Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules.

CONTEXT: Thyroid nodules are common in adults, but only a small fraction of them are malignant. Fine-needle aspiration (FNA) with cytological evaluation is the most reliable tool for cancer diagnosis in thyroid nodules. However, 10-40% of nodules are diagnosed as indeterminate by cytology, making it difficult to optimally manage these patients. OBJECTIVE: The aim of this study was to establish the feasibility and role of testing for tumor-specific mutations in improving the FNA diagnosis of thyroid nodules. DESIGN: The prospective study included 470 FNA samples of thyroid nodules from 328 patients. At the time of aspiration, a small portion of the material was collected and tested for BRAF, RAS, RET/PTC, and PAX8/PPARgamma mutations. The mutational status was correlated with cytology and either surgical pathology diagnosis or follow-up (mean, 34 months). RESULTS: A sufficient amount of nucleic acids were isolated in 98% of samples. Thirty-two mutations were found, including 18 BRAF, eight RAS, five RET/PTC, and one PAX8/PPARgamma. The presence of any mutation was a strong indicator of cancer because 31 (97%) of mutation-positive nodules had a malignant diagnosis after surgery. A combination of cytology and molecular testing showed significant improvement in the diagnostic accuracy and allowed better prediction of malignancy in the nodules with indeterminate cytology. CONCLUSIONS: These results indicate that molecular testing of thyroid nodules for a panel of mutations can be effectively performed in a clinical setting. It enhances the accuracy of FNA cytology and is of particular value for thyroid nodules with indeterminate cytology.

VEGF expression predicts survival in patients with peritoneal surface metastases from mucinous adenocarcinoma of the appendix and colon.

BACKGROUND: High levels of vascular endothelial growth factor (VEGF) in ovarian cancer metastases are associated with a worse prognosis in patients treated with chemotherapy. VEGF-directed therapy improves survival for those with metastatic colorectal cancer. Patients with mucinous adenocarcinomas metastatic to the peritoneal surfaces can be treated with cytoreductive surgery, and both tumor grade and cytoreduction status are prognostic. We hypothesized that angiogenic indices may be prognostic in patients undergoing cytoreductive surgery for mucinous adenocarcinoma of the appendix and colon. METHODS: Cytoreductive cases from a 5-year period from the University of Cincinnati peritoneal malignancy database were reviewed. CD 34 counts (blood vessels) and VEGF expression was evaluated by means of immunohistochemistry on specimens from patients undergoing cytoreductive surgery and intraperitoneal hyperthermic perfusion (IPHP) for mucinous adenocarcinoma. RESULTS: A total of 26 males and 9 females, with a mean age of 50 years, underwent cytoreductive surgery and IPHP for mucinous adenocarcinoma of appendiceal (n = 32) or colonic (n = 3) origin. With a mean follow-up of 18 months (range 1-63 months), 23 had disease recurrence and 12 were alive without recurrence. The mean survival was 19 months (range 1-63 months). CD34 counts did not correlate with recurrence or survival; however, average VEGF counts correlated with survival (P = 0.017), and, for patients with recurrence, this correlation was stronger (P = 0.002). CONCLUSIONS: These results suggest that markers of tumor angiogenesis may predict survival in patients with peritoneal surface metastases from mucinous adenocarcinoma. These findings provoke the hypothesis that antiangiogenic therapies may be effective in patients with this devastating disease.

Macrophages mediate inflammation-enhanced metastasis of ovarian tumors in mice.

The tumor microenvironment is known to have a profound effect on tumor progression in a highly context-specific manner. We have investigated whether peritoneal inflammation plays a causative role in ovarian tumor metastasis, a poorly understood process. Implantation of human ovarian tumor cells into the ovaries of severe combined immunodeficient mice resulted in peritoneal inflammation that corresponds temporally with tumor cell dissemination from the ovaries. Enhancement of the inflammatory response with thioglycolate accelerated the development of ascites and metastases. Suppression of inflammation with acetyl salicylic acid delayed ascites development and reduced tumor implant formation. A similar prometastatic effect for inflammation was observed when tumor cells were injected directly into the peritoneum of severe combined immunodeficient mice, and in a syngeneic immunocompetent mouse model. Inflammation-modulating treatments did not affect primary tumor development or in vitro tumor cell growth. Depletion of peritoneal macrophages, but not neutrophils or natural killer cells, reduced tumor progression, as assessed by ascites formation and peritoneal metastasis. We conclude that inflammation facilitates ovarian tumor metastasis by a mechanism largely mediated by macrophages, and which may involve stromal vascular endothelial growth factor production. The confirmation of these findings in immunocompetent mice suggests relevance to human disease. Identifying the mechanisms by which macrophages contribute to tumor metastasis may facilitate the development of new therapies specifically targeting immune cell products in the tumor microenvironment.

Lobular neoplasia at 11-gauge vacuum-assisted stereotactic biopsy: correlation with surgical excisional biopsy and mammographic follow-up.

OBJECTIVE: The objective of our study was to evaluate the outcome of lobular neoplasia diagnosed at 11-gauge stereotactic vacuum-assisted biopsy (SVAB). MATERIALS AND METHODS: Retrospective review of 1,819 lesions sampled with 11-gauge SVAB yielded 27 patients with lobular neoplasia as the most severe pathologic entity diagnosed. Patients with lobular neoplasia associated with atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), or infiltrating carcinoma were excluded. Twenty patients underwent surgical excisional biopsy, and seven patients were followed mammographically for a mean of 52 months (range, 14-67 months). Mammographic lesion type, number of specimens obtained per lesion, and specific histologic features related to lobular carcinoma in situ (LCIS) were assessed. Results were compared with histologic findings at surgery or mammographic follow-up. RESULTS: Nineteen lesions presented mammographically as microcalcifications, four as masses, three as masses with associated microcalcifications, and one as architectural distortion. A mean of 13 specimens were obtained per lesion. Carcinoma was found at surgical excision in 19% of the lesions (5/27). Lesions were upgraded to DCIS (n = 2), invasive lobular carcinoma (n = 2), and mixed invasive ductal and lobular carcinoma (n = 1). In addition to the diagnosis of lobular neoplasia at SVAB, one patient presented with synchronous infiltrating ductal carcinoma in the contralateral breast, and two patients developed metachronous infiltrating ductal carcinoma in a different quadrant of the ipsilateral breast. Twelve of the 27 lesions included LCIS. These lesions were evaluated pathologically to distinguish the classic (10/12) from the pleomorphic (2/12) form of this entity. Ten of the 12 LCIS cases underwent surgical excisional biopsy with four of the five upgrades occurring in these patients. Only one of these patients was shown to have the pleomorphic type of LCIS. Lesions in seven patients who underwent mammographic follow-up remained stable. CONCLUSION: The known association of lobular neoplasia with high-risk and malignant lesions at surgical biopsy requires careful consideration when lobular neoplasia is diagnosed as the most severe histologic entity at SVAB. The diagnosis of lobular neoplasia at 11-gauge SVAB is not reliable in view of the 19% upgrade rate at the time of surgical excisional biopsy in our study. No predictive mammographic features allowed distinction between the patients with lesions that were upgraded at the time of surgery from those whose lesions were not upgraded.

Granular cell tumor of the breast: a series of 17 cases and review of the literature.

Seventeen cases of granular cell tumor (GCT) of the breast are reviewed. The demographics and clinical features are reviewed and the radiologic and pathologic features as well as the immunohistochemistry are discussed. To our knowledge, our series of 17 breast GCT cases represent the largest series published to date.

Duodenal gangliocytic paraganglioma with lymph node metastasis: a case report and review of the literature.

A case of duodenal gangliocytic paraganglioma (DGP) in a 67-year-old woman is presented. The DGP arose in the second part of the duodenum. Although most of the reported cases of DGP are considered benign, in the present case, we found regional lymph nodes containing metastatic tumor. Previous reports have documented metastases containing only epithelioid cells. The current case demonstrates metastatic tumor in regional lymph nodes containing all 3 of the DGP components (spindle cells, ganglion-like cells, and epithelioid cells).