Two types of primary mucinous ovarian tumors can be distinguished based on their origin.

The origin of primary mucinous ovarian tumors is unknown. We explore the hypothesis that they originate from either Brenner tumors or teratomas and examine differences between the tumors that arise in these settings. A total of 104 Brenner tumor-associated mucinous tumors and 58 teratoma-associated mucinous tumors were analyzed. Immunohistochemistry for 21 antigens and fluorescence in situ hybridization for ERBB2 and MYC were performed. Genome-wide copy number analysis and mutation analysis for 56 cancer-related genes was carried out on a subset of mucinous ovarian tumors and their complementary Brenner tumor or teratoma. Patients with teratoma-associated mucinous tumors were significantly younger than patients with Brenner tumor-associated mucinous tumors (43 vs. 61 years). During progression from cystadenoma to atypical proliferative mucinous (borderline) tumor to carcinoma expression of typical gastrointestinal markers was increased in both Brenner tumor-associated and teratoma-associated mucinous tumors. Brenner tumor-associated mucinous tumors showed more frequently calcifications and Walthard cell nests, rarely expressed SATB2 and showed more often co-deletion of CDKN2A and MTAP. Teratoma-associated mucinous tumors were characterized by mucinous stromal dissection, SATB2 expression and RNF43 mutations. Other frequent mutations in both Brenner tumor-associated and teratoma-associated mucinous tumors were TP53 and KRAS mutations. Based on identical mutations or copy number profiles clonal relationships were indicated in two mucinous tumors and their associated Brenner tumor. Teratomas and Brenner tumors give rise to different subtypes of mucinous ovarian tumors. Subsequent progression pathways are comparable since both Brenner tumor-associated and teratoma-associated mucinous tumors develop a gastrointestinal immunophenotype during progression and show early mutations in KRAS and TP53. Teratoma-associated mucinous tumors may more closely resemble true gastrointestinal tumors, indicated by their expression of SATB2 and the presence of RNF43 mutations.

S100P is a useful marker for differentiation of ovarian mucinous tumors.

The S100P protein stimulates cell proliferation and survival, thereby contributing to tumor progression. The purpose of this study was to evaluate S100P expression in the three subtypes of mucinous cystic tumors, cystadenomas, borderline tumors, and adenocarcinomas. The authors examined nuclear S100P expression in 60 mucinous ovarian tumor specimens, including 24 specimens of mucinous cystadenoma, 15 of borderline tumors, and 21 of adenocarcinomas. Immunohistochemistry revealed S100P expression followed one of three patterns: (1) Expressed in most nuclei of mucinous epithelial cells, (2) sporadic (spotted or patchy) expression, or (3) absent or rarely expressed in the nuclei of mucinous epithelial cells. Most adenomas showed the first expression pattern, and borderline tumors often showed a patchy expression pattern. Adenocarcinomas generally demonstrated absence of S100P expression. These data suggest that S100P is a useful histological marker to differentiate between benign, borderline, and malignant mucinous tumors of the ovary.

Glycosylation variants of mucins and CEACAMs as candidate biomarkers for the diagnosis of pancreatic cystic neoplasms.

BACKGROUND AND AIMS: Cystic lesions of the pancreas are increasingly being recognized due to the widespread use of high resolution abdominal imaging. Since certain cyst types are precursors to invasive cancer, this situation presents an opportunity to intervene prior to malignant progression. Effective implementation of that strategy has been hampered by difficulties in clearly distinguishing cystic lesions with no malignant potential from those with malignant potential. Here we explored whether glycosylation variants on specific proteins in cyst fluid samples could serve as biomarkers to aid in this diagnosis. METHODS: We used a novel antibody-lectin sandwich microarray method to measure the protein expression and glycosylation of mucin (MUC)1, MUC5AC, MUC16, carcinoembryonic antigen, and other proteins implicated in pancreatic neoplasia in cyst fluid samples. Fifty-three cyst fluid samples were obtained from patients with mucinous cystic neoplasms (n=17), intraductal papillary mucinous neoplasms (n=15), serous cystadenomas (n=12), or pseudocysts (n=9), with confirmation of histologic diagnosis at surgical resection. RESULTS: The detection of a glycan variant on MUC5AC using the lectin wheat-germ agglutinin discriminated mucin-producing cystic tumors (mucinous cystic neoplasms+intraductal papillary mucinous neoplasms) from benign cystic lesions (serous cystadenomas+pseudocysts) with a 78% sensitivity at 80% specificity, and when used in combination with cyst fluid CA 19-9 gave a sensitivity of 87% at 86% specificity. These biomarkers performed better than cyst fluid carcinoembryonic antigen (37%/80% sensitivity/specificity). CONCLUSIONS: These results demonstrate the value of glycan variants for biomarker discovery and suggest that these biomarkers could greatly enhance the accuracy of differentiating pancreatic cystic tumors. Validation studies will be required to determine the clinical value of these markers.

Molecular and Immunohistochemical Analysis of Mucinous Cystic Neoplasm of the Liver.

OBJECTIVES: Mucinous cystic neoplasm of the liver is characterized by neoplastic mucinous and/or biliary epithelium surrounded by ovarian-type stroma. Immunohistochemical studies have shown that the ovarian-type stroma expresses estrogen receptor, suggesting potential hormonal responsiveness. The molecular biology of mucinous cystic neoplasm of the liver remains poorly studied. METHODS: Transcriptome sequencing and immunohistochemistry were performed on a series of mucinous cystic neoplasms. RESULTS: Mucinous cystic neoplasm of the liver exhibited significantly increased RNA expression of ovarian stromal markers WT1, PR, and ER2 and sex cord stromal markers SF-1, inhibin-α, and calretinin compared with nonneoplastic liver. Immunohistochemistry confirmed the RNA-level data. Evidence for sex hormone biosynthesis was identified by significant overexpression of multiple estrogen biosynthetic enzymes. Expression of 17ß-hydroxysteroid dehydrogenase 1 was confirmed immunohistochemically. Pathway analysis also identified significant upregulation of the hedgehog and Wnt pathways and significant downregulation of T-helper 1 and T-helper 2 pathways. CONCLUSIONS: Mucinous cystic neoplasm of the liver recapitulates ovarian stroma at the morphologic, DNA, RNA, and protein levels. These data support the concept that this tumor likely arises from ectopic primitive gonadal tissue and/or stromal cells with capacity to transdifferentiate to ovarian cortical cells.

Serous and mucinous ovarian tumors express different profiles of MMP-2, -7, -9, MT1-MMP, and TIMP-1 and -2.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play key roles in tumorigenesis, but little is known of their expression according to mucinous or serous type. This study aimed to evaluate the immunohistochemical expression of MMP-2, -7, -9, MT1-MMP, TIMP-1 and -2 in these tumors. A tissue microarray was set up including 99 serous (25 benign, 27 borderline, 47 malignant) and 79 mucinous (25 benign, 44 borderline, 10 malignant) ovarian tumors. Immunostaining results were scored by using the HSCORE and assessed by univariate, unsupervised hierarchical clustering and multidimensional scaling analyses. Epithelial expression of MMP-2, -7, -9, MT1-MMP, TIMP-2, but not TIMP-1, was higher in serous than mucinous tumors. Stromal expression of MMP-7 was higher in serous tumors. Alterations in MT1-MMP, MMP-7 and -9 were found in malignant serous tumors, while benign and borderline tumors shared similar expressions. By unsupervised hierarchical clustering analysis, mucinous and serous tumors were better differentiated by epithelial than stromal MMP and TIMP immunolabelling. By multidimensional scaling analysis, the expressions of MMPs and TIMPs were scattered in serous tumors and homogeneous for mucinous tumors. In conclusion, our results support the differential expression in MMPs and TIMPs of ovarian tumors according to serous or mucinous histology.

Undifferentiated carcinoma with osteoclast-like giant cells arising in a mucinous cystic neoplasm of the pancreas.

A 26-year-old woman presented with pain in the left hypochondrium, for which pancreatectomy and splenectomy was performed, with total gross excision of a mass. A tumor measuring 11 x 9 cm was found in the pancreas. On cut surface there were two cysts filled with a necrotic substance and hemorrhagic content. Spindle or ovoid-shaped cells, in the sarcomatous component, had diffusely infiltrated along the inner side of the walls of one cyst. Osteoclast-like giant cells (OGC) were also contained in the sarcomatous component. Adenoma components of mucinous epithelium with foci of borderline and adenocarcinomatous components were seen on the inner side of the other cyst. An ovarian-type stroma beneath the epithelial component was seen in the cyst wall. A diagnosis of undifferentiated carcinoma with OGC arising in a mucinous cystic neoplasm (MCN) of the pancreas, was made. Seven months after the initial operation the patient had a local recurrence, and the tumor was removed. One month after the second operation, the patient was free of symptoms. Only four cases of undifferentiated carcinoma with OGC arising in MCN, involving an ovarian-type stroma of the pancreas, have been reported.

The importance of cyst fluid analysis for differentiation of pancreatic cyst.

Cystic abnormalities of the pancreas encompass a wide variety of lesions ranging from the non-malignant pseudo-cyst to neoplastic lesions. Although cystic neoplasms of the pancreas are rare, differentiation is important in determining the proper treatment. A 55-year-old female presented with a cystic abdominal mass. Her computed tomography scan showed a cystic mass of 102 x 99 x 97 mm which was well-circumscribed and homogeneous with few thin septations and mild contrast enhancement of the fibrous wall located in the body of the pancreas. Percutaneous diagnostic aspiration of the cyst fluid was performed under ultrasonic guidance for proper diagnosis and management, which revealed a CEA greater than 200 ng/ml (0-3) and amylase within normal limits 30 U/L (< or = 100). High CEA and normal amylase values supported the diagnosis of mucinous cystadenoma rather than pseudo-cyst. With these findings, the patient underwent distal pancreatectomy with splenectomy. Pathological analysis revealed a mucinous cystadenoma of the pancreas. This report is a confirmation that cyst fluid analysis can provide a pre-operative classification of these diagnostically difficult lesions.

Diagnostic value of mucins (MUC1, MUC2 and MUC5AC) expression profile in endoscopic ultrasound-guided fine-needle aspiration specimens of the pancreas.

Mucins are aberrantly expressed in various malignancies. We immunohistochemically tested mucins expression (MUC1, MUC2 and MUC5AC) in EUS-FNA samples from pancreatic occupying lesions for the diagnostic utility. The prevalence of MUC1, MUC2 and MUC5AC expression in pancreatic cancers were 77.5% (31/40), 10.0% (4/40) and 80.0% (32/40), respectively, and in the benign pancreatic diseases 25% (4/16), 31.3% (5/16) and 43.8% (7/16). MUC1 and MUC5AC significantly overexpressed in pancreatic cancer, and MUC1 negatively related with tumor differentiation degree (p < 0.05). The prevalence of MUC1, MUC2 and MUC5AC expression in pancreatic mucinous neoplasms were 66.7% (12/18), 38.9% (7/18) and 88.9% (16/18), respectively, and in the pancreatic non-mucinous neoplasms 60.5% (23/38), 5.3% (2/38) and 57.9% (22/38). MUC2 and MUC5AC significantly overexpressed in pancreatic mucinous neoplasms, especially MUC2 in benign mucinous neoplasms (p < 0.05). Compared with cytology alone, the combination test of MUC1+cytology, and MUC5AC+cytology could achieve higher sensitivity (85 vs. 65%, 100 vs. 65%) and accuracy (89.3% vs. 73.2%, 91.1% vs. 73.2%) for pancreatic cancer diagnosis; the combination test of MUC2 + cytology, and MUC5AC + cytology could achieve higher sensitivity (77.8% vs. 38.9%, 100% vs. 38.9%), and specificity (97.4% vs. 60.5%, 71.1% vs. 60.5%) accuracy (100% vs. 51.8%, 80.4% vs. 51.8%) for mucinous neoplasm diagnosis. The panel MUC1+/MUC2-/MUC5AC+/ was higher specific in pancreatic cancer diagnosis, as well as MUC1-/MUC2+/MUC5AC+/ in pancreatic mucinous neoplasms. Our observations suggest the mucins expression profile in EUS-FNA specimens has higher value for the diagnosis of pancreatic cancer and mucinous neoplasms.

A comprehensive study of nondysplastic and dysplastic serrated polyps of the vermiform appendix.

Serrated colorectal polyps often show DNA hypermethylation and/or BRAF mutations and have been implicated in the "serrated neoplastic pathway." Although similar lesions occur in the appendix, they have never been systematically investigated. We evaluated a study group of 56 serrated polyps, a control group of 17 mucinous cystadenomas, and 4 adenocarcinomas with adjacent serrated polyps of the appendix to better understand their pathogenesis. The study cases were classified as nondysplastic or dysplastic serrated polyps and evaluated for MLH-1, MSH-2, MGMT, beta-catenin, p53, and Ki-67 expression, BRAF and KRAS mutations, and microsatellite instability. Serrated polyps usually occurred in older adults with no sex predilection. Most (59%) lacked dysplasia, but all showed similar molecular features, regardless of the degree of dysplasia present. Decreased MLH-1 (50%, P<0.001) and/or MGMT (59%, P<0.001) expression and BRAF (29%, P=0.007) mutations were significantly more common in serrated polyps, but BRAF mutations were detected in a minority of the extracted DNA in 15/16 cases. Of the 28 cases with decreased MLH-1 expression, none showed high-frequency microsatellite instability. Loss of MLH-1 (25%) or MGMT (50%) expression and BRAF or KRAS mutations (50%) were inconsistently present in adenocarcinomas and were not identified in combination in any cases. We conclude that molecular features of the "serrated neoplastic pathway" are present with similar frequencies among dysplastic and nondysplastic serrated appendiceal polyps and are not highly prevalent in adjacent carcinomas. These features, including BRAF mutations, may be more closely related to a serrated morphology in appendiceal polyps rather than biologically important changes.

Prognostic significance of extracellular matrix metalloproteinase inducer and matrix metalloproteinase 2 in epithelial ovarian cancer.

AIMS: We investigated the prognostic significance of extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase 2 (MMP-2) in epithelial ovarian cancer as well as their relation to hyaluronan (HA) expression. METHODS: The expression of EMMPRIN and MMP-2 was analyzed immunohistochemically in 295 primary epithelial ovarian cancer patients and 67 metastases. RESULTS: A low membranous EMMPRIN expression was detected more often in serous tumors than in other types (p < 0.0005) and it was associated with tumors of advanced stage (p = 0.012) or with a large primary residual (p = 0.011). A low expression of MMP-2 in cancer cells was associated with a high histologic grade (grade 3) of the tumor (p = 0.005) and endometrioid type of tumors (p < 0.0005). Stromal MMP-2 expression was significantly associated with strong stromal HA expression (p = 0.002, r = 0.187). In univariate analysis, 10-year disease-related (DRS) and recurrence-free survivals were significantly better when MMP-2 expression in cancer cells was high (p = 0.0057 and p = 0.0467, respectively). DRS was also better when membranous EMMPRIN expression was high (p = 0.013). In multivariate analysis, strong MMP-2 in cancer cells (RR = 1.48, CI = 1.07-2.04, p = 0.017) indicated favorable DRS. CONCLUSION: Our results show that EMMPRIN and MMP-2 in cancer cells are significant indicators of a favorable prognosis of epithelial ovarian cancer.

Primary retroperitoneal mucinous cystadenoma: A case report.

Primary retroperitoneal mucinous cystic tumors are extremely rare. These tumors can be classified as a primary retroperitoneal mucinous cystadenoma with or without borderline malignancy or primary retroperitoneal mucinous cystadenocarcinoma. The most common of these is primary retroperitoneal mucinous cystadenoma, which almost always occurs in female patients; only ten cases have been reported in males. The most common clinical findings for this tumor type include nonspecific abdominal pain and a palpable abdominal mass. A definitive diagnosis is usually obtained from histopathology after surgical excision. Here, we report the case of a 60-year-old female patient who complained of abdominal pain that had been present for 3 mo and presented with a palpable abdominal mass. Multidetector computed tomography scanning revealed a large, unilocular cystic mass in the left retroperitoneal space. Surgical intervention was performed and the tumor was completely removed. Histopathologic examination confirmed that the tumor was a primary retroperitoneal mucinous cystadenoma. Two years after surgery, the patient remains disease free.

Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors.

The clinicopathological features of 56 patients with mucinous cystic tumors (MCTs) of the pancreas were studied. Particular attention was paid to the prognosis of MCTs and the relationship to their ovarian, hepatic, and retroperitoneal counterparts. To distinguish MCTs from pancreatic intraductal papillary-mucinous tumors, MCTs were defined as tumors lacking communication with the duct system and containing mucin-producing epithelium, usually supported by ovarian-like stroma. All 56 tumors occurred in women (mean age 48.2 years) and were preferentially (93%) located in the body and tail of the pancreas. In accordance with the WHO classification, MCTs were divided into adenomas (n = 22), borderline tumors (n= 12), and noninvasive and invasive carcinomas (n = 22). Survival analysis revealed the extent of invasion to be the most significant prognostic factor (p<0.0001). Malignancy correlated with multilocularity and presence of papillary projections or mural nodules, loss of ovarian-like stroma, and p53 immunoreactivity. Stromal luteinization with expression of tyrosine hydroxylase, calretinin, or alpha inhibin was found in 66% of the cases. We conclude that the biologic behavior of MCTs is predictable on the basis of the extent of invasion. The similarities (i.e. gender, morphology, stromal luteinization) between pancreatic MCT and its ovarian, hepatobiliary, and retroperitoneal counterparts suggest a common pathway for their development.

CDX2 immunoreactivity in primary and metastatic ovarian mucinous tumours.

The caudal-related homeobox transcription factor CDX2 regulates the differentiation of intestinal epithelial cells. Recent studies have suggested that CDX-2 immunoreactivity is strictly confined to benign and malignant intestinal epithelium. In the present study, we evaluated the prevalence of CDX2 immunoreactivity in a series of benign, borderline and malignant primary ovarian mucinous neoplasms. We tested 62 mucinous tumours of the ovary, including 28 benign cystadenomas, 18 borderline tumours, 16 adenocarcinomas, 35 serous and endometrioid ovarian lesions and 10 ovarian metastases of colonic adenocarcinoma. Overall, the CDX2 prevalence in primary mucinous tumours was 79%, including 20 of 28 (71.5%) cystadenomas, 14 of 18 (77.7%) borderline tumours and 15 of 16 (93.5%) adenocarcinomas. Immunoreactivity usually correlated with intestinal differentiation of tumour cells, although wide heterogeneity in the distribution of immunolabelled cells was noted. No immunoreactivity was observed in serous lesions; whereas, 1 of 13 (7.7%) endometrioid adenocarcinomas and all of the 10 metastatic colonic adenocarcinomas were immunostained. These results indicate that CDX2 is detectable in the majority of benign, borderline and malignant ovarian mucinous tumours and, therefore, makes this marker unsuitable when distinguishing primary from metastatic ovarian mucinous adenocarcinomas. However, CDX2 immunoreactivity could be useful in the distinction between endocervical and intestinal-type mucinous tumours of the ovary, which may have clinical relevance.

Mucinous cystic tumor of the pancreas: immunohistochemical assessment of "ovarian-type stroma".

The new histopathological classification of exocrine pancreatic tumors by the World Health Organization, now includes "ovarian-type stroma" ("OS") in the definition of mucinous cystic tumor of the pancreas (MCT-P). This study investigated the clinicopathological findings of the MCT-P according to WHO classification and scrutinize the function of "OS" in MCT-P immunohistochemically. Thirty-four cases of MCT-P (28 adenomas, 2 borderline tumors and 4 adenocarcinomas) were examined clinicopathologically. The "OS" of 34 MCTs-P were studied immunohistochemically and compared with the stroma of 10 mucinous cystic tumors of the ovary (MCTs-O), 10 conventional pancreatic carcinomas and 6 normal ovaries. Almost all 34 MCTs-P were located in the body-tail of the pancreas of middle-aged women. Histologically the "OS" cells exhibited luteinization in 11/34 (32.4%). Immunohistochemically, both "OS" cells and the stromal cells in MCT-O showed similar positivity rates; calponin (34/34 and 9/10), h-caldesmon (28/34 and 8/10), alpha-inhibin (29/34 and 9/10), estrogen-receptor (21/34 and 6/10) and progesterone-receptor (28/34 and 9/10, respectively). Some neoplastic epithelial cells of MCT-P were positive for human chorionic gonadotropin (hCG) (21/34, 61.8%). This study indicates the predominance of MCT in the distal pancreas of middle-aged women. Furthermore, the immunohistochemical and histological results demonstrate that the "OS" of MCT-P and the stroma of MCT-O share the same characteristics. The results also suggested that the hCG produced by the neoplastic epithelium probably plays an important role in the luteinization of the stroma of MCT-P. We therefore conclude there is a possibility that MCT-P originates from the left remnant primordial gonadal cells which migrated to the pancreatic anlage during the early development of the fetus.

CA 125 in ovarian cysts, serous effusions and peritoneal washings: immunocytochemical expression.

The immunocytochemical expression of CA 125 in ovarian cysts, serous effusions and peritoneal washings was examined in patients with primary ovarian malignancies (22) and benign gynecologic conditions (96). The immunostaining of CA 125 was assessed in serous ovarian cysts (CA 125 was detected in 3 out of 14 serous ovarian cysts), follicular ovarian cysts (0/5), luteinized cysts (3/3), endometriotic cysts (6/11), serous cystoadenomas (4/4) and mucinous cystoadenomas (0/2). Reactive mesothelial cells (6/6) showed a low but homogeneous staining which was never found in negative peritoneal washings (0/47). Neoplastic cells in positive peritoneal washings were highly positive (20/22), except for 2 mucinous cystoadenocarcinomas. The reactivity of OC 125 with endometrial and reactive mesothelial cells shows the importance of employing a combination of MoAbs to improve conventional morphologic diagnosis.

Retroperitoneal mucinous cystadenoma.

Primary retroperitoneal mucinous cystadenoma is an uncommon tumor found exclusively in women. Herein, we describe a patient who had resection of a large retroperitoneal cystic mass. Histologic, immunohistochemical, and electron microscopic examination of the lining epithelial cells showed features of mesothelial cells in addition to ovarian mucinous cystadenoma. These findings suggest that these tumors arise from inclusions of mesothelial cells and subsequent mucinous metaplasia of the lining cells to form a cystadenoma. Estrogen receptors may be implicated in tumor promotion, explaining the occurrence exclusively in women.

Multiple primary neoplasms. Ovarian carcinoid tumor, mucinous cystadenoma of low malignant potential tumor of left ovary, and adenocarcinoma of the colon.

We describe a case of primary left ovarian carcinoid tumor with metastases to the right paraovarian tissue, left fallopian tube, the right lung, omentum, cul-de-sac, pericolonic fat, and, most likely, metastasis to the contralateral ovary, as well as a simultaneous left ovarian mucinous cystadenoma of low malignant potential and a well-differentiated colonic adenocarcinoma. Primary ovarian carcinoids are almost always unilateral. Metastases from such tumors to the lung and adrenal gland are very rare. To our knowledge, no such combination of all the above tumors has been reported.

Expression of interleukin-8 in human obstructive pancreatitis.

CONTEXT: Obstructive pancreatitis is a specific form of pancreatitis, which is caused by the obstruction of the main pancreatic duct due to tumors or some other causes. Interleukin-8 is induced in acute pancreatitis, but its expression in obstructive pancreatitis has not been clarified. OBJECTIVE: We attempted to provide some insight into the significance of interleukin -8 in the pathogenesis of pancreatic fibrosis. PATIENTS: Fifteen cases of pancreatic cancer, 7 cases of mucinous cystadenoma, 3 cases of Vater's papilla cancer and 9 normal pancreases were included in this study. MAIN OUTCOME MEASURES: The obstructive pancreatitis portions of the above pathologies were evaluated for interleukin-8 expression by means of immunohistochemistry and in situ hybridization. RESULTS: Interleukin-8 was positive in 72% of cases of obstructive pancreatitis. The positive rate was not significantly related to the etiology of the obstruction (P=0.972). Interleukin-8 was expressed in infiltrating cells, proliferating ductular cells and acinar cells. In contrast, normal pancreases and tumor cells lacked interleukin-8 expression (P<0.001 vs. obstructive pancreatitis). Both immunohistochemistry and in situ hybridization demonstrated that interleukin-8 was expressed mostly in acinar cells in mild pancreatic fibrosis, whereas it was expressed in stromal and ductular cells in moderate and severe pancreatic fibrosis. CONCLUSIONS: These results suggest that interleukin-8 expression is related to the fibrotic process in obstructive pancreatitis.