Urachal carcinoma: from gross specimen to morphologic, immunohistochemical, and molecular analysis.

Urachal carcinoma (UrC) is an exceedingly rare neoplasm that develops from the urachus, an embryologic remnant of the urogenital sinus and allantois. The most commonly encountered histologic subtype is adenocarcinoma. The aim of this study is to characterize a series of UrC by morphology, immunohistochemistry, and molecular analysis. We retrospectively investigated seven cases of UrCs and assessed patient symptoms, imaging, histologic features, immunohistochemical profile, molecular characteristics, pathologic stages, and type of treatment. Immunostaining for CK7, CK20, Muc-2, CDX2, GATA3, ß-catenin, and CK34ßE12 was carried out on each neoplasm and on seven non-neoplastic urachal remnants as the control group. Additionally, a mutational analysis was performed using the QIAact Actionable Insights Tumor Panel Kit, which analyzes KRAS, NRAS, KIT, BRAF, PDGFRA, ALK, EGFR, ERBB2, PIK3CA, ERBB3, ESR1, and RAF1. Our cohort comprised five females and two males with a mean age of 64 years. UrCs consisted of two mucinous cystadenocarcinomas and five invasive, non-cystic adenocarcinomas. Carcinoma antigen expression profile was positive for CK20 and negative for CK34ßE12 and GATA3 in all cases. Five of seven cases stained positively for Muc-2 and CDX2. On the contrary, non-neoplastic urachal remnants were immunoreactive for CK34ßE12, CK7, and GATA3. Mutational analysis gave a positive result in four out of seven (57.1%) cases. All four positive tumors showed RAS mutation and one an additional mutation in PIK3CA. Urachal tumors exhibit peculiar morphologic, immunohistochemical, and molecular features. Due to the advanced stage at presentation, individualized treatment should be undertaken.

Primary mammary mucinous cystadenocarcinoma: cytological and histological findings.

Mucinous cystadenocarcinoma (MCA), commonly encountered in the ovary or pancreas, is rare in the breast and was only recently described as a distinct variant of invasive ductal carcinoma of the breast. Only 11 cases of primary mammary MCA have been reported. In this article, we report a case of primary mammary MCA with focus on cytological and histological findings. A 65-year-old female noticed right palpable breast mass. Sonography showed an irregularly shaped 2.8 × 2.4 cm lesion in the upper outer quadrant of the right breast. Fine-needle aspiration cytology was performed on the right breast nodule, and cytopathologic examination suggested an adenocarcinoma composed of tall columnar cells with mucin. A partial mastectomy of the right breast and the axillary lymph nodes dissection was performed. The gross examination revealed a well-demarcated and mucus-filled tumor. Histologically, it had complex papillae, some of which were supported by delicate fibrovascular stroma lined by simple to slightly stratified columnar neoplastic epithelial cells with intracellular mucin, coexisting with MCA in situ and ordinary intraductal carcinoma component (ICC). Immunohistochemically, ICC was HER2-negative and estrogen receptor/progesterone receptor-positive, while MCA was triple negative. MCA might be derived from a metaplasia of ordinary ICC, but its pathogenesis and biologic behavior remains unclear. Despite the invasive nature of mammary MCA, these carcinomas appear to be associated with a good prognosis. The patient has remained well and disease-free for 6 months after the operation.

Primary retroperitoneal mucinous tumors: a clinicopathologic study of 18 cases.

Primary retroperitoneal mucinous tumors (PRMTs) are uncommon neoplasms occurring almost exclusively in women. PRMTs are divided into mucinous cystadenoma (MC), mucinous borderline tumors or tumors of low malignant potential (MLMP), and mucinous carcinomas (MCas). In this retrospective study, we present the clinicopathologic features of 18 such cases, the largest series to date. All patients were women, ranging in age from 20 to 63 years (mean 38.6 y). All except 2 patients presented with an enlarged mass during a routine examination or by self-palpation. All tumors were located exclusively in the retroperitoneum, with histologic or clinical confirmation of the lack of ovarian involvement. The tumors ranged from 7 to 26 cm (mean 13.2 cm). The gross appearance was variable: unilocular cyst with a thin wall (4 cases), predominantly cystic with papillary areas or nodule(s) (8 cases), multiloculated cyst with or without nodules (1 case each), and predominantly solid with cystic areas (4 cases). Histologically, there were 2 cases of MC, 7 of MLMP (7 cases; 3 of them with intraepithelial carcinoma and 1 with microinvasion), and 9 of MCas (9 cases, 5 of them associated with MLMP and 1 associated with MC). Three of the MCas had areas of anaplastic or sarcomatoid carcinoma whereas 1 had an associated sarcoma. Immunohistochemical studies were performed in 6 cases. Cytokeratin 7 was diffusely positive in all cases studied, whereas cytokeratin 20 and cytokeratin 17 were focally positive in 4 and 2 cases, respectively. All patients underwent surgical resection of the entire tumor. Two patients with MCa and sarcoma or sarcomatoid carcinoma received chemotherapy. Follow-up was available in 16 cases, ranging from 1 to 148 months (mean 40 mo, median 22 mo). Two patients died of disease at 5 and 9 months; both had MCa with anaplastic carcinoma or sarcoma. Three patients with MCa were alive with disease at 14, 26, and 58 months. The remaining patients were alive with no evidence of disease. In this study, MLMP and MCa were more common than MC. PRMTs seem to be nonaggressive neoplasms, except in cases containing anaplastic carcinoma or sarcoma.

Mucinous metaplasia of breast carcinoma with macrocystic transformation resembling ovarian mucinous cystadenocarcinoma in a case of synchronous bilateral infiltrating ductal carcinoma.

Mammary mucinous cystadenocarcinoma (MCA) is a rare, invasive ductal carcinoma (IDC) of the breast that is virtually identical morphologically to MCA of the ovary, pancreas or appendix. Synchronous bilateral breast tumors, not uncommonly encountered in fibroadenoma and lobular carcinoma, are unusual in IDC. Reported herein is a primary MCA of the right breast coexisting with a bilateral ordinary IDC in a 55-year-old Taiwanese woman who underwent modified radical mastectomy of both breasts with bilateral axillary level I and II lymph node dissection. In the right breast a 2.5 cm unilocular mucus-filled cyst was found. It had complex papillae, some of which were supported by delicate fibrovascular stroma, lined by simple to slightly stratified columnar neoplastic epithelial cells with intracellular mucin and an abundance of intracystic extracellular mucin, coexisting with a low-grade ordinary IDC. In the left breast a high-grade ordinary IDC was discovered. The patient had undergone simple abdominal total hysterectomy for myoma uteri along with bilateral salpingo-oophorectomy 10 years previously. Based on pathological studies and a literature review, it is suggested that mammary MCA arises from mucinous metaplasia and macrocystic transformation of ordinary breast carcinoma. A brief discussion of bilateral breast cancers is also given.

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.

Immunohistochemical similarities between pancreatic mucinous cystic tumor and ovarian mucinous cystic tumor.

OBJECTIVE: Pancreatic mucinous cystic tumor (MCT(P)) and ovarian mucinous cystic tumor (MCT(O)) show common features. However, there are few studies showing a comparison of both types of tumor. We immunohistochemically studied both types of tumor to clarify their characteristics. METHODS: Eight patients with MCT(P) and 21 patients with MCT(O) were examined. The tumors were immunohistochemically examined using antibodies against female sex hormone receptors (estrogen receptor, progesterone receptor, and alpha-inhibin), pancreatobiliary tissue markers (carbohydrate antigen 19-9 and DUPAN2) and cell cycle regulators (p27kip1 and phosphorylated retinoblastoma). Samples from 7 female patients with invasive pancreatic ductal carcinoma (DC), 8 female patients with normal pancreatic tissue, and 10 patients with normal ovarian tissue were also examined. RESULTS: In the tumor epithelial cells, the expressions of DUPAN2 and p27/kip1 were similar between MCT(P) (38% and 88%, respectively) and MCT(O) (14% and 76%, respectively), but significantly different between both tumors and DC (100% and 0%). In the stromal cells, the expressions of estrogen receptor, progesterone receptor, alpha-inhibin, and p27/kip1 were similar between MCT(P) (63%, 75%, 50%, and 63%, respectively) and MCT(O) (57%, 71%, 81%, and 57%, respectively), but significantly different between both tumors and DC (0%, 0%, 0%, and 0%, respectively). CONCLUSIONS: MCT(P) and MCT(O) have several immunohistochemical similarities and are significantly different from DC. The female sex hormone system may play a major role in the development of both MCT(P) and MCT(O). A frequent p27/kip1 expression level was associated with nonaggressive progression of both tumors.

Cystic neoplasms of the exocrine pancreas.

The increasing use of radiological imaging has led to greater detection of small and asymptomatic cystic lesions of the pancreas. Most are resectable, but not all are neoplastic. This review provides an update on the histopathology, immunohistochemistry, molecular biology, pathogenesis and management of cystic neoplasms of the exocrine pancreas. These include the serous, the mucinous cystic, the intraductal papillary mucinous and the solid pseudopapillary neoplasms. Recently reported variants are described and very rare cystic variants of other pancreatic epithelial and mesenchymal neoplasms are briefly mentioned.

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.

The level of carcinoembryonic antigen and the presence of mucin as predictors of cystic pancreatic mucinous neoplasia.

OBJECTIVES: Characterization of pancreatic cysts using endoscopic ultrasound-guided fine-needle aspiration includes cytological interpretation and chemical analysis. We prospectively analyzed the contribution of carcinoembryonic antigen (CEA) and cytological identification of extracellular mucin as predictors of mucinous neoplasia and malignancy. METHODS: From January 2003 to October 2005, all patients referred to the University of Virginia with cystic lesions of the pancreas underwent endoscopic ultrasound-guided fine-needle aspiration with cytological evaluation and CEA level analysis. Data were collected prospectively and confirmed by resection or tissue biopsy. Univariate and multivariate analyses were performed on the following variables with regard to their ability to predict mucinous neoplasia: age (<55 or >55 years), sex, CEA level (<300 or >300 ng/mL), and cytological appreciation of extracellular mucin (positive or negative). P values less than 0.05 were considered significant. RESULTS: A total of 43 patients were included in this study. There were 19 men and 24 women with a mean age of 63 +/- 14 years. The only complication was pancreatitis secondary to cyst leak in one patient. Multivariate analysis confirmed CEA level greater than 300 ng/mL (P= 0.007) and the identification of mucin (P < 0.001) as significant predictors. CONCLUSIONS: With pancreatic cyst fluid analysis, the strongest predictor of mucinous neoplasia is the presence of identifiable mucin, followed by a CEA level greater than 300 ng/mL. The workup of cystic lesions of the pancreas should include chemical analysis for the CEA level and cytological examination with particular attention to extracellular mucin.

Mucinous cystadenocarcinoma of the pancreas developing during hormone replacement therapy.

Hormone replacement therapy (HRT) containing estrogens is generally used to relieve climacteric symptoms and to prevent osteoporosis and coronary heart disease [1], however, there has been increasing evidence of the HRT as the risk of hormone-dependent neoplasms including breast cancer [2], uterine endometrial cancer [3], ovarian cancer [4], and even lung cancer [5]. Noteworthy is mucinous cyst neoplasms (MCNs) of the pancreas, characterized by mucin-producing columnar epithelium supported by "ovarian-like" mesenchymal stroma, occur mostly in females expressing estrogen receptors [6, 7]. Although several reports regarding the closed relationship between MCNs and pregnancy [8, 9] might imply potential sex hormone-dependency of the MCNs [10], no correlation has been reported. This is the first case report of malignant MCN developing during continuous HRT after hysterectomy.

Primary broad ligament cystadenocarcinoma with mucinous component: a case report with immunohistochemical study.

Primary cystadenocarcinoma that arises in the broad ligament is extremely rare, especially when it is mucinous. We report the case of a 59-year-old woman with a cystic mass of the right broad ligament who underwent a complete excision of the mass (7 x 7 x 3 cm) with hysterectomy, right salpingo-oophorectomy, omentectomy, appendicectomy, and peritoneal biopsies. Pathologic examination showed a low-grade cystadenocarcinoma with a mucinous component limited to the broad ligament. Despite the chemotherapy (cisplatinum and cyclophosphamide) performed, early tumor recurrence occurred after approximately 6 months. Our observation revealed an abundant mucin production with pools of mucin similar to those of pseudomyxoma peritonei and an inflammatory infiltrate with prominent lipid phagocytosis. Immunohistochemical analysis demonstrated a strong and diffuse positivity for both cytokeratin 7 and epithelial membrane antigen. A less extensive staining with carcinoembryonic antigen and a focal unequivocal positivity with cytokeratin 20, particularly in mucin-secreting cells, were also observed. This finding could indicate a metaplastic process toward colonic phenotype similar to primary ovarian tumors.

The value of serum and tissular expression of CA 125 antigen, in evaluation of the response to second line chemotherapy for the relapsed ovarian carcinoma.

PURPOSE: The purpose of this study is to compare the predicted value of the blood levels variations of CA 125 antigen and the imunohistochemical expression of CA 125, with imagistic criteria (The Response Evaluation Criteran in Solid Tumor--RECIST) regarding the survival estimation of female patients with relapsed ovarian carcinoma which undergo to second line chemotherapy. MATERIAL AND METHOD: We included in this study 40 female patients diagnosed with ovarian carcinoma in the Oncology Clinic of the Emergency County Hospital Craiova, in a period of two years (from 2000 to 2002), which have fulfilled the following criteria: ovarian carcinoma IC-IV stage, according to FIGO system, first line treatment represented by the association between paclitaxel and a platinum salt, refractory or recurrent disease, indications for beginning the second line chemotherapy represented by topotecan or paclitaxel and carboplatin. The serial CA 125 antigen was determined in all patients before starting the chemotherapy and after each two sequences of chemotherapy, and the imunohistochemical expression of CA 125 was evaluated from surgery extracts before the second line chemotherapy (11 cases). The imagistic evaluation of the treatment response was done after 4 sequences of chemotherapy. RESULTS: All patients had measurable disease according to RECIST criteria and had high values (at least double) of the CA 125 antigen blood level at the time of diagnosis. The imunohistochemically expression of CA 125 was correlated in most cases with the blood level of CA 125. The evaluation criterion of the CA 125 antigen has been shown to be more efficient in estimation the survival rate compared with the RECIST system. In a various analysis, which included numerous potential prognostic factors, only the variation of blood levels of these antigen and the free disease interval from the finalization of the first line chemotherapy have been identified as predictive factors of survival, while the other variables, including the RECIST criteria, had no impact on the prognosis regarding the survival. CONCLUSIONS: The response evaluation criteria based on the blood levels variations of CA 125 antigen are a better instrument for the estimation of the compared prognosis with the RECIST criteria, for patients on second line chemotherapy for relapsed ovarian carcinoma.

Retroperitoneal mucinous cystadenoma: report of two cases and review of the literature.

Primary retroperitoneal cystic tumor is extremely rare, and its histogenesis and biological behavior remain speculative. Two surgical cases of retroperitoneal mucinous cystadenoma (Case 1, an 18-year-old woman; and Case 2, an 85-year-old woman) are reported. The cystadenomas in these cases were mainly lined by a monolayer of columnar or thin flat cells. Case 1 was positive for mucin and epithelial membrane antigen, whereas Case 2 was positive for a mesothelial marker (calretinin). Ciliated epithelium was also interspersed in Case 2. Some parts showed papillary projections, resembling well-differentiated papillary mesothelioma. Within the cyst walls of both cases, ovarian-like stroma that was positive for both estrogen and progesterone receptors was found. Interestingly, focal nodular hyperplasia of the liver was also detected in Case 1. We believe the retroperitoneal mucinous cystadenoma might have arisen from the peritoneum via mucinous epithelial metaplasia with a phenotype of extragenital Mullerian system.

Characterisation of oestrogen receptor, progesterone receptor, trefoil factor 1, and epidermal growth factor and its receptor in pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma.

BACKGROUND AND AIMS: The pancreatic cystic neoplasms, including solid pseudopapillary tumour (SPT), mucinous cystic neoplasm (MCN), and intraductal papillary mucin producing tumour (IPMT), have their characteristic clinicopathological features. A systematic investigation of oestrogen receptor (OR), progesterone receptor (PR), trefoil factor 1(TFF1), and epidermal growth factor and its receptor (EGF and EGFR) expressed in pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma was determined to elucidate their corresponding sex and age predilection, cell origin, and pathway of malignant transformation. METHODS: Surgical specimens of SPT (n=10), MCN (n=12), IPMT (n=10), and ductal adenocarcinoma (n=20) were studied. The expression of OR, PR, TFF1, EGF, and EGFR were each determined in each disease entity using monoclonal antibodies by immunohistochemical method. The results were correlated with the clinicopathological data. RESULTS: PR was expressed in all 10 SPT, whereas OR was expressed in none of 10 SPT. TFF1 was not or weakly expressed in SPT. Although EGF was strongly expressed in seven of 10 SPT, synchronous expression of EGF and its receptor was expressed in none of 10 SPT. Of the 12 MCN, six had PR expression in the stroma cells but not in the neoplastic epithelium, seven had a moderate or strong expression of TFF1, and 10 had no or weak EGFR expression, irrespective of their benigneity or malignancy. Synchronous expression of EGF and EGFR was observed in only one of 12 MCN. Among 10 IPMT, TFF1 and EGFR were moderately or strongly expressed in all six malignancies, whereas TFF1 and EGFR were not or weakly expressed in three of four benigneity. Of 20 ductal adenocarcinomas, TFF1 and EGFR were moderately or strongly expressed in 16 and 12, respectively. Synchronous expression of EGF and EGFR was observed in six of 10 IPMT and nine of 20 ductal adenocarcinoma, respectively. CONCLUSION: PR was uniquely expressed in SPT, and OR and PR were expressed in stroma of MCN, reflecting their sex and age predilection. TFF1 expression was related to EGFR such as in IPMT and ductal adenocarcinoma, not related to EGFR such as in MCN, and not related to hormonal receptors such as in SPT. EGF and its receptor might play a part in the malignant transformation of IPMT and ductal adenocarcinoma, but not of SPT and MCN.

Expression of survivin is associated with malignant potential in epithelial ovarian carcinoma.

Survivin is a new member of the inhibitor of apoptosis family of anti-apoptotic proteins. It has been reported that survivin is expressed during fetal development and in cancer tissues. Because suppression of apoptosis is important for carcinogenesis and tumor growth, we investigated the expression of survivin in human endometrial carcinomas. We analyzed serial frozen sections for survivin protein expression in 26 patients with ovarian epithelial carcinoma and 10 patients with benign cystadenoma of the ovary by fluorescent immunohistochemistry. We analyzed the relationship between the percentages of survivin-stained cells and the characteristics of the patient including histological classification, clinical stage, histological grade, and clinical outcome. Survivin was weakly detected in some benign ovarian cystadenomas (0-12.1%). There was, however, abundant survivin immunoreactivity in the nucleus and/or cytoplasm of the epithelial ovarian carcinoma cells. Scoring on the basis of the percentage of positive cells indicated that survivin expression was significantly associated with PCNA-labeling index, clinical stage, histological grade, clinical outcome, and survival rate (p<0.01, respectively). We conclude that the survivin protein is a defining diagnostic marker for epithelial ovarian carcinomas that may also yield prognostic information.

Expression of 5alpha-reductases in human epithelial ovarian cancer: its correlation with androgen receptor status.

Androgen metabolism and possible actions are considered to play some roles in human epithelial ovarian neoplasms, but the details have not been well studied. We have examined the expression of 5alpha-reductase type 1 and type 2, which catalyze the conversion of testosterone to more active androgen, 5alpha-dehydrotestosterone, and androgen receptor (AR), using immunohistochemistry (104 cases) and reverse transcription-polymerase chain reaction (RT-PCR) (16 cases) as a first step toward understanding the metabolism and possible actions of androgens in human common epithelial ovarian carcinoma. 5alpha-Reductase type 1 was immunopositive in 75 / 104 cases (72.0%), and 5alpha-reductase type 2 in 52 / 104 cases (50.0%) (P < 0.001). There was no significant correlation between patterns of immunolocalization and clinicopathological parameters examined. Median labeling index (LI) for AR was 17.8% (range 0 - 84.4%) which was significantly higher in serous carcinoma than other histological types (P < 0.001). There was a significant positive correlation between 5alpha-reductase type 1 immunoreactivity and AR LI (P = 0.0027), but no significant correlation was detected in 5alpha-reductase type 2. Results of RT-PCR analysis were also consistent with those of immunohistochemistry. The relatively wide distribution of 5alpha-reductase type 1, and its correlation to AR status in human epithelial ovarian malignancies suggest that this isozyme plays important roles in androgen metabolism and actions in these tumors.

Differential expression of human spasmolytic polypeptide (trefoil factor family-2) in pancreatic carcinomas, ampullary carcinomas, and mucin-producing tumors of the pancreas.

Human spasmolytic polypeptide (hSP) is a member of the trefoil peptide group, thought to be involved in mucin production and cell growth. It has been reported that hSP protein is expressed in digestive cancers but not in normal pancreas. The expression of hSP in pancreatic neoplasms has not been investigated in detail. The immunohistochemical expression of hSP protein was investigated in pancreatic carcinomas, ampullary carcinomas, mucin-producing tumors, serous cystadenomas and islet cell tumors of the pancreas. hSP was expressed in 23% of pancreatic duct cell carcinomas, and hSP protein was more frequently detected in cases of early-stage or histologically low-grade duct cell carcinomas than in cases of late-stage or histologically high-grade carcinomas. Patients with hSP protein expression showed a better prognosis than did those with negative hSP expression. hSP expression was detected in 92% of mucin-producing tumors, but was not detected in serous cystadenoma or islet cell tumors. Immunohistochemical hSP expression is related to differentiation and a better prognosis in pancreatic duct cell carcinomas. Furthermore, hSP protein is related to the pathogenesis and clinical characteristics of mucin-producing tumors of the pancreas.