenocarcinoma (n=5), mucosal hyperplasia (n=5), hyperplastic polyp (n=1), adenomatous polyp (n=1). On the basis of the WHO 2019 classification, pathology reports were prepared as follows: low-grade mucinous neoplasm (n=17), simple retention cysts (n=6), hyperplastic polyp (n=6), mucinous adenocarcinoma (n=5), ruptured appendiceal diverticula (n=2), sessile serrated lesion (n=1). CONCLUSION: The term of appendiceal mucinous lesion, which is recently introduced into medical literature is suitable to distinguish between lesions with and without malignancy potential. The WHO 2019 classification system has been an important step in simplifying the classification of non- neuroendocrine tumors of the appendix vermiformis.

Primordial germ cells as a potential shared cell of origin for mucinous cystic neoplasms of the pancreas and mucinous ovarian tumors.

Mucinous ovarian tumors (MOTs) morphologically and epidemiologically resemble mucinous cystic neoplasms (MCNs) of the pancreas, sharing a similar stroma and both occurring disproportionately among young females. Additionally, MOTs and MCNs share similar clinical characteristics and immunohistochemical phenotypes. Exome sequencing has revealed frequent recurrent mutations in KRAS and RNF43 in both MOTs and MCNs. The cell of origin for these tumors remains unclear, but MOTs sometimes arise in the context of mature cystic teratomas and other primordial germ cell (PGC) tumors. We undertook the present study to investigate whether non-teratoma-associated MOTs and MCNs share a common cell of origin. Comparisons of the gene expression profiles of MOTs [including both the mucinous borderline ovarian tumors (MBOTs) and invasive mucinous ovarian carcinomas (MOCs)], high-grade serous ovarian carcinomas, ovarian surface epithelium, Fallopian tube epithelium, normal pancreatic tissue, pancreatic duct adenocarcinomas, MCNs, and single-cell RNA-sequencing of PGCs revealed that both MOTs and MCNs are more closely related to PGCs than to either eutopic epithelial tumors or normal epithelia. We hypothesize that MCNs may arise from PGCs that stopped in the dorsal pancreas during their descent to the gonads during early human embryogenesis, while MOTs arise from PGCs in the ovary. Together, these data suggest a common pathway for the development of MCNs and MOTs, and suggest that these tumors may be more properly classified as germ cell tumor variants. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Evaluation of appendiceal mucinous neoplasms with a new classification system and literature review.

Appendiceal mucinous neoplasms constitute a diagnostic spectrum ranging from adenoma to mucinous adenocarcinoma. To date, many classification systems have been proposed to reflect the histomorphological diversity of neoplasms in this range and their clinical correspondence, and also to form a common terminology between the pathologist and clinicians. The aim of this review is to provide an updated perspective on the pathological features of appendiceal mucinous neoplasms. Using the 2016 Modified Delphi Consensus Protocol (Delphi) and the Eighth Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 19 cases presented from June 2011 to December 2016 were evaluated and diagnosed with appendiceal mucinous neoplasia. According to the Delphi, non-carcinoid epithelial tumours of the appendix were categorized in eight histomorphological architectural groups. These groups are adenoma, serrated polyp, low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm, mucinous adenocarcinoma, poorly-differentiated adenocarcinoma with signet-ring, signet-ring cell carcinoma and adenocarcinoma. The most common symptom was right lower quadrant pain. The median age of these cases was 60±15 years. There was a preponderance of females (F/M: 15/4). In our re-evaluation, six cases were diagnosed as serrated polyp. There were 11 cases in the LAMN group and two cases in the mucinous adenocarcinoma group. Using the Delphi and the AJCC manual, there were many changes in the classification, evaluation and treatment of appendiceal mucinous neoplasms. These classification systems have facilitated the compatibility and communication of clinicians and pathologists and have guided clinicians on treatment methods.

Time trends in the incidence of hysterectomy-corrected overall, type 1 and type 2 endometrial cancer in Denmark 1978-2014.

OBJECTIVE: To investigate time trends in the incidence of overall, type 1 and type 2 endometrial cancer in Denmark 1978-2014, correcting for hysterectomy. METHODS: Based on the Danish Cancer Registry and the Danish National Patient Registry we calculated hysterectomy-corrected incidence rates of overall, type 1 and type 2 endometrial cancer. Separate analyses for women <55years (defined as pre- and perimenopausal age) and women aged ≥55years (defined as postmenopausal age) and analyses allowing for different time trends before and after the study period midyear 1996 were performed. Log-linear Poisson models were used to estimate annual percentage change (APC) in incidence with 95% confidence intervals (CI). RESULTS: The overall incidence of endometrial cancer decreased slightly from 1978 to 1995, but in the last two decades of the study period the incidence has been stable (APC=0.16; 95% CI: -0.19; 0.50). In the study period (1978-2014) type 1 endometrial cancer incidence decreased slightly (APC=-0.67; 95% CI:-0.83; -0.52), whereas the incidence of type 2 endometrial cancer increased substantially (APC=4.85; 95% CI: 4.47; 5.23). The decrease in type 1 endometrial cancer was most pronounced before 1996 in women younger than 55 years (APC=-2.79; 95% CI: -3.65; -1.91), while the largest increase in type 2 endometrial cancer was observed after 1996 (APC=6.42; 95% CI: 5.72; 7.12). CONCLUSIONS: Over a period of more than 35 years, the incidence of type 1 endometrial cancer decreased, mainly in pre- and perimenopausal women, while type 2 endometrial cancer incidence increased.

A contemporary series of renal masses with emphasis on recently recognized entities and tumors of low malignant potential: A report based on 624 consecutive tumors from a single tertiary center.

INTRODUCTION: A number of new renal tumor entities have been recognized by the 2016 World Health Organization classification of urologic tumors. The classification includes tumors with different behavior and introduces one tumor with low malignant potential, the multilocular cystic clear cell renal cell neoplasm of low malignant potential (mcCCRCNLMP). However, some categories still labeled as "carcinoma", such as clear cell papillary renal cell carcinoma (CCPRCC), renal angioleiomyomatous tumor (RAT), and tubulocystic carcinoma (TCRCC), all with a particularly good prognosis when diagnosed as low stage, show no malignant behavior: in fact, no metastases have been reported in these categories when surgically excised. Current experience is limited to supporting these neoplasms as benign entities although, recent literature data is defining these entities as "low malignant potential tumors". MATERIAL AND METHODS: We conducted a search through our files on a consecutive series of 624 renal tumors diagnosed over a period of 2 years to address the incidence of this category of tumors. RESULTS: Applying strict histological criteria, the "low malignant potential" tumors, comprised 7% of renal masses that are less than 4cm in size and 3.8% of renal masses measuring 4-7cm in the series of 624 renal tumors. When benign tumors are taken into considerations, the benign and "low malignant potential tumors" represent about one third of renal masses <4cm and one sixth of renal masses between 4 and 7cm. All these cases have not shown recurrence or metastasis at follow-up, mean follow-up of 18 months (range 6-30 months). CONCLUSIONS: This information may assist urologists in developing guidelines for counseling and proper clinical management for patients with "low malignant potential" tumors or small renal masses.

Molecular approaches for classifying endometrial carcinoma.

Endometrial carcinoma is the most common cancer of the female genital tract. This review article discusses the usefulness of molecular techniques to classify endometrial carcinoma. Any proposal for molecular classification of neoplasms should integrate morphological features of the tumors. For that reason, we start with the current histological classification of endometrial carcinoma, by discussing the correlation between genotype and phenotype, and the most significant recent improvements. Then, we comment on some of the possible flaws of this classification, by discussing also the value of molecular pathology in improving them, including interobserver variation in pathologic interpretation of high grade tumors. Third, we discuss the importance of applying TCGA molecular approach to clinical practice. We also comment on the impact of intratumor heterogeneity in classification, and finally, we will discuss briefly, the usefulness of TCGA classification in tailoring immunotherapy in endometrial cancer patients. We suggest combining pathologic classification and the surrogate TCGA molecular classification for high-grade endometrial carcinomas, as an option to improve assessment of prognosis.

Low progression of intraductal papillary mucinous neoplasms with worrisome features and high-risk stigmata undergoing non-operative management: a mid-term follow-up analysis.

OBJECTIVE: To evaluate mid-term outcomes and predictors of survival in non-operated patients with pancreatic intraductal papillary mucinous neoplasms (IPMNs) with worrisome features or high-risk stigmata as defined by International Consensus Guidelines for IPMN. Reasons for non-surgical options were physicians' recommendation, patient personal choice or comorbidities precluding surgery. METHODS: In this retrospective, multicentre analysis, IPMNs were classified as branch duct (BD) and main duct (MD), the latter including mixed IPMNs. Univariate and multivariate analysis for overall survival (OS) and disease-specific survival (DSS) were obtained. RESULTS: Of 281 patients identified, 159 (57%) had BD-IPMNs and 122 (43%) had MD-IPMNs; 50 (18%) had high-risk stigmata and 231 (82%) had worrisome features. Median follow-up was 51 months. The 5-year OS and DSS for the entire cohort were 81% and 89.9%. An invasive pancreatic malignancy developed in 34 patients (12%); 31 had invasive IPMNs (11%) and 3 had IPMN-distinct pancreatic ductal adenocarcinoma (1%). Independent predictors of poor DSS in the entire cohort were age >70 years, atypical/malignant cyst fluid cytology, jaundice and MD >15 mm. Compared with MD-IPMNs, BD-IPMNs had significantly better 5-year OS (86% vs 74.1%, p=0.002) and DSS (97% vs 81.2%, p<0.0001). Patients with worrisome features had better 5-year DSS compared with those with high-risk stigmata (96.2% vs 60.2%, p<0.0001). CONCLUSIONS: In elderly patients with IPMNs that have worrisome features, the 5-year DSS is 96%, suggesting that conservative management is appropriate. By contrast, presence of high-risk stigmata is associated with a 40% risk of IPMN-related death, reinforcing that surgical resection should be offered to fit patients.

The oncocytic subtype is genetically distinct from other pancreatic intraductal papillary mucinous neoplasm subtypes.

In 2010, the World Health Organization reclassified the entity originally described as intraductal oncocytic papillary neoplasm as the 'oncocytic subtype' of intraductal papillary mucinous neoplasm. Although several key molecular alterations of other intraductal papillary mucinous neoplasm subtypes have been discovered, including common mutations in KRAS, GNAS, and RNF3, those of oncocytic subtype have not been well characterized. We analyzed 11 pancreatic 'oncocytic subtype' of intraductal papillary mucinous neoplasms. Nine pancreatic 'oncocytic subtype' of intraductal papillary mucinous neoplasms uniformly exhibited typical entity-defining morphology of arborizing papillae lined by layers of cells with oncocytic cytoplasm, prominent, nucleoli, and intraepithelial lumina. The remaining two were atypical. One lacked the arborizing papilla and had flat oncocytic epithelium only; the other one had focal oncocytic epithelium in a background of predominantly intestinal subtype intraductal papillary mucinous neoplasm. Different components of this case were analyzed separately. Formalin-fixed, paraffin-embedded specimens of all cases were microdissected and subjected to high-depth-targeted next-generation sequencing for a panel of 300 key cancer-associated genes in a platform that enabled the identification of sequence mutations, copy number alterations, and select structural rearrangements involving all targeted genes. Fresh frozen specimens of two cases were also subjected to whole-genome sequencing. For the nine typical pancreatic 'oncocytic subtype' of intraductal papillary mucinous neoplasms, the number of mutations per case, identified by next-generation sequencing, ranged from 1 to 10 (median=4). None of these cases had KRAS or GNAS mutations and only one had both RNF43 and PIK3R1 mutations. ARHGAP26, ASXL1, EPHA8, and ERBB4 genes were somatically altered in more than one of these typical 'oncocytic subtype' of intraductal papillary mucinous neoplasms but not in the other two atypical ones. In the neoplasm with flat oncocytic epithelium, the only mutated gene was KRAS. All components of the intestinal subtype intraductal papillary mucinous neoplasms with focal oncocytic epithelium manifested TP53, GNAS, and RNF43 mutations. In conclusion, this study elucidates that 'oncocytic subtype' of intraductal papillary mucinous neoplasm is not only morphologically distinct but also genetically distinct from other intraductal papillary mucinous neoplasm subtypes. Considering that now its biologic behavior is also being found to be different than other intraductal papillary mucinous neoplasm subtypes, 'oncocytic subtype' of intraductal papillary mucinous neoplasm warrants being recognized separately.

Stratified mucin-producing intraepithelial lesion with invasive carcinoma: 12 cases with immunohistochemical and ultrastructural findings.

Stratified mucin-producing intraepithelial lesion (SMILE) is considered to be a variant of adenocarcinoma in situ (defined as intraepithelial malignant glandular epithelium without invasion) or adenosquamous carcinoma in situ of the uterine cervix. However, recent study suggested that SMILE is more similar to high-grade squamous epithelial lesion by their immunohistochemical findings. An invasive form of SMILE "invasive stratified mucin-producing carcinoma (ISMC)" has been also proposed, but immunohistochemical features are not well documented. Therefore, this study aimed to clarify the immunohistochemical characteristics of SMILE and ISMC. Twelve cases of SMILE were found among 445 patients (2.7%) with high-grade intraepithelial lesions or invasive carcinomas, 3 of whom had solely intraepithelial disease with SMILE component (mean age, 37 years; range, 30-48 years) and 9 with invasive carcinomas (mean age, 47 years; range, 37-66 years; including ISMC). Immunohistochemically, SMILE and ISMC were diffusely positive for p16 and CAM5.2, focally for IMP3, and almost negative or only focally positive for p63. Nuclear signals in SMILE and invasive carcinomas were detected by human papillomavirus (HPV) in situ hybridization; 5 cases showed HPV16 and/or HPV18 polymerase chain reaction products. The ultrastructural study of 1 case showed surface microvilli and small vacuolar structure in SMILE; ISMC had mucous-like vacuoles, many mitochondria and intracytoplasmic lumen but lacked tonofilament. These findings were more similar to adenocarcinoma in situ or adenocarcinoma than squamous intraepithelial lesion or squamous cell carcinoma. We suggest that SMILE is an intraepithelial neoplasm and ISMC is an invasive form of SMILE.

Interobserver variability in intraductal papillary mucinous neoplasm subtypes and application of their mucin immunoprofiles.

Intraductal papillary mucinous neoplasm is considered a precursor lesion to pancreatic adenocarcinoma. These are further classified into four histologic subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. The first aim of this study was to assess the interobserver variability among five gastrointestinal pathologists in diagnosing intraductal papillary mucinous neoplasm subtypes by morphology alone. The second aim of the study was to compare intraductal papillary mucinous neoplasm subtypes, which received consensus diagnoses (≥80% agreement) with their respective mucin immunoprofiles (MUC1, MUC2, MUC5AC, MUC6, and CDX2). A consensus histologic subtype was reached in 58% of cases (29/50) among the five gastrointestinal pathologists. Overall there was moderate agreement (κ=0.41, P<0.01) in subtyping intraductal papillary mucinous neoplasms without the use of immunohistochemistry. The histologic subtype with the best interobserver agreement was intestinal type (κ=0.56, P<0.01) followed by pancreatobiliary, gastric, mixed, and oncocytic types (κ=0.43, P<0.01; κ=0.38, P<0.01; κ=0.17, P<0.01; κ=0.08, P<0.04, respectively). Both kappa values for mixed and oncocytic subtypes were likely artificially low due to the underrepresentation of these subtypes in this study and not a true indication of poor interobserver agreement. Following an intradepartmental consensus meeting between two gastrointestinal pathologists, 68% of cases (34/50) received a consensus intraductal papillary mucinous neoplasm subtype. Sixty-nine percent of cases (11/16) that did not receive a consensus intraductal papillary mucinous neoplasm subtype could be classified based on their respective immunoprofiles. Standardizing the use of immunohistochemistry with a mucin immunopanel (MUC1, MUC2, MUC5AC, and MUC6) may improve the agreement of diagnosing intraductal papillary mucinous neoplasm histologic subtypes.

Morphological and Immunohistochemical Reevaluation of Tumors Initially Diagnosed as Ovarian Endometrioid Carcinoma With Emphasis on High-grade Tumors.

Ovarian endometrioid carcinomas (OEC) of low grade have characteristic morphologic features, but high-grade tumors can mimic high-grade serous and undifferentiated carcinomas. We reviewed tumors initially diagnosed as OEC to determine whether a combination of pathologic and immunohistochemical features can improve histologic subclassification. Tumors initially diagnosed as OEC were reviewed using World Health Organization criteria. We also noted the presence of associated confirmatory endometrioid features (CEFs): (i) squamous metaplasia; (ii) endometriosis; (iii) adenofibromatous background; and (iv) borderline endometrioid or mixed Mullerian component. A tissue microarray was constructed from 27 representative tumors with CEF and 14 without CEF, and sections were stained for WT-1, p16, and p53. Of 109 tumors initially diagnosed as OEC, 76 (70%) tumors were classified as OEC. The median patient age was 55 years, and 75% of patients were younger than 60 years. Ninety-two percent presented with disease confined to the pelvis, and 87% of tumors were unilateral. The median tumor size was 11.8 cm. Only 3% of tumors were high grade (grade 3of 3). Eighty percent of cases had at least 1 CEF, and 59% had at least 2 CEFs. Eleven percent overexpressed p16, 0% overexpressed p53, and 3% expressed WT-1. Only 10% of patients died of disease at last follow-up. Thirty-three (33) tumors, or 30% of tumors originally classified as endometrioid, were reclassified as serous carcinoma (OSC). The median patient age was 54.5 years, and 59% of patients were younger than 60 years of age. Only 27% had disease confined to the pelvis at presentation, 52% of tumors were unilateral, and the median tumor size was 8 cm. Associated squamous differentiation, endometrioid adenofibroma, and endometrioid or mixed Mullerian borderline tumor (CEFs) were not present in any case, but 6% of patients had endometriosis. Approximately one half of the reclassified OSC demonstrated SET-pattern morphology (combinations of glandular, cribriform, solid, and transitional cell-like architecture) and were immunophenotypically indistinguishable from OSCs with papillary architecture. Sixty percent of OSC overexpressed p16, 50% overexpressed p53, and 82% expressed WT-1. At last follow-up, 52% had died of disease. Compared with OSC, OEC patients more frequently presented below 60 years of age (P=0.046), had low-stage tumors (P<0.001), were more frequently unilateral (P<0.001), more frequently had synchronous endometrial endometrioid carcinomas (P<0.001); and had no evidence of disease at last follow-up (P<0.001). Their tumors were of lower grade (P<0.001), had more CEFs (P<0.001), and less frequently overexpressed p16 and p53 (P=0.003 and P<0.001, respectively) and less frequently expressed WT-1 (P<0.001). This analysis emphasizes the diagnostic value of CEFs, the presence of a low-grade gland-forming endometrioid component, and WT-1 negativity, as valid, clinically relevant criteria for a diagnosis of OEC. Glandular and/or cribriform architecture alone may be seen in both OECs and OSCs and are therefore not informative of diagnosis. Further study is needed to elaborate the characteristics of the exceedingly rare high-grade OEC.

Intraductal Papillary Mucinous Neoplasms Often Contain Epithelium From Multiple Subtypes and/or Are Unclassifiable.

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are subclassified into gastric, intestinal, pancreatobiliary, and oncocytic subtypes based on histologic features. The WHO classification scheme suggests use of immunohistochemical stains to help subtype IPMNs with ambiguous histology. Seventy-two pancreatic IPMN resections between 2008 and 2014 were retrospectively evaluated. Immunohistochemistry for CDX2, MUC2, and MUC5AC was performed on cases where the histologic subtype could not be determined on routine hematoxylin and eosin (H&E) sections. There were 41 gastric (57%), 8 intestinal (11%), 4 pancreatobiliary (6%), and 1 oncocytic (1%) IPMNs. Eighteen (25%) IPMNs were either unclassifiable due ambiguous morphology or contained distinct epithelium from >1 subtype (i.e., "mixed"). Two IPMNs initially unclassifiable strictly by H&E morphology were definitively classified as intestinal after positive immunohistochemical staining with CDX2, MUC2, and MUC5AC. Immunohistochemistry for another 7 IPMNs unclassifiable by H&E did not indicate a clear subtype and often contained discordant results (e.g., discordant CDX2 and MUC2 staining). In our experience, a considerable number of IPMNs are either unclassifiable or contain epithelium from >1 subtype. Furthermore, among those IPMNs initially unclassifiable by H&E morphology, application of immunohistochemical stains to aid in subtyping allow for definite classification in only a small subset of cases. These data, when taken in context with the significant ranges in the reported prevalence of specific histologic subtypes, suggest that accurate IPMN subtyping is poorly reproducible in up to 25% of cases, and in these problematic cases, immunohistochemistry adds little value.

A Consensus for Classification and Pathologic Reporting of Pseudomyxoma Peritonei and Associated Appendiceal Neoplasia: The Results of the Peritoneal Surface Oncology Group International (PSOGI) Modified Delphi Process.

Pseudomyxoma peritonei (PMP) is a complex disease with unique biological behavior that usually arises from appendiceal mucinous neoplasia. The classification of PMP and its primary appendiceal neoplasia is contentious, and an international modified Delphi consensus process was instigated to address terminology and definitions. A classification of mucinous appendiceal neoplasia was developed, and it was agreed that "mucinous adenocarcinoma" should be reserved for lesions with infiltrative invasion. The term "low-grade appendiceal mucinous neoplasm" was supported and it was agreed that "cystadenoma" should no longer be recommended. A new term of "high-grade appendiceal mucinous neoplasm" was proposed for lesions without infiltrative invasion but with high-grade cytologic atypia. Serrated polyp with or without dysplasia was preferred for tumors with serrated features confined to the mucosa with an intact muscularis mucosae. Consensus was achieved on the pathologic classification of PMP, defined as the intraperitoneal accumulation of mucus due to mucinous neoplasia characterized by the redistribution phenomenon. Three categories of PMP were agreed-low grade, high grade, and high grade with signet ring cells. Acellular mucin should be classified separately. It was agreed that low-grade and high-grade mucinous carcinoma peritonei should be considered synonymous with disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis, respectively. A checklist for the pathologic reporting of PMP and appendiceal mucinous neoplasms was also developed. By adopting the classifications and definitions that were agreed, different centers will be able to use uniform terminology that will allow meaningful comparison of their results.

Mucinous tubular and spindle cell renal cell carcinoma: a review of clinicopathologic aspects.

Mucinous tubular and spindle cell renal cell carcinoma is a rare, recently described variant of renal cell carcinoma characterized by an admixture of cuboidal cells in tubules and sheets of spindle cells, and variable amounts of mucinous stroma. It has been recognized as a distinct entity in the 2004 World Health Organization tumor classification. Since then, several dozen of these tumor have been reported with additional complementary morphologic characteristics, immunohistochemical profile, and molecular genetic features that have further clarified its clinicopathologic aspects. Although originally considered as a low grade renal cell carcinoma on the basis of its bland appearing nuclear features and indolent clinical course, mucinous tubular and spindle cell renal cell carcinoma has currently been proven to be a tumor that has a histological spectrum ranging from low to high grade that includes sarcomatoid differentiation. In this review, we present a detailed summary of the current knowledge regarding the clinicopathologic, immunohistochemical, molecular genetic, and prognostic characteristics, as well as differential diagnoses of mucinous tubular and spindle cell renal cell carcinoma.

Atypical postcesarean epithelioid trophoblastic lesion with cyst formation: a case report and literature review.

We report an extremely rare case of atypical postcesarean epithelioid trophoblastic lesion with cyst formation. A 41-year-old Chinese woman presented with lower abdominal pain and menstrual disorder. Her serum human chorionic gonadotropin (hCG) was low (0.373 IU/L), and her urine hCG was negative. Ultrasound images showed a 3.7×2.8×2.5 cm(3) mass on the surface of the lower uterine segment, and a laparoscopy indicated a cystic mass in the serosal surface of the lower uterine segment. Histology indicated a cystic lesion consisting of epithelioid trophoblastic cells with an intermediate pattern between a classical placental site nodule and an epithelioid trophoblastic tumor; thus, the term atypical postcesarean epithelioid trophoblastic lesion with cyst formation was appropriate. As in atypical placental site nodule, serum hCG monitoring after treatment is necessary.

Premalignant cystic neoplasms of the pancreas.

Due to increasing utilization of cross-sectional imaging, asymptomatic pancreatic cysts are frequently being diagnosed. Many of these cysts have premalignant potential and offer a unique opportunity for cancer prevention. Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm are the major premalignant cystic neoplasms of pancreas. The prediction of the risk of malignancy (incidental and future risk of malignant transformation) and balancing the risks of watchful waiting with that of operative management with associated mortality and morbidity is the key to the management of these lesions. We review the literature that has contributed to the development of our approach to the management of these cystic neoplasms. We provide an overview of the key features used in diagnosis and in predicting malignancy. Particular attention is given to the natural history and management decision making.

New insights in the pathophysiology of ovarian cancer and implications for screening and prevention.

Despite advances in medicine, ovarian cancer remains the deadliest of the gynecological malignancies. Herein we present the latest information on the pathophysiology of ovarian cancer and its significance for ovarian cancer screening and prevention. A new paradigm for ovarian cancer pathogenesis presupposes 2 distinct types of ovarian epithelial carcinoma with distinct molecular profiles: type I and type II carcinomas. Type I tumors include endometrioid, clear-cell carcinoma, and low-grade serous carcinoma and mostly arise via defined sequence either from endometriosis or from borderline serous tumors, mostly presenting in an early stage. More frequent type II carcinomas are usually high-grade serous tumors, and recent evidence suggests that the majority arise from the fimbriated end of the fallopian tube. Subsequently, high-grade serous carcinomas usually present at advanced stages, likely as a consequence of the rapid peritoneal seeding from the open ends of the fallopian tubes. On the other hand, careful clinical evaluation should be performed along with risk stratification and targeted treatment of women with premalignant conditions leading to type I cancers, most notably endometriosis and endometriomas. Although the chance of malignant transformation is low, an understanding of this link offers a possibility of prevention and early intervention. This new evidence explains difficulties in ovarian cancer screening and helps in forming new recommendations for ovarian cancer risk evaluation and prophylactic treatments.

Incidence of serous tubal intraepithelial carcinoma (STIC) by algorithm classification in serous ovarian tumor associated with PAX8 expression in tubal epithelia: a study of single institution in Japan.

Serous ovarian carcinoma is now hypothesized to originate from fallopian tube epithelium (FTE). We investigated the FTE abnormalities in the patients with epithelial ovarian tumors. Our study included 55 cases of serous tumors (24 carcinomas, 8 borderline tumors, and 23 adenomas), 14 mucinous carcinomas, 22 endometrioid carcinomas, 5 clear cell carcinomas, and 2 malignant Brenner tumors. FTE was diagnosed by the diagnostic algorithm, which combines the data of morphology, and p53, Ki-67 immunostaining, as serous tubal intraepithelial carcinoma, serous tubal intraepithelial lesion, p53 signature, and normal/reactive. Serous tubal intraepithelial carcinoma, serous tubal intraepithelial lesion, p53 signature, and normal/reactive were observed in 5, 3, 0, and 16 cases in serous carcinoma; 0, 3, 0, and 5 cases in serous borderline tumor; 0, 1, 1, and 21 cases in serous adenoma; 0, 0, 1, and 13 cases in mucinous carcinoma; 0, 0, 3, and 19 cases in endometrioid carcinoma; 0, 0, 0, and 5 cases in clear cell carcinoma; and 0, 1, 0, and 1 case in malignant Brenner tumor. Among tumors of serous histology and between carcinomas, FTE abnormalities differed significantly (P<0.05). Serous tubal intraepithelial carcinomas were only found in serous carcinoma. The incidence of secretory cell proliferation (SCP) was examined by PAX8 expression. The rate of SCP was extremely high in serous carcinoma (96%). Among tumors of serous histology and between carcinomas, an incidence of SCP differed significantly (P<0.05). Patients with SCP were significantly older (P<0.0001). Our observations were concordant with the hypothesis of serous ovarian carcinogenesis. The SCP has a meaningful association with serous ovarian cancer.