Faculty Bibliography

The cytologic diagnosis of primary conventional renal-cell adenocarcinoma (cRCC) is usually straightforward; however, metastatic cRCC must be distinguished from a variety of neoplasms with clear-cell features. CD10, a cell membrane-associated neutral endopeptidase, and renal-cell carcinoma marker (RCCma), an antibody against human proximal tubular brush border antigen, have recently been shown to be useful in the diagnosis of cRCC. We compared CD10 and RCCma in cell block material from fine-needle aspiration biopsies (FNABs) to assess their utility in the diagnosis of metastatic cRCC, in cytologic specimens. Seven primary and sixteen metastatic cRCCs were immunostained with CD10 and RCCma. The immunoreactivity results were compared with those of a variety of neoplasms originating from other sites such as the liver, lungs, breast, and the gastrointestinal tract. The sensitivity and specificity of CD10 for cRCC were 100% and 59%, respectively. The sensitivity and specificity of RCCma for cRCC were 35% and 100%, respectively. We conclude that CD10 has limited value in confirming the diagnosis of cRCC because of its low specificity. RCCma, when positive, is highly specific for cRCC, but its low sensitivity hinders its diagnostic usefulness. Diagn. Cytopathol. 2005;33:3-7. (c) 2005 Wiley-Liss, Inc

We studied the staining patterns of bronchioloalveolar carcinoma (BAC) with antibodies to cytokeratin (CK) 7, CK20, and thyroid transcription factor-1 (TTF-1) to determine the diagnostic usefulness of this panel in differentiating BAC from metastatic adenocarcinoma in material obtained by fine-needle aspiration biopsy (FNAB) of the lung. We identified 16 cases of BAC. Of these, 6 were mucinous, 4 were nonmucinous, and 6 were mixed with focal mucinous differentiation. Immunohistochemical analysis with antibodies to CK7, CK20, and TTF-1 was performed on cell-block sections. Of the 6 mucinous BACs, 4 (67%) were CK7+, CK20+, and TTF-1-. All 4 nonmucinous BACs were CK7+ and CK20-, and 2 (50%) were TTF-1+. All 6 mixed BACs were diffusely positive for CK7 and focally positive for CK20; 5 (83%) were TTF-1+. Nonmucinous BACs display CK7, CK20, and TTF-1 immunoreactivity similar to conventional pulmonary adenocarcinoma. Mucinous and mixed BACs have an immunohistochemical phenotype that is different from that of conventional pulmonary adenocarcinoma. Knowledge of these staining patterns is crucial for distinguishing mucinous and mixed BACs from metastatic adenocarcinoma involving the lungs

A 62-year-old woman with a history of breast carcinoma being treated with tamoxifen presented with a rapidly enlarging pelvic mass. Imaging studies suggested a uterine leiomyoma with possible sarcomatous transformation. Laparotomy revealed a 15-cm, oval, well-circumscribed mass emanating from the posterior cervix and left uterosacral ligament. The tumor had a variegated fleshy, tan, myxoid, and necrotic sectioned surface. Microscopic examination revealed a variety of patterns and cell types characteristic of liposarcoma that included myxoid/round cell, storiform/pleomorphic, epithelioid, and spindle cell areas. Lipogenic areas exhibited a 'crow's feet' vasculature and characteristic lipoblasts. The tumor cells were highly pleomorphic with numerous mitotic figures, some of them atypical. The tumor cells were immunoreactive for vimentin, estrogen receptors, and S-100. The tumor recurred 9 months postoperatively. Although a variety of uterine tumors have been associated with tamoxifen treatment, this appears to be the first example of tamoxifen-associated uterine liposarcoma

Leiomyosarcoma of the breast is rarely encountered in fine-needle aspiration (FNA) cytologic material. We report a case of primary leiomyosarcoma of the breast in a 52-yr-old female. Aspiration cytology showed large, dissociated round to spindle cells with abundant vacuolated cytoplasm, pleomorphic nuclei, prominent nucleoli, and occasional intranuclear cytoplasmic invaginations. Mitotic figures, osteoclast-like giant cells, and stromal fragments were identified. A diagnosis of malignant neoplasm representing either a sarcoma, a poorly differentiated carcinoma, or a metaplastic carcinoma was made. The patient underwent a wide excision of the lesion after negative work-up. Histologic examination and immunohistochemical studies established the diagnosis of leiomyosarcoma. This case is presented here because we feel that, although FNA cytology with eventual ancillary studies is a valuable diagnostic tool to evaluate any breast mass, malignant spindle cell neoplasms of the breast still represent a diagnostic challenge for the cytopathologist. Recognition of all cytologic features of leiomyosarcoma may help to formulate a correct diagnosis. Diagn. Cytopathol. 2003;29:172-178

Induction of wild-type p53 in mouse fibroblasts causes cell cycle arrest at the G(1) phase, whereas coexpression of p53 and the protooncogene c-myc induces apoptosis. Although p53 transcriptional activity generally is required for both pathways, the molecular components mediating p53-dependent apoptosis are not well understood. To identify factors that could mediate p53-induced cell death, we used a comparative RNA differential display procedure. We have identified Pw1/Peg3 as a gene product induced during p53/c-myc-mediated apoptosis. Pw1/Peg3 is not induced during p53-mediated G(1) growth arrest nor by c-myc alone. Although it is not clear whether the induction of Pw1/Peg3 depends on p53 activity, we show that Pw1/Peg3 interacts with a p53-inducible gene product Siah1a. We demonstrate that coexpression of Pw1/Peg3 with Siah1a induces apoptosis independently of p53 whereas expression of Pw1/Peg3 or Siah1a separately has no effect on cell death. These data suggest that Siah1a and Pw1/Peg3 cooperate in the p53-mediated cell death pathway. Furthermore, we show that inhibiting Pw1/Peg3 activity blocks p53-induced apoptosis. The observation that Pw1/Peg3 is necessary for the p53 apoptotic response suggests a pivotal role for this gene in determining cell death versus survival

Mouse erythroleukemia (MEL) cell erythroid differentiation induced by dimethyl sulfoxide or hexamethylene bisacetamide (HMBA) is accompanied by the production of hemoglobin, terminal cell division and decreases in lactate production and fructose 2,6-bisphosphate levels. A number of studies have suggested that decreases in the cellular level of protein phosphotyrosine content may play a role in MEL cell differentiation. In particular, it was shown that the expression of several protein tyrosine phosphatase genes accompany this process and that the transfection of one of these genes into MEL cells followed by its subsequent expression induced eythroid differentiation. However, none of the physiological substrates for these protein tyrosine phosphatases have been identified. It is shown here that MEL cell differentiation is accompanied by decreases in tyrosine phosphorylation of Vav and possibly of the erythropoietin receptor (EpoR). Immunoprecipitation of the EpoR and analysis of co-precipitated proteins, indicates that the EpoR associates with Vav, STAT5 and an unidentified 60 Kd protein, . HMBA-induced erythroid differentiation abrogates these associations. The phosphatase inhibitors, Na3VO4 and levamisole, inhibit HMBA-induced differentiation as well as the association of the EpoR with Vav, STAT5 and the 60 Kd protein. This is of interest since Na3VO4, at the concentrations used here, has been shown to be a potent inhibitor of the activity of protein tyrosine phosphatases. These results suggest that levamisole, at least indirectly, acts by a molecular mechanism similar to that of Na3VO4 and that the loss of the association of the EpoR with Vav, STAT5, and and/or the reduction in the level of tyrosine phosphorylation of these proteins may play a role in MEL cell differentiation

Tumor necrosis factor (TNF) mediates a variety of biological activities including cell proliferation, differentiation and programmed cell death. The specific response to TNF depends upon cell type and reflects the presence of specific regulatory proteins that participate in the TNF response pathway. TNF signal transduction is mediated by TRAF2 which binds the TNF Receptor2 (TNFR2) and activates NFkappaB. We previously identified a gene Pw1, which encodes a large zinc-finger containing protein. We have determined that Pw1 is identical to Peg3, a paternally expressed gene of unknown function (and will therefore be referred to as Peg3 throughout this text). We report here that Peg3 associates specifically with TRAF2 but not with other TRAF family members. Peg3 expression activates NFkappaB via IkappaB-NFkappaB dissociation and acts synergistically with TRAF2. Transfection of a truncated Peg3 containing the TRAF2 interaction site, abolishes NFkappaB activation by TRAF2 and/or TNF. We conclude that Peg3 is a regulator of the TNF response. These data reveal the involvement of an imprinted gene in this pathway