Recent advances have revealed a significant contribution of chemokines and their receptors in tumor growth, survival after chemotherapy, and organ-specific metastasis. The CXC chemokine receptor-7 (CXCR7) is the latest chemokine receptor implicated in cancer. Although over expressed in breast cancer cell lines and tumor tissues, its mechanism of action in breast cancer (BrCa) growth and metastasis is unclear. Studies in other cancers have implicated CXCR7 in cell proliferation, anti-apoptotic activity and cell-cell adhesion. The present study was initiated to examine the pattern of CXCR7 expression and its role in regulation of growth signaling in breast cancer. The contribution of CXCR7 in BrCa cell proliferation was investigated in representative cell lines using real time quantitative PCR (q-PCR), proliferation assays, immunohistochemistry and immunoblotting. Phenotypic changes were examined after CXCR7 specific cDNA and siRNA transfection and expression levels were monitored by q-PCR. Further, the association of CXCR7 with epidermal growth factor receptor (EGFR) and modulation of its activity were investigated by western blotting, immunofluorescence, and in-situ proximity ligation assays in human BrCa cells and tissues. CXCR7 was expressed in both, estrogen receptor (ER) positive and negative BrCa cell lines. CXCR7 was also expressed unevenly in normal breast tissues and to a much higher extent in ER + cancer tissues. Depletion of CXCR7 in MCF7 BrCa cells by RNA interference decreased proliferation and caused cell cycle arrest. Further, proximity ligation assay (PLA) revealed colocalization of CXCR7 with EGFR in cancer tissues and cancer cell lines. CXCR7 depletion reduced levels of phospho-EGFR at Tyrosine1110 after EGF-stimulation and also reduced phosphorylation of ERK1/2, indicating a potentially direct impact on mitogenic signaling in MCF7 cells. Using siRNA to knockdown β-arrestin2 in cells with EGFR over expression we were able to nearly deplete the CXCR7-EGFR colocalization events, suggesting that β-arrestin2 acts as a scaffold to enhance CXCR7 dependent activation of EGFR after EGF stimulation. These results demonstrate coupling of CXCR7 with EGFR to regulate proliferation of BrCa cells and suggest an important ligand-independent role of CXCR7 in BrCa growth. Thus, the CXCR7-EGFR axis is a promising target for breast cancer therapy.

Most adrenocortical neoplasms and pheochromocytomas can be diagnosed by a combination of clinical findings and morphologic features. Occasionally, however, this histologic differential diagnosis requires ancillary tests, such as immunohistochemistry. Both tumors are generally negative for epithelial markers but express synaptophysin. Inhibin and chromogranin are used for the diagnosis of adrenocortical neoplasms and pheochromocytomas, respectively. Both antigens, however, are expressed focally and may be completely negative, particularly in small biopsies. The authors investigated the potential value of adding calretinin to inhibin in the differential diagnosis of these tumors. Fifty-five primary adrenal neoplasms including 33 adrenocortical tumors (21 adenomas and 12 carcinomas), 22 pheochromocytomas, and 7 healthy adrenal glands were examined immunohistochemically for the expression of calretinin and inhibin. Inhibin was demonstrated in 24 (73%) adrenocortical neoplasms. When calretinin was added, the number of tumors staining positively for the two markers alone or in combination increased to 31 (94%). Both antigens showed a focal pattern of distribution in many cases. None of the pheochromocytomas reacted for any of these two markers. Healthy adrenal gland showed a distinct positive and negative pattern of immunoreactivity for both antigens in cortex and medulla, respectively. There were no differences between staining patterns of calretinin and inhibin in healthy adrenal cortex, adrenocortical adenomas, and adrenocortical carcinomas. The authors conclude that the addition of calretinin to inhibin increases the sensitivity of the diagnosis of adrenocortical neoplasms. When used together, they are highly specific and sensitive for the differential diagnosis of these tumors from pheochromocytomas. These markers, however, do not distinguish between benign and malignant adrenocortical neoplasms.

BACKGROUND In 1996, the National Cancer Institute (NCI) recommended five categories for the diagnosis of breast aspiration cytology: benign, atypical, suspicious, malignant, and unsatisfactory. The authors evaluated the usefulness of separating inconclusive diagnoses into the aforementioned atypical and suspicious categories. The current study examined the correlation between cytologic and histologic findings made in breast aspiration cytology specimens that were categorized in accordance with these NCI guidelines. METHODS From 1992 to 2000, 7727 breast aspirations were performed at the University of Miami/Jackson Memorial Medical Center (Miami, FL). Aspirates were classified using criteria similar to the NCI recommendations. Four hundred eighty-nine aspirates (6%) were classified as being cytologically ‘atypical’ or ‘suspicious’. Of those, 225 ‘atypical’ aspirates and 162 ‘suspicious’ aspirates had available histologic follow-up data and were included in the study. RESULTS Among the ‘atypical’ aspirates, 118 (52%) yielded malignant findings on histologic evaluation. Infiltrating ductal carcinoma (n = 87; 74%) was the most common malignant diagnosis, followed by infiltrating lobular carcinoma (n = 12; 10%). Among ‘suspicious’ aspirates, 135 (83%) yielded malignant findings on histologic analysis. The most common benign diagnosis in both ‘atypical’ and ‘suspicious’ aspirates was proliferative fibrocystic changes with or without atypia, followed by fibroadenoma. CONCLUSIONS Most aspirates that yielded suspicious findings on cytologic examination proved to be malignant, as did > 50% of aspirates that yielded atypical findings. Infiltrating lobular carcinoma commonly was underdiagnosed as being atypical on cytologic examination. Benign lesions with atypical or suspicious cytologic diagnoses included certain cases of atypical ductal hyperplasia. The authors concluded that the distinction between the atypical and suspicious categories, as recommended by the NCI, is not warranted. Therefore, they suggest the use of a single term, such as ‘equivocal’, to describe inconclusive diagnoses on breast fine-needle aspiration cytology. Cancer (Cancer Cytopathol) 2004. © 2004 American Cancer Society.

Heterotopic pancreas is a relatively infrequent lesion most often found in the stomach. Four histologic types are recognized: total, canalicular, exocrine, and endocrine heterotopia. To our knowledge, only 2 cases of purely endocrine heterotopic pancreas have been reported in detail. We describe the case of a patient with gastric and duodenal ulcers and gastric endocrine heterotopia. The lack of mass formation, histomorphology, and immunohistochemical features simulating islets of Langerhans supported the diagnosis. We conclude that purely endocrine heterotopic pancreas is a very rare entity that, when present, can simulate a primary or metastatic neuroendocrine tumor. Adequate sampling of the specimen, histomorphologic pattern, and immunohistochemistry are important for the purpose of distinguishing between a neuroendocrine tumor and purely endocrine pancreatic heterotopia.

Primary angiosarcoma of the spleen is a very rare neoplasm with a poor prognosis. The definitive diagnosis is usually based on the histologic evaluation of the splenectomy specimen. We describe a case of angiosarcoma diagnosed by fine-needle aspiration cytology prior to splenectomy. A 69-year-old white woman presented with heterogeneous lesions in the spleen during a follow-up computed tomographic scan for a history of liposarcoma of the right buttock. A malignant endothelial neoplasm was diagnosed by fine-needle aspiration cytology using immunocytochemistry, and a splenectomy confirmed the presence of angiosarcoma. To our knowledge, this is the first well-documented and confirmed case of primary angiosarcoma of the spleen diagnosed by fine-needle aspiration cytology. This report emphasizes the value of fine-needle aspiration cytology as an important diagnostic tool in splenic neoplasms.