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ABSTRACT: Clear cell papillary renal cell carcinoma (CCPRCC) shares morphologic overlap with clear cell renal cell carcinoma, although it lacks chromosome 3p and VHL gene abnormalities. Rare cases have been reported in von Hippel-Lindau (VHL) patients (germline mutation of the VHL gene), the significance of which is uncertain. We analyzed morphologic, immunohistochemical, and molecular features in 14 CCPRCC-like tumors and 13 clear cell renal cell carcinomas from 12 patients with VHL disease. Gross appearance of CCPRCC-like tumors ranged from yellow-orange to tan, red-brown, or extensively cystic. Histologic features included: small papillary tufts (79%), branched tubules (71%), branched papillae (64%), flattened peripheral cysts (64%), and apically aligned nuclei (43%). Almost all CCPRCC-like tumors (82%) lacked the characteristic immunoprofile of sporadic CCPRCC (CK7, CAIX, CD10, AMACR), often showing diffuse CD10 labeling (64%), negative or focal CK7 reactivity (55%), or both (18%). Three tumors (27%) showed strong AMACR staining. Chromosome 3p deletion was often present (82%), similar to that observed in clear cell renal cell carcinomas (80%); no CCPRCC-like tumor had chromosome 7 or 17 abnormalities. In summary, tumors that histologically resemble CCPRCC sometimes occur in patients with VHL disease but usually lack the characteristic immunohistochemical and molecular profile, suggesting that they do not share the same pathogenesis.
The American journal of surgical pathology 05/2013; · 4.06 Impact Factor
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Qiu Rao,
Sean R Williamson,
Antonio Lopez-Beltran,
Rodolfo Montironi,
Wenbin Huang,
John N Eble,
David J Grignon,
Michael O Koch,
Muhammad T Idrees,
Robert E Emerson,
Xiao-Jun Zhou,
Shaobo Zhang, Lee Ann Baldridge,
Liang Cheng
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ABSTRACT: Glandular neoplasms involving the urinary bladder carry a challenging differential diagnosis including primary and secondary processes. We investigated the potential diagnostic utility of cadherin-17 and GATA3 in 25 primary adenocarcinomas of the urinary bladder, as compared with other commonly used markers including β-catenin and p63. Urothelial carcinoma with glandular differentiation (11), colorectal adenocarcinoma secondarily involving the bladder (25), and primary colorectal adenocarcinoma (22) were also analyzed and the results were compared using a Fisher exact test. Cadherin-17 was expressed in 23/25 primary bladder adenocarcinomas (92%), 23/25 colorectal adenocarcinomas involving the bladder (92%), 21/22 primary colorectal adenocarcinomas (95%) and entirely negative (0/11) in both components of urothelial carcinoma with glandular differentiation (P<0.001). In urothelial carcinoma with glandular differentiation, positive nuclear staining for GATA3 was evident in the urothelial component for 18% (2/11) and the glandular component for 9% (1/11) with additional tumors showing only cytoplasmic staining. Nuclear reactivity for GATA3 was not present in primary bladder adenocarcinoma and primary/secondary colorectal adenocarcinoma (P<0.05). Positive nuclear and cytoplasmic immunostaining for β-catenin was evident in 21/22 primary colorectal adenocarcinomas (95%) and 23/25 cases of secondary involvement by colorectal adenocarcinoma (92%). In contrast, positive membranous and cytoplasmic staining for β-catenin was observed in 23/25 primary bladder adenocarcinomas (92%) and 11/11 urothelial carcinomas with glandular differentiation (100%, P<0.001). p63 was expressed only in the urothelial component of urothelial carcinoma with glandular differentiation and not in the glandular component (P<0.001). In summary, cadherin-17 is a relatively specific and sensitive marker for primary adenocarcinoma of the urinary bladder, distinguishing it from urothelial carcinoma with glandular differentiation. However, it does not distinguish primary bladder adenocarcinoma from secondary involvement by colorectal adenocarcinoma. The pattern of reactivity for β-catenin remains the most useful marker for distinguishing these two tumors.Modern Pathology advance online publication, 25 January 2013; doi:10.1038/modpathol.2012.229.
Modern Pathology 01/2013; · 4.79 Impact Factor
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Sean R Williamson,
Shams Halat,
John N Eble,
David J Grignon,
Antonio Lopez-Beltran,
Rodolfo Montironi,
Puay-Hoon Tan,
Mingsheng Wang,
Shaobo Zhang,
Gregory T Maclennan, Lee Ann Baldridge,
Liang Cheng
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ABSTRACT: Multilocular cystic renal cell carcinoma (RCC) is an uncommon renal neoplasm composed of thin fibrous septa lining multiple cystic spaces and associated with an excellent prognosis. Clear cells with generally low-grade nuclear features line the cystic spaces and may be present within the fibrous septa, although solid mass-forming areas are by definition absent. Despite the excellent prognosis, molecular-genetic alterations are similar to those of clear cell RCC. Immunohistochemical staining characteristics, however, have not been well elucidated. We studied 24 cases of multilocular cystic RCC, classified according to the 2004 World Health Organization System. Immunohistochemical analysis was performed using an automated immunostainer for CD10, cytokeratin 7 (CK7), α-methylacyl-CoA-racemase, epithelial membrane antigen (EMA), cytokeratin CAM 5.2, carbonic anhydrase IX (CA-IX), estrogen/progesterone receptors, smooth muscle actin, PAX-2, and vimentin. Twenty-four cases of grade 1 to 2 clear cell RCC were stained for comparison. Multilocular cystic RCC and control cases of clear cell RCC showed the following results, respectively: CD10 (63%, 96%), CK7 (92%, 38%), α-methylacyl-CoA-racemase (21%, 67%), vimentin (58%, 33%), estrogen receptor (8%, 8%), CAM 5.2 (100%, 96%), EMA, CA-IX, PAX-2 (all 100%), and progesterone receptor (0%). Smooth muscle actin highlighted myofibroblastic cells within the septa of multilocular cystic RCC and the fine capillary vascular network of clear cell RCC. In summary, multilocular cystic RCC showed expression of common clear cell RCC markers CA-IX, EMA, and PAX-2, supporting the hypothesis that multilocular cystic RCC is a subtype of clear cell RCC. In contrast to clear cell RCC, tumors less frequently expressed CD10 (63% and often focal vs. 96% and diffuse) and more frequently expressed CK7 (92%), often diffusely (63%). Coexpression of CA-IX and CK7 represents a point of overlap with the recently described clear cell papillary RCC, which also may show a prominent cystic architecture. However, the latter lacks mutation of the VHL gene and deletion of chromosome 3p by molecular methodologies.
The American journal of surgical pathology 10/2012; 36(10):1425-1433. · 4.06 Impact Factor
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ABSTRACT: Lymphoepithelioma-like carcinoma (LELC) in the urinary tract is a rare malignancy, named for its resemblance to nasopharyngeal undifferentiated carcinoma or lymphoepithelioma. Investigation of immunohistochemical and molecular characteristics of bladder LELC is limited. The pathogenesis and biological behavior of these tumors are controversial.
We examined clinicopathologic features of the urinary tract LELC, including light microscopy; immunohistochemistry for cytokeratin 7 (CK7), CK20, 34βE12, p53, p63, α-methylacyl-CoA racemase, thyroid transcription factor-1, Epstein-Barr virus latent membrane protein-1, and CD30; in situ hybridization for human papillomavirus; and UroVysion fluorescence in situ hybridization (FISH).
We identified tumors from 34 patients, the largest series to date, (male:female, 2.8:1), ranging from 54 to 84 years of age (mean, 70 years). Urothelial carcinoma in situ was identified in 50% of patients. 34βE12 (75%), CK7 (57%), and p63 (53%) were frequently positive in tumor cells, whereas thyroid transcription factor-1 and CD30 were consistently negative. Expression of p53 was noted in a subset of tumors (61%), whereas CK20 staining was negative with weak positivity in a single case. UroVysion FISH showed frequent chromosomal abnormalities similar to those of urothelial carcinoma. In tumors with concurrent urothelial, squamous, sarcomatoid, and glandular components, identical FISH abnormalities were noted in both areas. In situ hybridization for human papillomavirus and immunostaining for Epstein-Barr virus were negative in all studied lesions. Five patients with pure or predominant LELC tumors treated with transurethral resection and followed by chemotherapy were alive without evidence of disease at 2 to 5 years. In contrast, 2 patients treated in this manner with <50% LELC morphology had death from disease or distant metastasis.
Urinary tract LELC is a rare histologic variant of urothelial carcinoma. The frequent presence of UroVysion FISH abnormalities, urothelial carcinoma in situ, and p53 positivity by immunohistochemistry in cases of urinary tract LELC suggests a similar pathogenesis to high-grade invasive urothelial carcinoma. In contrast to typical urothelial carcinoma, CK20 is frequently negative in LELC. Our findings support the hypothesis that pure or predominant LELC may be treated with transurethral resection and chemotherapy. However, a large-scale study with long-term follow-up is needed to better understand the biological behavior of urinary bladder LELC.
The American journal of surgical pathology 03/2011; 35(4):474-83. · 4.06 Impact Factor
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Journal of Clinical Oncology 01/2009; 27(3):460-3. · 18.37 Impact Factor
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Andrew B Armstrong,
Mingsheng Wang,
John N Eble,
Gregory T MacLennan,
Rodolfo Montironi,
Puay-Hoon Tan,
Antonio Lopez-Beltran,
Shaobo Zhang, Lee Ann Baldridge,
Helena Spartz,
Liang Cheng
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ABSTRACT: Sarcomatoid urothelial carcinoma of the urinary bladder is an uncommon neoplasm with biphasic morphology exhibiting both epithelial and sarcomatoid components. Whether this tumor arises from a single cancer stem cell with subsequent differentiation or represents collision of the progeny of two separate cancer stem cells is a matter of controversy. To clarify its clonal origin, we analyzed the TP53 mutation status of a series of 17 sarcomatoid urothelial carcinomas using single-strand conformation polymorphism, DNA sequencing and p53 immunohistochemistry. Sarcomatoid and epithelial tumor components were separately microdissected using laser capture microdissection. Five out of the 17 sarcomatoid urothelial carcinomas contained TP53 point mutations in exons 5 and 8. In all five cases, the TP53 point mutations were identical in both the epithelial and sarcomatoid components. The sarcomatoid and epithelial tumor components in all 17 cases showed concordant p53 expression patterns. Our results suggest that despite their conspicuous divergence at the phenotypic level, the sarcomatoid and carcinomatoid elements of this uncommon tumor share a common clonal origin.
Modern Pathology 12/2008; 22(1):113-8. · 4.79 Impact Factor
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ABSTRACT: Sarcomatoid carcinoma (carcinosarcoma) of the upper urinary collecting system is a rare aggressive malignancy composed of malignant epithelial and stromal components. Because of the paucity of reported cases, the clinical behavior, molecular alterations, and potential therapies for this malignancy are not well understood. Eight cases of sarcomatoid carcinoma involving the upper urinary tract were studied. Clinicopathologic characteristics were reviewed. Immunohistochemical expression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2)/neu, c-kit, and p53 was analyzed in each case. Evaluation for amplification of EGFR and HER2 genes was performed by interphase fluorescence in situ hybridization (FISH). Each tumor was also examined for gains of chromosomes 3, 7, and 17 and for loss of chromosome 9p21 by UroVysion FISH (Vysis, Downers Grove, IL). The patients we studied were 5 females and 3 males, ranging in age from 56 to 78 years (mean age, 69 years). Presenting symptoms included gross hematuria, flank mass, urinary obstruction, fever, or sepsis. Radical nephroureterectomy was performed on all patients. Tumor size ranged from 2 to 13 cm. Coexisting urothelial carcinoma was present in all 8 cases. Heterologous osteosarcoma was identified in 2 cases. Pathologic stage was pT4 in 5 cases and pT3 in 3 cases. Lymph node metastases were present in 5 patients at the time of surgery. Of 8 patients, 7 died within 2 years after surgery. EGFR immunostaining had moderately to strongly positive results in 6 of 8 cases. Both HER2/neu and c-kit immunostaining had negative results in all cases. p53 immunostaining had positive results in 5 of 8 cases. The EGFR polysomy was demonstrated in 7 of 8 cases. No amplification of HER2/neu was present in any case. UroVysion FISH showed abnormalities typical of urothelial carcinoma in all 8 cases. In conclusion, the prognosis of sarcomatoid carcinoma of the upper urinary tract is extremely poor, most patients died within 2 years (7/8 patients). Gains of chromosome 3, 7, and 17 and loss of chromosome 9p21 were commonly observed in these tumors. Our findings suggest that targeted therapy may be a rational strategy in the management of these patients.
Human pathology 10/2008; 40(2):211-7. · 3.03 Impact Factor
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Daniela Matei,
Robert E Emerson,
Jeanne Schilder,
Nancy Menning, Lee Ann Baldridge,
Cynthia S Johnson,
Tim Breen,
John McClean,
Doyle Stephens,
Charles Whalen,
Gregory Sutton
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ABSTRACT: Ovarian tumors frequently express c-Kit and/or platelet-derived growth factor receptors (PDGFRs). Imatinib mesylate blocks the growth of ovarian cancer cells in vitro and may enhance the activity of chemotherapy. This study was conducted to determine the activity of imatinib in combination with docetaxel in patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC).
Eligible patients had recurrent, platinum-resistant, or refractory EOC that expressed PDGFRalpha or c-kit, as determined by immunohistochemistry. Imatinib mesylate at a dose of 600 mg orally once daily was administered continuously with docetaxel at a dose of 30 mg/m(2) given intravenously once weekly in Weeks 1 through 4 of every 6-week cycle. The primary endpoint was objective response rate (ORR) as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST).
Thirty-four patients were screened for PDGFRalpha and c-kit expression to enroll 23 patients between December 2003 and October 2005. Four patients had c-kit-positive/PDGFR-negative tumors, 11 patients had PDGFR-positive/c-kit-negative tumors, and 8 patients had c-kit-positive/PDGFR-positive tumors. The median patient age was 56 years (range, 33-76 years). Patients had received a median of 3 prior treatments. The ORR was 21.7% and included 1 complete and 4 partial responses. An additional 3 patients had stable disease for more than 4 months. Expression of PDGFR, c-kit, phosphatase and tensin homolog (PTEN), and phosphorylated protein kinase B (Akt) did not predict response to therapy. The most common adverse events encountered were fatigue (83%), nausea (74%), diarrhea (61%), anorexia (52%), and edema (65%), and the majority of those events were graded as grade 1 or 2.
The combination imatinib and docetaxel was tolerated in patients with heavily pretreated EOC that expressed c-kit or PDGFRalpha. Few patients had sustained responses or stable disease.
Cancer 08/2008; 113(4):723-32. · 4.77 Impact Factor
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Rebecca A Marks,
Shaobo Zhang,
Rodolfo Montironi,
Ryan P McCarthy,
Gregory T MacLennan,
Antonio Lopez-Beltran,
Zhong Jiang,
Honghong Zhou,
Suqin Zheng,
Darrell D Davidson, Lee Ann Baldridge,
Liang Cheng
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ABSTRACT: The progression of normal prostatic epithelium to androgen-dependent cancer and, eventually, hormone-refractory prostate cancer is a complex process involving many different growth regulatory signals. Activation of epidermal growth factor receptor (EGFR) has been implicated in prostate cancer cell growth.
This study was undertaken to investigate both amplification of EGFR gene by fluorescence in situ hybridization (FISH) and over-expression of EGFR by immunohistochemical staining in prostate tissue from 71 patients treated by hormonal therapy.
EGFR gene amplification was present in 1 of 71 tumors, and polysomy of chromosome 7 was present in 24 of 71 tumors. Immunohistochemically, EGFR expression was demonstrable in 57 of 71 tumors. Membranous immunostaining for EGFR was observed in >75% of tumor cells in 11% of cases, in 51-75% of tumor cells in 20% of cases, in 26-50% of tumor cells in 21% of cases, in 11-25% of tumor cells in 21% of cases, and in 1-10% of tumor cells in 7% of cases. No immunostaining for EGFR was seen in 20% of cases. There was no correlation between EGFR protein expression and gene amplification. There was also no correlation between EGFR expression and clinicopathological characteristics or clinical outcome.
We found that EGFR gene expression was detectable in 35% of this large series of hormone-treated prostate cancer, and that EGFR protein is frequently expressed in tissue from these patients. EGFR over-expression may serve as a reasonable target for therapeutic intervention in this otherwise difficult to treat subset of prostate cancer.
The Prostate 07/2008; 68(9):919-23. · 3.48 Impact Factor
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ABSTRACT: Formation of new lymphatic channels, or lymphangiogenesis, has been associated with poor prognosis in a number of human cancers. Its prognostic significance in prostate cancer is uncertain. We analyzed 122 radical prostatectomy specimens. Immunohistochemistry for lymphatic vessels was performed using a mouse monoclonal antibody reactive with an O-linked sialoglycoprotein found on lymphatic endothelium (clone D2-40, Signet Laboratories, Dedham, Mass). The mean lymphatic vessel densities (LVDs) of the 3 prostate compartments were compared. Lymphatic vessel densities were correlated with other clinical and pathologic characteristics. Mean values for intratumoral, peritumoral, and normal prostate LVD were 3.0, 5.2, and 4.8 lymphatic vessels per 200x field, respectively. The intratumoral LVD was significantly lower than the peritumoral or normal LVD (P < .001), and the LVD of the latter 2 compartments was not significantly different (P = .29). The prostate LVD did not correlate with other clinical and pathologic parameters. In conclusion, LVD is reduced in the intratumoral compartment compared with the peritumoral and normal prostate compartments, whereas the latter 2 have similar LVD. In contrast to other malignancies, quantitation of lymphangiogenesis in prostatic adenocarcinoma does not appear to offer useful prognostic information.
Human Pathlogy 05/2008; 39(4):610-5. · 2.88 Impact Factor
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ABSTRACT: Carcinoids are neuroendocrine tumors and most frequently occur within tissues derived from the embryonic gut. These tumors can occur in any organ site but are rare in the testis. The cell type giving rise to testicular carcinoid is unknown. We hypothesized that testicular carcinoid may have a germ cell origin.
We describe our analysis of protein and genetic markers of germ cell neoplasia, using immunohistochemistry and fluorescence in situ hybridization, in four testicular carcinoid tumors.
All four cases of testicular carcinoid tumor arose in a background of mature teratoma. Isochromosome 12p was identified in carcinoid tumor cells in all four samples. 12p overrepresentation was also observed in three cases. Isochromosome 12p and 12p overrepresentation were present in cells of coexisting mature teratoma in three cases. Carcinoid tumors showed strong immunoreactivity for synaptophysin and chromogranin, but no immunoreactivity for OCT4, CD30, c-kit, TTF-1, and CDX2. Membranous and cytoplasmic staining for beta-catenin was detected in three cases.
Our findings suggest that testicular carcinoid represents a phenotypic expression of testicular teratoma and is of germ cell origin.
Clinical Cancer Research 04/2008; 14(5):1393-6. · 7.74 Impact Factor
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Timothy D Jones,
Shaobo Zhang,
Antonio Lopez-Beltran,
John N Eble,
Ming-Tse Sung,
Gregory T MacLennan,
Rodolfo Montironi,
Puay-Hoon Tan,
Suqin Zheng, Lee Ann Baldridge,
Liang Cheng
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ABSTRACT: Inverted papilloma of the urinary bladder and urothelial carcinoma with an inverted (endophytic) growth pattern may be difficult to distinguish histologically, especially in small biopsies. The distinction is important as these lesions have very different biologic behaviors and are treated differently. We examined histologic features and undertook immunohistochemical staining and UroVysion fluorescence in situ hybridization (FISH) to determine whether these methods could aid in making this distinction. We examined histologic sections from 15 inverted papillomas and 29 urothelial carcinomas with an inverted growth pattern. Each tumor was stained with antibodies to Ki-67, p53, and cytokeratin 20. In addition, each tumor was examined with UroVysion FISH for gains of chromosomes 3, 7, and 17 and for loss of chromosome 9p21 signals. None of the inverted papillomas stained positively for Ki-67 or for cytokeratin 20. Only 1 of 15 inverted papillomas stained positively for p53. By contrast, 66%, 59%, and 59% of urothelial carcinomas with an inverted growth pattern stained positively for Ki-67, p53, and cytokeratin 20, respectively. Only 3 of the urothelial carcinomas stained negatively for all 3 immunohistochemical markers. UroVysion FISH produced normal results for all cases of inverted papilloma. By contrast, 21 of 29 cases (72%) of urothelial carcinoma with an inverted growth pattern demonstrated chromosomal abnormalities typical of urothelial cancer and were considered positive by UroVysion FISH criteria. Morphologic features, as well as immunohistochemical stains (including stains for Ki-67, p53, and cytokeratin 20) and/or UroVysion FISH can help to distinguish inverted papilloma from urothelial carcinoma with an inverted growth pattern.
American Journal of Surgical Pathology 01/2008; 31(12):1861-7. · 4.35 Impact Factor
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ABSTRACT: Angiogenin is a polypeptide involved in the formation and establishment of new blood vessels necessary for growth and metastasis of numerous malignant neoplasms, including prostatic adenocarcinoma. Antiangiogenin therapy inhibits the establishment, growth, and metastasis of prostatic adenocarcinoma in animal studies. In this study, we have investigated the expression of angiogenin in prostatic adenocarcinoma, high-grade prostatic intraepithelial neoplasia, and adjacent benign prostatic epithelium in a large cohort of prostatectomy specimens.
We have studied the expression of angiogenin by immunohistochemistry in prostatic adenocarcinoma, high-grade prostatic intraepithelial neoplasia, and adjacent benign prostatic tissue in 107 human total prostatectomy specimens.
The percentage of cells staining positively for angiogenin in benign prostatic glandular epithelium (mean = 17%) was significantly less than for high-grade prostatic intraepithelial neoplasia (mean = 58%, P < 0.001) and prostatic adenocarcinoma (mean = 60%, P < 0.001). Compared with adjacent benign prostatic epithelium, the staining intensity was significantly greater in high-grade prostatic intraepithelial neoplasia (P < 0.001) and prostatic adenocarcinoma (P < 0.001). Furthermore, staining intensity has significantly stronger in prostatic adenocarcinoma versus high-grade prostatic intraepithelial neoplasia (P = 0.0023). However, there was no correlation of angiogenin expression with various clinical and pathologic variables examined, including age at surgery, Gleason scores, pathologic stage, tumor extent, angiolymphatic invasion, extraprostatic extension, seminal vesical invasion, lymph node metastasis, surgical margin status, presence of prostatic intraepithelial neoplasia, and perineural invasion.
Angiogenin expression in prostatic tissue increases as prostatic epithelial cells evolve from a benign to an invasive phenotype. The increasing expression of prostatic adenocarcinoma in the progression from benign prostate to high-grade prostatic intraepithelial neoplasia and ultimately to prostatic adenocarcinoma are consistent with previous studies showing the influential role that angiogenin plays in the growth, invasion, and metastasis of prostatic adenocarcinoma and many other malignant tumors.
Clinical Cancer Research 12/2005; 11(23):8358-63. · 7.74 Impact Factor
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ABSTRACT: T-cell homing to infected skin is not well studied in humans. We examined sites experimentally infected with Haemophilus ducreyi by immunohistochemistry and flow cytometry for expression of receptors and ligands involved in cutaneous T-cell homing and determined the phenotypes of the T cells that trafficked to skin. Endothelial cells expressed E-selectin in infected but not uninfected skin, while peripheral node addressin (PNAd) was minimally expressed in all samples. CC chemokine ligand 27 (CCL27) was expressed in the epidermis and endothelium of both infected and uninfected skin. Interestingly, CCL21, a chemokine thought to be associated principally with T-cell trafficking in the lymphatic compartment, was highly expressed on the endothelium of infected skin. Few naive cells were present in experimental lesions, emphasizing the combined role of PNAd and CCL21 in trafficking of this subset. Memory cells (CD45RA-) dominated both CD4 and CD8 T-cell populations at the site of infection. Effector memory (CD45RA- CD27-) CD4+ and CD8+ T cells were enriched in lesions. Although the CC chemokine receptor 7-positive (CCR7+) population of both central memory (CD45RA- CD27+) and effector memory cells was not enriched in the skin compared to peripheral blood, CCR7+ cells were not precluded from entering infected skin. Taken together with our previous work (D. Soler, T. L. Humphreys, S. M. Spinola, and J. J. Campbell, Blood 101:1677-1683, 2003), these studies led us to propose a model of memory T-cell trafficking to skin in response to experimental H. ducreyi infection.
Infection and Immunity 08/2005; 73(7):3896-902. · 4.16 Impact Factor
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Timothy D Jones,
Kevin M Kernek,
Ximing J Yang,
Antonio Lopez-Beltran,
Gregory T MacLennan,
John N Eble,
Haiqun Lin,
Chong-Xian Pan,
Maria Tretiakova, Lee Ann Baldridge,
Liang Cheng
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ABSTRACT: Small cell carcinoma of the urinary bladder is a rare and aggressive tumor resembling small cell carcinoma of the lung. Thyroid transcription factor 1 (TTF-1) expression is common in small cell carcinomas arising in the lung. However, studies of its expression in extrapulmonary small cell carcinomas have yielded varying results. Because information concerning the immunohistochemical profile of small cell carcinoma of the urinary bladder is limited, we investigated the immunoreactivity of this tumor to a battery of antibodies in a series of 44 cases. Using 5-mum sections cut from paraffin-embedded tissue blocks, immunohistochemistry was performed to detect TTF-1, cytokeratin (CK) 7, CK20, and uroplakin antigenicity in 44 cases of small cell carcinoma of the urinary bladder. None of the patients had primary lung tumors. The TTF-1 immunohistochemical stain showed nuclear positivity in 17 cases (39%). Positive immunostaining for CK7 was observed in 26 cases (59%). There was no positive staining with either CK20 or uroplakin. There was no correlation between TTF-1 expression and survival (P = .27). In addition, TTF-1 expression did not correlate with clinicopathological characteristics, including age (P = .74), sex (P = .53), smoking history (P = .96), clinical stage (P = .10), pathological T stage (P = .50), lymph node metastasis (P = .40), and distant metastasis (P = .58). In summary, TTF-1 expression in small cell carcinoma of the urinary bladder was found in 39% of the tumors, demonstrating that this marker is expressed in small cell carcinomas other than those of pulmonary origin. Small cell carcinoma of the urinary bladder is positive for CK7 immunostaining in 59% of cases consistent with its origin from urothelium. Unlike urothelial carcinoma, expression of CK20 and uroplakin in small cell carcinoma of the urinary bladder is consistently negative, and thus, these stains do not appear to be useful in the diagnosis of this neoplasm. TTF-1 positivity is not a significant prognostic factor in small cell carcinoma of the urinary bladder.
Human Pathlogy 08/2005; 36(7):718-23. · 2.88 Impact Factor
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ABSTRACT: The proto-oncogene c-kit encodes a tyrosine kinase receptor, c-kit (CD117), which has been implicated in the development of a number of human malignancies. While the preferential expression of this protein has been well documented in testicular seminomas, there is little data concerning its expression in dysgerminomas of the ovary. We examined the expression of c-kit in 30 cases of ovarian dysgerminomas using immunohistohemical staining with a polyclonal anti-CD117 antibody. Staining was graded in a semiquantitative manner as follows: negative (no staining), 1+ (1–10% staining), 2+ (10–29% staining), 3+ (30–50% staining), or 4+ (>50% staining). Of the 30 cases examined, 26 (87%) demonstrated immunoreactivity for CD117. In total, 10 (33%) demonstrated 4+ staining; 9 (30%) demonstrated 3+ staining; 3 (10%) demonstrated 2+ staining; 4 (13%) demonstrated 1+ staining; and 4 (13%) demonstrated no staining. In conclusion, CD117 immunoreactivity was detected in 87% of ovarian dysgerminomas, a finding that correlates with previously reported frequencies of CD117 expression in seminomas (78–100%). Thus, antibodies to c-kit may be a useful diagnostic marker for ovarian dysgerminoma. Although the prognosis of patients with dysgerminoma is generally good, this receptor could potentially serve as a target for site-specific immunotherapy as an alternative and/or complement to conventional treatment options.Keywords: ovary, germ cell tumors, c-kit (CD117), differential diagnosis, OCT4, dysgerminoma
Modern Pathology 07/2005; 18(11):1411-1416. · 4.79 Impact Factor
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Liang Cheng,
Timothy D Jones,
Ryan P McCarthy,
John N Eble,
Mingsheng Wang,
Gregory T MacLennan,
Antonio Lopez-Beltran,
Ximing J Yang,
Michael O Koch,
Shaobo Zhang,
Chong-Xian Pan, Lee Ann Baldridge
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ABSTRACT: In most cases, small-cell carcinoma of the urinary bladder is admixed with other histological types of bladder carcinoma. To understand the pathogenetic relationship between the two tumor types, we analyzed histologically distinct tumor cell populations from the same patient for loss of heterozygosity (LOH) and X chromosome inactivation (in female patients). We examined five polymorphic microsatellite markers located on chromosome 3p25-26 (D3S3050), chromosome 9p21 (IFNA and D9S171), chromosome 9q32-33 (D9S177), and chromosome 17p13 (TP53) in 20 patients with small-cell carcinoma of the urinary bladder and concurrent urothelial carcinoma. DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. A nearly identical pattern of allelic loss was observed in the two tumor types in all cases, with an overall frequency of allelic loss of 90% (18 of 20 cases). Three patients showed different allelic loss patterns in the two tumor types at a single locus; however, the LOH patterns at the remaining loci were identical. Similarly, the same pattern of nonrandom X chromosome inactivation was present in both carcinoma components in the four cases analyzed. Concordant genetic alterations and X chromosome inactivation between small-cell carcinoma and coexisting urothelial carcinoma suggest that both tumor components originate from the same cells in the urothelium.
American Journal Of Pathology 06/2005; 166(5):1533-9. · 4.89 Impact Factor
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ABSTRACT: The transcription factor nuclear factor-kappaB (NF-kappaB) promotes the production of angiogenic, antiapoptotic, and prometastatic factors that are involved in carcinogenesis.
Electromobility gel shift assays were used to evaluate NF-kappaB DNA binding in vitro. The functional relevance of NF-kappaB DNA binding was assessed by both cDNA array analyses and proliferation assays of prostate cancer cells with and without exposure to an NF-kappaB inhibitor, parthenolide. Immunohistochemistry staining for the p65 NF-kappaB subunit was used to determine the frequency and location of NF-kappaB in 97 prostatectomy specimens. The amount of staining was quantified on a 0-3+ scale.
An electromobility gel shift assay confirmed the presence of NFkappaB DNA binding in all four prostate cancer cell lines tested. The binding was inhibited by parthenolide, and this agent also decreased multiple gene transcripts under the control of NF-kappaB and inhibited proliferation of prostate cancer cells. The staining results revealed overexpression of p65 in the prostatic intraepithelial neoplasia and cancer compared with the benign epithelium. Specifically, there was a predominance of 1+ and 2+ with no 3+ staining in benign epithelium, whereas there was only 2+ and 3+ staining (30 and 70%, respectively) in the cancerous areas. These differences were statistically different. There was no correlation with tumor grade or stage.
NF-kappaB is constitutively activated in prostate cancer and functionally relevant in vitro. Immunohistochemistry of human prostatectomy specimens demonstrated overexpression of the active subunit of NF-kappaB, p65, and that this occurs at an early stage in the genesis of prostate cancer. This work supports the rationale for targeting NF-kappaB for the prevention and/or treatment of prostate cancer.
Clinical Cancer Research 09/2004; 10(16):5501-7. · 7.74 Impact Factor
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ABSTRACT: OCT4 (POU5F1) is a transcription factor expressed in embryonic stem and germ cells and is involved in the regulation and maintenance of pluripotency. It has been detected in primary testicular germ cell tumors with pluripotent potential, seminoma, and embryonal carcinoma. We undertook immunohistochemical staining of OCT4 in a wide variety of primary testicular neoplasms (germ cell tumors and other tumors) to assess the specificity and usefulness of this marker as a diagnostic tool. We examined histologic sections from 91 primary testicular neoplasms, including 64 cases of mixed germ cell tumors containing embryonal carcinoma (54), seminoma (51), yolk sac tumor (38), mature teratoma (31), immature teratoma (20), and choriocarcinoma (15). In addition, we examined sections from spermatocytic seminomas (5), Leydig cell tumors (8), Sertoli cell tumors (6), unclassified sex-cord stromal tumors (4), adenomatoid tumors (2), testicular tumor of adrenogenital syndrome (1), and granulosa cell tumor (1). Each tumor was examined with hematoxylin and eosin staining and with antibodies to OCT4. In all cases of mixed germ cell tumor with components of embryonal carcinoma (54) and seminoma (51), there was greater than 90% nuclear staining of the embryonal carcinoma and seminoma tumor cells with little to no background staining. In all but 1 of these cases (embryonal carcinoma), there was strong (3+) staining intensity. The other germ cell tumor components (yolk sac tumor, mature teratoma, immature teratoma, and choriocarcinoma) showed no staining. Syncytiotrophoblast cells, which were present in 15 of the cases, were also completely negative, as were all 5 of the spermatocytic seminomas. The 22 cases of non-germ cell tumors were all immunohistochemically negative for OCT4. Fifteen of the 54 germ cell tumors containing embryonal carcinoma were also examined with antibodies to CD30. These embryonal carcinoma components were all positive for CD30 with staining of greater than 90% of the tumor cells but with variable staining intensity. We conclude that immunostaining with antibodies to OCT4 is a useful diagnostic tool in the identification of primary testicular embryonal carcinomas and "usual," but not spermatocytic, seminomas. OCT4 immunostaining has comparable sensitivity but greater consistency compared with CD30 in the diagnosis of embryonal carcinoma.
American Journal of Surgical Pathology 08/2004; 28(7):935-40. · 4.35 Impact Factor
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Liang Cheng,
Chong-Xian Pan,
Jian-Ting Zhang,
Shaobo Zhang,
Michael S Kinch,
Lang Li, Lee Ann Baldridge,
Christopher Wade,
Zhiqiang Hu,
Michael O Koch,
Thomas M Ulbright,
John N Eble
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ABSTRACT: The 14-3-3 family proteins are highly conserved over many mammalian species. The sigma isoform (also called HME-1 or stratifin) is expressed in epithelial cells. Loss of 14-3-3sigma is associated with failure to arrest the cell cycle at the G(2)-M phase checkpoint after DNA damage that leads to increased G(2)-type chromosomal aberrations. The role of 14-3-3sigma in prostatic carcinogenesis is uncertain.
We studied one hundred and eleven specimens of invasive prostate adenocarcinoma with paired, adjacent high-grade prostatic intraepithelial neoplasia and normal prostate epithelium. Immunohistochemistry was used to detect the expression of 14-3-3sigma. The findings were correlated with various clinical pathological parameters.
14-3-3sigma is ubiquitously expressed at high levels in normal prostate epithelium. Its expression is significantly decreased in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Ninety percent of samples of prostatic intraepithelial neoplasia had no or low 14-3-3sigma expression. Ninety-seven percent of invasive adenocarcinomas had no or low 14-3-3sigma expression. In most specimens (90%), suppression of 14-3-3sigma expression occurred during the development of prostatic intraepithelial neoplasia from normal epithelium.
Our data suggest that loss of 14-3-3sigma contributes to the development of prostate adenocarcinoma. 14-3-3sigma expression is significantly decreased during the progression of normal prostatic epithelium to prostatic intraepithelial neoplasia and invasive cancer.
Clinical Cancer Research 06/2004; 10(9):3064-8. · 7.74 Impact Factor
