Carlo Patriarca

Epithelial cell adhesion molecule expression (CD326) in cancer: A short review

Epithelial cell adhesion molecule (EpCAM, CD326) is a pleiotropic molecule that potentially offers therapeutic applications in cancer treatment. Initially described as a dominant surface antigen on human colon carcinoma, it is a transmembrane glycoprotein mediating epithelial-specific intercellular cell-adhesion. Recent data suggest that EpCAM is also involved in cell signaling, migration, proliferation and differentiation. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker. Testing for EpCAM is based on morphology and phenotypical staining and can be performed with primary carcinoma tissue and cells harvested from malignant effusions. Stable or highly expressed EpCAM has been detected in most adenocarcinomas and has also been found in metastases, malignant effusions, and cancer stem cells. EpCAM may thus be an ideal tumor antigen candidate to detect circulating and metastasizing cancer cells by microchip technologies. In certain tumor types overexpression was linked to advanced stage of disease and worse overall survival, suggesting EpCAM as a potential prognostic marker. In addition to its diagnostic and prognostic role, EpCAMs broad expression and apparent involvement in tumorigenesis and metastasis point to its potential as a target for immunotherapeutic strategies. The first EpCAM targeting, trifunctional antibody catumaxomab (Removab®) has shown clear clinical benefits in treatment of malignant ascites associated with EpCAM positive carcinomas. Further research and clinical studies should unravel EpCAMs complex role in oncological processes, and expand potential therapeutic applications of EpCAM targeted strategies.

Diagnostic Accuracy of Clathrin Heavy Chain Staining in a Marker Panel for the Diagnosis of Small Hepatocellular Carcinoma

The American Association for the Study of Liver Diseases guidelines recommend the use of all available markers for improving the accuracy of the diagnosis of small hepatocellular carcinoma (HCC). To determine whether clathrin heavy chain (CHC), a novel HCC marker, is effective in combination with glypican 3 (GPC3), heat shock protein 70, and glutamine synthetase, we compared the performances of a three‐marker panel (without CHC) and a four‐marker panel (with CHC) in a series of small HCCs (≤2 cm) and nonsmall HCCs by core biopsy with a 20‐ to 21‐gauge needle. The series included 39 nonsmall HCCs and 47 small HCCs (86 in all); the latter showed a well‐differentiated histology [small grade 1 (G1)] in 30 cases (63.8%). The panel specificity was analyzed with the adjacent/extranodular cirrhotic liver (n = 30) and low‐grade (n = 15) and high‐grade dysplastic nodules (n = 16) as a control group. Absolute specificity (100%) for HCC was obtained only when at least two of the markers were positive (which two markers were positive did not matter). The addition of CHC to the panel increased the diagnostic accuracy for small HCCs (from 76.9% to 84.3%), and there was an important gain in sensitivity (from 46.8% to 63.8%). The four‐marker panel had lower rates of accuracy (67.4%) and sensitivity (50%) for small G1 HCCs versus nonsmall G1 HCCs (93.9% and 88.2%, respectively). In seven cases (including six small G1 HCCs), there was no staining with any of the markers. Cirrhotic control livers were stained for CHC in four cases (13.3%) and for GPC3 in one case (3.3%). Conclusion: The addition of CHC to the panel supports the diagnosis of small HCCs in challenging nodules on thin core biopsy samples. Small G1 HCCs include a group of earlier tumors characterized by a more silent phenotype and the progressive acquisition of the markers under study. The search for additional markers for early HCC diagnosis is warranted. (HEPATOLOGY 2011;)

Lymphomas of the Bone: A Pathological and Clinical Study of 54 Cases

We examined 28 cases of primary bone lymphomas (PBL; stage IE) and 26 cases of systemic lymphomas involving the bone (SBL; stage IIE to IV). Two histologic types were prevalent: Diffuse large B-cell lymphomas (DLBCL; 26 PBL and 21 SBL) and CD30+ anaplastic large cell lymphomas (ALCL; 1 PBL and 4 SBL). A mature B phenotype (CD45+, CD20+, CD79a+, CDw75+/-, CD10-/+) was established in the DLBCL group. Bcl-2 immunoreactivity was demonstrated in 13/37 cases (35%), and bcl-6 immunostaining was observed in 22/32 cases (69%). ALCL showed null/T phenotype (CD3-/+; CD43+/-; CD30+), with ALKI-1 expression in 3/3 cases. With use of a FR3A primer, a monoclonal pattern was demonstrated by PCR analysis in 22/41 lymphomas (54%). Bcl-2 translocation was identified in 2/41 cases (5%). This study details the clinical and pathological characteristics of bone lymphomas. Our immunohistochemical and molecular data suggest that most of them are “de novo” DLBCL and support their follicle center origin.

Cell Discohesion and Multifocality of Carcinoma In situ of the Bladder: New Insight From the Adhesion Molecule Profile (e-Cadherin, Ep-CAM, and MUC1)

Urothelial cell carcinoma in situ (CIS) of the bladder is a superficially diffusive and highly discohesive disease. The authors analyzed the expression of some adhesion molecules (e-cadherin and Ep-CAM) and MUC1 in 32 unifocal and multifocal bladder urothelial cell CIS in an attempt to clarify this discohesion. E-cadherin was strongly expressed, in more than 75% of the cases. The presence of methylation of the CDH1 e-cadherin promoter gene was also investigated, but methylation was found in only one case. Ep-CAM was present in all the cases with a heterogeneous staining pattern. Similarly, MUC1/episialin was variously present in 94% of the cases without a polarized staining pattern and was expressed more strongly in cases with multifocal disease. Because loss of MUC1 polarization leads to interference with cell—cell adhesion mechanisms mediated by cadherins, these findings help explain why bladder urothelial cell CIS often shows a discohesive morphology and multifocality despite a strongly expressed adhesion molecule profile. Finally, Ep-CAM expression might provide some support for future target therapy trials.

CD138-Positive Plasmacytoid Urothelial Carcinoma of the Bladder

an epithelial phenotype characterized by cytokeratin 7, cytokeratin 20, cam 5.2, epithelial membrane antigen, epidermal growth factor receptor, and p16 positivity, e-cadherin negativity with β-catenin dotlike positivity, and hematological markers (including CD79a and light chain K and lambda) negativity. We read with interest the description of a plasmacytoid transitional cell carcinoma in the specialty conference section of the USCAP 2005 annual meeting. In contrast to our case, that case was CD138 negative. Also, in another correspondence, the authors describe these plasmacytoid changes in the in situ urothelial carcinoma component. This feature, which was focally present also in our case, evokes the plasticity of in situ urothelial carcinoma stressed by the recent descriptions of morphological variants of in situ cancer of the bladder until the most extreme forms of in situ adenocarcinoma described by Chan Editor

Histopathological findings after radiofrequency (RITA) treatment for prostate cancer

Radiofrequency interstitial tumor ablation (RITA) is a thermal ablation method that uses needles and low radiofrequency (RF) energy. The aim of our study was to evaluate the histopathology of thermal lesions induced by RF energy delivered interstitially in prostate cancer patients who subsequently underwent prostatectomy, and to determine the feasibility, effectiveness and safety of this new method in a pilot study.

Nest-Like Features in Bladder, Simulating the Nested Variant of Urothelial Carcinoma

Nest-like structures are the cardinal lesion of different benign and malignant bladder entities. These entities emphasize the biological relevance of the subtle morphological nest plasticity. The authors present 25 benign and malignant neoplasms, sharing the presence of florid nest-like growth and the scarcity or absence of superficial papillary components. Differential diagnostic clues are discussed.

Perianal Pulse Granuloma

Among the histological oddities of unclear pathogenesis, pulse granuloma is one of the best characterized: a cluster of hyaline ring-like structures, size 200 to 400 μm in diameter, that enclose vessels and inflammatory cells. Bundles of collagen fibrils and foreign body–type giant cells are abundantly present in between and sometimes within these circular structures. A former report taught us what pulse granulomas are not: They are neither amyloid deposits nor infectious granulomas or fungal structures. But maybe they are not vegetable particles of ingested legume origin, despite the name and the frequent occurrence of pulse granulomas in the oral cavity (oral vegetable granuloma) with the alleged dietary pathogenesis. Indeed, similar ring structures have been reported in gallbladder, fallopian tube, skin, prostate, and rectal submucosa as well. The vascular nature of the circular hyaline findings, which has undergone degenerative changes as documented by the absence of elastic lamina, seems much more reasonable. The present finding belongs to a biopsy of the perianal region in a 41-year-old man who presented with swelling and pain lasting for about 1 year (Figure 1). Only isolated cases of rectal or rectocutaneous pulse granulomas have been described in the literature.

Feasibility and Clinical Roles of Different Substaging Systems at First and Second Transurethral Resection in Patients with T1 High-Grade Bladder Cancer

BACKGROUND Decision making in T1 high-grade bladder cancer patients remains a challenging issue in urologic practice. OBJECTIVE To assess the feasibility and potential prognostic role of three different substaging systems in specimens from both primary and second transurethral resection (TUR) of the bladder in T1 high-grade bladder cancer patients. DESIGN, SETTING, AND PARTICIPANTS A total of 250 consecutive, confirmed pure transitional T1 high-grade bladder tumors submitted to second TUR entered the retrospective study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Feasibility of two already clinically tested microstaging systems (anatomy-based T1a/T1b/T1c and micrometric T1m/T1e with 0.5-mm thresholds of invasion) and that of a micrometric substage designed by the authors and based on a 1-mm threshold of invasion (Rete Oncologica Lombarda [ROL] system) was assessed by five independent uropathologists on both first and second TUR specimens. Univariable Cox proportional hazards models were attempted to identify significant independent predictors of recurrence and progression after TUR. Kaplan-Meier curves were plotted to compare different substaging methods analyzing recurrence and progression. RESULTS AND LIMITATIONS The ROL system proved to be feasible in nearly all cases at both first and second TUR. Median follow-up was 60 mo. The univariate Cox regression analysis documented the ROL substage (ROL2 vs ROL1) to be the only statistically significant predictor of progression (hazard ratio: 2.01; 95% CI, 1.03-3.79; p<0.03). For the first time to our knowledge, the substage was investigated and used to assess T1 tumors found at second TUR, registering a high rate of feasibility. CONCLUSIONS T1 microstaging using different procedures is feasible on both primary- and second-TUR specimens. A high rate of feasibility may be expected for T1m/T1e and ROL systems. The clinical role of microstaging on second TUR remains to be defined. PATIENT SUMMARY The Rete Oncologica Lombarda system showed feasible results in T1 high-grade bladder tumors. Our substratification was predictive of progression of disease.

The Oncofetal Protein IMP3: A Novel Grading Tool and Predictor of Poor Clinical Outcome in Human Gliomas

Morphologic criteria illustrated in WHO guidelines are the most significant prognostic factor in human gliomas, but novel biomarkers are needed to identify patients with a poorer outcome. The present study examined the expression of the oncofetal protein IMP3 in a series of 135 patients affected by high-grade (grade III and IV) gliomas, correlating the results with proliferative activity, molecular parameters, and clinical and follow-up data. Overall, IMP3 expression was higher in glioblastomas (68%) than in grade III tumors (20%, P < 0.0001), and IMP3-positive high-grade gliomas showed a shorter overall and disease-free survival than negative ones (P = 0.0002 and P = 0.006, resp.). IMP3 expression was significantly associated with the absence of mutations of IDH1 gene (P = 0.0001) and with the unmethylated phenotype of MGMT in high-grade gliomas (P = 0.004). High Ki67 levels were correlated with better prognosis in glioblastomas but IMP3 expression was not correlated with the proliferation index. These findings confirm the role of IMP3 as a marker of poor outcome, also in consideration of its association with IDH1 wild-type phenotype and MGMT unmethylated status. The data suggest that IMP3 staining could identify a subgroup of patients with poor prognosis and at risk of recurrence in high-grade gliomas.