Clinicopathological study of intraductal carcinoma of the salivary gland, with emphasis on the apocrine type.

Intraductal carcinoma (IC) is a rare salivary gland tumor with low- to intermediate-grade cytological features. It is further classified into intercalated duct type and apocrine type based on its distinct histologic and immunohistochemical expression. Conventional salivary duct carcinoma (SDC) is an aggressive carcinoma with high-grade features and is usually associated with poor prognosis. In this study, immunohistochemistry and mutation analyses (including HRAS/PIK3CA mutations, RET rearrangement, and human epidermal growth factor receptor 2 [HER2] amplification) of 9 ICs (including 3 pure ICs, 6 ICs with invasive carcinoma) and 24 conventional SDCs were performed and the results were compared. Four intercalated duct-type cases were positive for SOX10 and S100 and negative for AR; five apocrine-type cases showed opposite results. All five apocrine-type cases had cysts with relatively circumscribed tumor borders and morphologically mimicking breast low-grade ductal carcinoma in situ or papillary carcinoma. RET fusion is detected in half of the 4 intercalated duct-type IC but not in the apocrine-type or conventional SDC. HER2 amplification was only observed in conventional SDC. The monoclonal antibody (clone RBT-NRAS) against NRAS Q61R is a sensitive and specific marker used for detecting HRAS Q61R mutation in the salivary gland tumors. The apocrine-type IC had different cytological grades, distinct tumor growth patterns, and no evidence of low- to high-grade transition, suggesting that apocrine-type IC should be distinguished from apocrine SDC with an in situ component.

Submandibular gland cystadenocarcinoma with mucinous adenocarcinoma-like areas: a case report.

Cystadenocarcinoma is primarily characterized by cystic structures of varying sizes, that are lined by epithelial cells. As a rare neoplasm, only four cases of cystadenocarcinoma of submandibular glands have been previously reported. Herein, we reported a unique case of submandibular gland cystadenocarcinoma in a 44-year-old man. By in large, this case had typical morphologic cystadenocarcinoma features. However, mucinous adenocarcinoma-like areas were additionally observed in the tumor tissues. This case was initially misdiagnosed as mucinous adenocarcinoma due to the low incidence of submandibular gland cystadenocarcinoma and the presentation of mucinous adenocarcinoma-like areas in the tumor tissues. Histopathology of additional tumor tissues revealed that mucinous adenocarcinoma-like areas accounted for only a small percentage of the tumor tissues, confirming the submandibular gland cystadenocarcinoma diagnosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1387916949121142.

Ovarian cancer initially presenting with isolated ipsilateral superficial inguinal lymph node metastasis: a case study and review of the literature.

Isolated superficial inguinal metastases without any extended intra-abdominal spread is a rare event in patients with ovarian carcinoma. Here we report an isolated superficial inguinal metastasis in a patient with primary ovarian cancer. A 54-year-old Chinese patient with primary ovarian cancer, had an isolated painless enlarged right groin swelling (3×2cm) as the only manifestation, preoperative pathology confirmed metastatic adenocarcinoma. Gynecologic examination, transvaginal ultrasonography of the abdominopelvic cavity revealed a 5-cm mixed, right adnexal mass. At exploratory laparotomy, there was little intra-abdominal tumor dissemination but 100 ml of faint yellow peritoneal fluid and a 5-cm right ovarian tumor with intact capsule. Staging operation was performed and postoperative pathology confirmed adenocarcinoma located within right ovarian, with no evidence of involvement of other sites. Then the patient received adjuvant chemotherapy for Stage IVB. Five years later, the patient is currently still alive without evidence of recurrent disease. This case indicate that ovarian carcinoma isn't a disease localized only within the intra-peritoneal cavity, isolated superficial inguinal lymph node metastasis might occur in rare cases via potential lymphatic and (or) hematogenous route under special conditions. We propose the need to investigate the possible mechanisms, risk factors, metastatic patterns, the biology and natural history of such patients in a large-scale and multicenter analysis. Furthermore, efforts should be made for earlier and differential diagnosis and finally prolong survival time for such patients.

Searching for mammary analogue [corrected] secretory carcinoma of salivary gland among its mimics.

Mammary analog secretory carcinoma of salivary gland is a recently described entity with unique morphologic, clinical, and genetic characteristics, including the characteristic t(12;15)(p13;q25) with ETV6-NTRK3 translocation found in secretory carcinomas of the breast. Before their initial description, these salivary gland tumors were generally diagnosed as acinic cell carcinoma or adenocarcinoma. For the purpose of this study, all cases of salivary gland acinic cell carcinoma, cribriform cystadenocarcinoma, and adenocarcinoma, not otherwise specified (NOS), diagnosed over a 10-year period were retrieved from our surgical pathology files. There were a total of 11 cases diagnosed as acinic cell carcinoma, 10 cases of adenocarcinoma, NOS, and 6 cases of cribriform cystadenocarcinoma. All slides were reviewed by two pathologists (AP, CGF) and tumors that show morphologic features of mammary analog secretory carcinoma according to the recent literature were selected. This process narrowed down the initial number to six cases originally diagnosed as acinic cell carcinoma, three cases originally diagnosed as adenocarcinoma, NOS, and one case originally diagnosed as cribriform cystadenocarcinoma. The 10 cases were subjected to immunohistochemistry for S-100, mammaglobin, and ANO1, as well as fluorescence in situ hybridization analysis for t(12;15)(p13;q25) with ETV6-NTRK3 fusion rearrangement. The ETV6-NTRK3 gene rearrangement was detected in three tumors. These three tumors, initially diagnosed as acinic cell carcinomas, stained positive for S-100 and mammaglobin, and negative for ANO1 by immunohistochemistry. Two of the three patients were male (2/3). In summary, mammary analog secretory carcinoma is a newly described diagnostic entity that should be in the differential diagnosis of salivary gland tumors that morphologically mimic other neoplasms, mainly acinic cell carcinomas. They differ from conventional acinic cell tumors immunohistochemically and molecularly. Positivity for mammaglobin and S-100, and negativity for ANO1 are useful screening tools before confirmatory molecular studies.

Low-grade cribriform cystadenocarcinoma of salivary glands: report of two cases and review of the literature.

Low-grade cribriform cystadenocarcinoma (LGCCC) is a recently described rare tumor of salivary gland which exhibits clinically indolent behavior. This tumor predominantly consists of intraductal components and frequently exhibits papillary-cystic or cribriform proliferation pattern. Considering the histological features of LGCCC, it should be distinguished with papillocystic variant of acinic cell carcinoma, conventional salivary duct carcinoma, cystadenocarcinoma, polymorphous low-grade adenocarcinoma, carcinoma ex pleomorphic adenoma and mammary analogue secretory carcinoma. Herein, we presented two cases of LGCCC. One arose in the left parotid region in a 48-year-old male, and the other one arose in the right parotid gland in a 59-year-old female. For both cases, immunohistochemically, the luminal tumor cells showed diffuse expression of CK and S100; p63 and smooth muscle actin displayed a continuous rim of myoepithelial cells around all tumor islets; no myoepithelial cells were admixed with the luminal cells. Both patients were alive with no tumor recurrence or metastasis at follow-up. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2593621568999135.

Cytologic features of low-grade cribriform cystadenocarcinoma of the submandibular gland: a case report.

BACKGROUND: Low-grade cribriform cystadenocarcinomas (LGCCC) are rare salivary gland tumors, classified into a variant of cystadenocarcinoma by the 2005 WHO classification. All previously reported cases arose from parotid glands, except for a case from a minor salivary gland. We report here for the first time a case of LGCCC arising from the submandibular gland. CASE: A 65-year-old man presented with a 4-cm multicystic mass in the left submandibular gland. Smears from fine-needle aspiration cytology showed tumor cells, appearing solitarily or partly in clusters, with thick cytoplasm and central nuclei. Some clustering tumor cells showed large cytoplasmic vacuoles and peripherally dislocated nuclei. Although these findings indicated a possible mucoepidermoid carcinoma in the submandibular gland, the final diagnosis of the resected specimen was LGCCC. CONCLUSION: LGCCC can arise not only from the parotid glands, but also in the submandibular glands. LGCCC is thought to be of low-grade malignancy; no reported cases have shown tumor metastasis and there are no patients who are known to have died of this disease. Thus, differential diagnosis of this tumor from other malignant salivary gland tumors is quite important; however, this might be difficult when based solely on cytological findings.

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.

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.

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.

Cyst fluid analysis obtained by EUS-guided FNA in the evaluation of discrete cystic neoplasms of the pancreas: a prospective single-center experience.

BACKGROUND: Accurate assessment of pancreatic cystic neoplasms is imperative before selecting available treatment options, such as surgical resection, drainage, or conservative therapy. Available modalities, CT and magnetic resonance imaging, have been inconsistent in diagnosis. Reports involving EUS and cyst fluid analysis have been encouraging, including studies of EUS features and/or cyst fluid analysis, which may differentiate pancreatic cystic neoplasms. OBJECTIVE: To retrospectively determine cyst fluid characteristics that differentiate cystic neoplasms. DESIGN: Patient evaluation included (1) EUS features (reported elsewhere) and (2) cyst fluid analysis (carcinoembryonic antigen [CEA], carbohydrate antigen 19-9 [CA 19-9], amylase and lipase, viscosity [VIS], mucin stain, and cytology). Exclusion criteria included the following: intraductal papillary mucinous tumor lesions, bloody cyst aspirate, neuroendocrine tumors, and patients without surgical histopathology. SETTING: Pancreatic Biliary Center, St Luke's Medical Center, Milwaukee, Wisconsin. PATIENTS: A total of 102 patients (60 women, 42 men; age, 23-76 years) presented for evaluation of pancreatic cystic neoplasm; 71 underwent surgical resection. RESULTS: Seventy-one of 102 patients who underwent surgery presented the following histopathologic correlates: 23 pseudocysts (PC), 13 serous cystadenoma (SCyA), 21 mucinous cystadenoma (MCyA), and 14 mucinous cystadenocarcinoma (MCyA-CA). Cyst fluid analysis of these patients showed the following: VIS was lower in PC (mean, 1.3) and SCyA (1.27) when compared with MCyA (1.84) and MCyA-CA (1.9). All mucinous neoplasms had VIS >1.6, whereas only 2 mucinous cystic neoplasms (MCN) had VIS = 1.6 (both PC). The CEA level was significantly higher in MCyA (adenoma [878 ng/mL], carcinoma [27,581 ng/mL]) vs PC (189 ng/mL), and SCyA (121 ng/mL). Amylase levels were higher in PC (7210 U/L) compared with cystic neoplasm (SCyA, 679 U/L; MCyA, 1605 U/L; MCyA-CA, 569 U/L). CONCLUSIONS: Differential diagnosis of pancreatic cystic neoplasm is significantly enhanced by cyst fluid analysis. Elevated CEA (> or =480 ng/mL) and VIS (>1.6) accurately predict MCN from SCyA and PC. Malignant from benign MCN can be differentiated by CEA levels > or =6000 ng/mL.

Vascular endothelial growth factor and its soluble receptor in ovarian pathology.

OBJECTIVE: The soluble form of the vascular endothelial growth factor (VEGF) receptor, s-VEGFR-1, may negatively regulate the action of VEGF. Our purpose was to better understand the regulation of angiogenetic processes in ovarian cysts. METHODS: Seventy-three women, 36 with serous cystoadenoma, 30 with ovarian endometriosis and seven with cystoadenocarcinoma, were enrolled. We calculated both VEGF and s-VEGFR-1 levels in cystic fluid and a VEGF activity index by means of the ratio VEGF/s-VEGFR-1. Student's t test was used for the statistical analysis. RESULTS: We found higher VEGF concentration in both endometriotic and malignant lesions than in serous cystoadenoma (p=0.03 and 0.001, respectively). Also s-VEGFR-1 concentration was higher in endometrioma than in serous cysts (p=0.005); however, there was no statistically significant difference between cystoadenoma and the malignant lesions (p=0.15). VEGF activity index in cystoadenoma, endometriotic and malignant lesions was 0.61, 0.27 and 0.50, respectively. CONCLUSIONS: VEGF certainly has an important role in both ovarian endometriosis and for cancer progression; however, the activity index may be better to investigate the real role of VEGF in the pathology we have considered.

Acinar cell cystadenocarcinoma of the pancreas: report of rare case and review of the literature.

Most exocrine pancreatic tumors are of ductal origin, whereas acinar cell adenocarcinomas are unusual (1% to 2% of all exocrine pancreatic neoplasms). We recently found a cystic adenocarcinoma of the pancreatic body whose cells had the characteristics of acinar cells, which we term acinar cell cystadenocarcinoma. Macroscopically, this tumor consists of a large multilocular cystic mass with a pseudocapsule and a spongy appearance on the cut surface. Microscopically, the cysts are lined by a single layer of cuboid/columnar cells. The cytoplasm has the characteristics of acinar cells, with eosinophilic granules in the apex and prominent nucleoli. Immunohistochemically, the cells express alpha1-antitrypsin, trypsin, and lipase in their cytoplasm, thus confirming the acinar origin of the tumor. A review of the literature revealed only 5 other cases of this tumor reported since its first description in 1981. Follow-up data are available for 4 of these; all of the affected patients had metastases at presentation or a few months later, and 2 died of the disease, at 13 and 37 months after diagnosis. Although this variant of adenocarcinoma of the pancreas is not prognostically different from the classic solid type (few patients survive more than 5 years), we believe that it is important because of its extreme rarity.

Differential tumor microenvironment in human ovarian cystic tumors.

AIMS AND BACKGROUND: Cells and soluble mediators obtained from tumor effusions are useful in evaluating the tumor microenvironment. Our aim was to examine cytologically and to quantify the leukocyte infiltrate, nitric oxide, cytokines and tumor markers in the intracystic fluid from patients with a cystic adnexal mass, for a possible differentiation between benign and malignant findings. METHODS AND STUDY DESIGN: Sixty-six women who had their cystic fluids collected were prospectively divided into benign tumor (22, 33.3%), malignant tumor (10, 15.2%) or other gynecological alterations (34, 51.5%). Cytology, total and differential leukocyte counts were determined by light microscopy. Tumor markers, cytokines and nitric oxide were assayed in the supernatants using the Immulite system, ELISA and Griess reaction, respectively. RESULTS: The sensitivity and specificity of the cytological analysis was 66.7% and 97.7%, respectively. The levels of CA 19.9, CA 15.3, alpha-fetoprotein, carcinoembryonic antigen, progesterone and beta-HCG were significantly higher in the benign and/or malignant group than in the other gynecological alterations. Also, the local concentrations of CA 15.3 and beta-HCG were significantly higher in malignant than in benign tumors. In malignant tumors, increased leukocyte counts and higher concentrations of IL-6, IL-10 and nitric oxide were detected than in benign tumors or other gynecological alterations. CONCLUSIONS: In malignant tumors, the microenvironment could be differentiated from benign tumors or other gynecological alterations by cystic fluid analysis.

WT1 immunoreactivity in uterine papillary serous carcinomas is different from ovarian serous carcinomas.

WT1 diffusely stains most ovarian serous carcinomas; reactivity of uterine papillary serous carcinomas has not been evaluated. We studied WT1 expression in 13 International Federation of Gynecology and Obstetrics stage 1 and 5 stage 3 or 4 uterine papillary serous carcinomas without ovarian metastases and compared their reactivity with the WT1 staining of 30 ovarian serous carcinomas. WT1 reactivity was evaluated with the C19 and 6F-H2 antibody clones. All 18 uterine papillary serous carcinomas were nonreactive for WT1. The nonovarian metastases of the 5 high-stage uterine papillary serous carcinomas also were nonreactive for WT1. In contrast, 29 (97%) of 30 ovarian serous carcinomas were reactive for WT1. WT1 reactivity in an unknown primary serous carcinoma would suggest it is from a nonuterine site. The mechanisms underlying these findings are unknown. They raise the possibility of genetic differences between the 2 morphologically similar neoplasms.

Antimetastasis gene expression and numerical chromosomal abnormalities of chromosomes 1 & 17 in serous tumours of the ovary.

OBJECTIVE(S): The aim of this study was to examine the expression of the antimetastasis gene nm23 and numerical changes on chromosome 1 and 17 in ovarian tumours. METHODS: In this study 20 serous cystadenocarcinomas, ten borderline and five benign tumours were analysed for expression of the nm23 antimetastasis gene by immunohistochemistry and for numerical chromosomal abnormalities of chromosomes 1 and 17 by interphase cytogenetics. RESULTS: Strong intracytoplasmic immunoreactivity with the antimetastasis gene was observed in late stage carcinomas but not in benign or borderline tumours or in lymph node metastases. Numerical abnormalities were only observed in carcinomas. CONCLUSION(S): These sets of data are consistent with the majority of benign and borderline tumours lacking invasive potential. Odds Ratio (OR) assessment indicates that the presence of numerical aberrations correlates with immunopositivity.

WT1 is an integral component of an antibody panel to distinguish pancreaticobiliary and some ovarian epithelial neoplasms.

We investigated whether a panel of antibodies including WT1 could separate pancreaticobiliary and ovarian carcinomas by staining 64 pancreaticobiliary adenocarcinomas, 41 ovarian serous carcinomas, and 12 primary ovarian mucinous neoplasms with WT1, cytokeratin (CK) 17, CK20, carcinoembryonic antigen (CEA), and CA-125. Moderate or strong intensity reactivity in more than 25% of cells was a positive result. Of the ovarian serous carcinomas, 38 (93%) were WT1 reactive and 22 (54%) WT1 positive, 9 (22%) had CK20 reactivity, and 3 (7%) were CK20 positive in fewer than 50% of cells. All were CK17 or CEA nonreactive. Of the ovarian mucinous neoplasms, all were WT1 and CK17 nonreactive and 11 (92%) were CEA reactive, 8 (67%) CEA positive, 10 (83%) CK20 reactive, and 6 (50%) CK20 positive. Of the pancreaticobiliary adenocarcinomas, 19 (30%) were CK20 positive, 27 (42%) CK17 positive, and 52 (81%) CEA positive. All were WT1 nonreactive. A panel including WT1, CK17, CK20, and CEA is useful to distinguish pancreaticobiliary and ovarian serous carcinomas. Extensive CK17 reactivity is supportive of a pancreaticobiliary adenocarcinoma when the differential diagnosis includes ovarian mucinous neoplasm. None of the antibodies positively identified ovarian mucinous neoplasms.

Immunohistochemical pattern of hMSH2/hMLH1 in familial and sporadic colorectal, gastric, endometrial and ovarian carcinomas with instability in microsatellite sequences.

Alterations of DNA mismatch repair (MMR) genes are involved in carcinogenesis of sporadic and inherited human cancers characterised by instability of DNA microsatellite sequences (MSI). MSI tumours are usually identified using molecular analysis. In the present investigation, hMLH1 and hMSH2 immunohistochemistry was tested in order to evaluate the utility of this method in predicting MMR deficiency. Colorectal (72), gastric (68), endometrial (44) and ovarian (17) carcinomas were independently evaluated for familial history, histological type of tumour, MSI status and immunohistochemical results. Loss of expression of either hMLH1 or hMSH2 was observed in 51 of 55 (92.8%) MSI tumours, while 145 of 146 microsatellite stable (MSS) tumours expressed both the hMLH1 and hMSH2 gene products. Independently of tumour site, an overall agreement between immunohistochemical and molecular results was observed in 15 hereditary non-polyposis colorectal cancer-related tumours. Among sporadic tumours, only 2 of 60 colorectal and 2 of 66 gastric carcinomas, displaying MSI, expressed both hMLH1 and hMSH2 gene products. All 39 endometrial and 16 ovarian tumours presented a concordant molecular and immunohistochemical profile. These data show that immunohistochemistry is an accurate and rapid method to predict the presence of defective DNA MMR genes and to identify both sporadic and familial MSI tumours.