Multiplicity and history have a detrimental effect on survival of patients with T1G3 bladder tumors selected for conservative treatment.

PURPOSE: In the absence of Tis tumor we assessed whether history and multiplicity have a detrimental effect on conservative treatment in carefully selected patients with T1G3 bladder carcinoma. MATERIALS AND METHODS: Between January 1976 and December 1999, 165 select patients with T1G3 bladder tumors were conservatively treated with transurethral resection plus adjuvant intravesical therapy. Patients with concomitant or previous Tis, previous T1G3, tumor size greater than 3 cm and more than 3 lesions were excluded from analysis. Repeat transurethral resection was not routinely performed. However, cytology had to be negative for atypia before the start of adjuvant intravesical therapy. RESULTS: Recurrence-free survival at 1, 3 and 5 years was 71.8%, 55.6% and 45%, respectively. Of the cases 14 (8.4%) progressed with a median progression-free survival of 149 months. A total of 23 patients (14%) died. The 5-year recurrence-free survival rate was 52%, 34% and 15% in cases of single and/or primary, multiple and recurrent tumors, respectively. Median overall survival was 144 months. The 5-year disease-free overall survival rate was 85%, 83%, 79% and 69% in cases of primary, single, multiple and recurrent tumors, respectively. An intact bladder was maintained in 137 patients (83%) with a mean disease-free overall survival of 102.7 months. Patients with recurrent and/or multiple T1G3 tumors showed worse survival (p = 0.0021 and 0.0142, respectively). CONCLUSIONS: History and multiplicity are relevant predictors of survival even in highly selected patients with TIG3 bladder tumors that are conservatively treated.

Immunohistochemistry differentiates papillary thyroid carcinoma arising in ectopic thyroid tissue from secondary lymph node metastases.

OBJECTIVE: To verify whether immunohistochemistry might be useful in the distinction between a true laterocervical metastasis of an undetected thyroid carcinoma and a primary tumor outside the gland. DESIGN: Galectin-3, cytokeratin 19, and HBME-1 were assessed in six cases (group A) of laterocervical masses harboring papillary thyroid carcinoma (PTC) but without a thyroid tumor, and in eight cases (group B) showing PTC both in the thyroid and in the laterocervical masses. In both groups, normal-looking follicles adjacent to the laterocervical neoplasia were present. MAIN OUTCOME: We found that the apparently normal follicles in group A were negative for all the antibodies, while group B showed strong and diffuse positive immunostaining. The neoplastic areas were always positive for all the antibodies in both groups. CONCLUSION: Even if immunohistochemical patterns of residual follicles of group B are very well differentiated that they resemble normal thyroid parenchyma, they may well be metastatic carcinomas. On the contrary, the presence of morphologically and immunohistochemically normal-looking follicles in group A, with no intrathyroid tumor, suggests that the primary PTC might possibly develop in the ectopic thyroid tissue. In cases showing morphologically and immunohistochemically normal-looking follicles in laterocervical masses, these findings might lead to a reduction of the overdiagnosis of metastatic disease of an undetected carcinoma.

Different expression of thymidylate synthase in primary tumour and metastatic nodes in breast cancer patients.

BACKGROUND: To date an accurate evaluation of predictive markers in breast cancer is mainly conducted at the primary site, although the main goal of the adjuvant therapy is the control of micrometastases. Adjuvant therapy drugs need a high proliferative cell rate to be effective. The proliferating activity can be evaluated by the Ki-67 marker and even by thymidylate synthase (TS), a cell cycle enzyme present in proliferating cells. In this study the TS levels in primary tumours were compared to those of their metastases. PATIENTS AND METHODS: The TS expression and Ki-67 were evaluated by means of immunohistochemistry in 80 primary breast tumours (PTs) and in their matched axillary metastatic lymph-nodes (ALNs). RESULTS: In 16% of patients, malignant cells of involved nodes showed a lower TS expression than the PTs. In the same group, we also found a lower number of Ki-67 immunoreactive cells in lymph node metastases when compared with primary tumours. CONCLUSION: The group of patients with lower TS and Ki-67 expression in lymph node metastatic cells may be less sensitive to 5-fluorouracil and high dose methotrexate requiring them to be treated with other drug combinations.

PED mediates AKT-dependent chemoresistance in human breast cancer cells.

Killing of tumor cells by cytotoxic therapies, such as chemotherapy or gamma-irradiation, is predominantly mediated by the activation of apoptotic pathways. Refractoriness to anticancer therapy is often due to a failure in the apoptotic pathway. The mechanisms that control the balance between survival and cell death in cancer cells are still largely unknown. Tumor cells have been shown to evade death signals through an increase in the expression of antiapoptotic molecules or loss of proapoptotic factors. We aimed to study the involvement of PED, a molecule with a broad antiapoptotic action, in human breast cancer cell resistance to chemotherapeutic drugs-induced cell death. We show that human breast cancer cells express high levels of PED and that AKT activity regulates PED protein levels. Interestingly, exogenous expression of a dominant-negative AKT cDNA or of PED antisense in human breast cancer cells induced a significant down-regulation of PED and sensitized cells to chemotherapy-induced cell death. Thus, AKT-dependent increase of PED expression levels represents a key molecular mechanism for chemoresistance in breast cancer.

Amelanotic conjunctival melanoma.

Conjunctival melanoma is a rare condition of the eye pigment predominantly affecting white adults. We describe a 32-year-old white man with an amelanotic malignant melanoma of the conjunctiva that is not associated with primary acquired melanosis (PAM) or melanocytic nevus. The patient presented with a 2-year history of nonpigmented vascularized nodules of the right eye. Results of hematoxylin and eosin (H and E) staining of the lesion showed an invasive nodule with vertical spreading, invasion of the substantia propria corneae, and ulceration. S100 protein was expressed in the cells of the invasive nodule. HMB45 protein was highly positive in the melanoma cells. The de novo amelanotic malignant melanoma of the conjunctiva we describe is an extremely uncommon tumor mainly affecting white adults.

Overexpression of cyclin D1 and interaction between p27Kip1 and tumour thickness predict lymph node metastases occurrence in lower lip squamous cell carcinoma.

We have attempted to identify those subgroups of patients most likely to develop lymph node metastases from squamous cell carcinoma of the lower lip (LLSSC). A total of 97 subjects, who did not undergo elective neck dissection, were recruited into the 60-month disease-free survival study. After univariate analysis, tumour size, histological grading, maximal thickness, perineural invasion and immunoreactivity to cyclin D1 and p27Kip1 proteins proved to be significant factors. Tests of the effect of interaction between p27Kip1 LI and tumour thickness yielded that the impact of tumour thickness on the risk of lymph node metastases was modified by the percentage of p27Kip1 positive cells. Subsequent to models of multivariate analysis, tumour size, positive cyclin D1 protein expression, maximal thickness (> 5 mm), p27Kip1 LI (%) and the interaction term between p27Kip1 LI and tumour thickness retained strong independent predictive values for lymph node metastases. We suggest that immunohistochemistry for cyclin D1 and p27Kip1 may prove to be valuable ancillary tests for identifying LLSSC with metastatic potential.

Expression of cytokeratin 7 and 20 in pathological conditions of the bile tract.

Expression of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) helps to establish the origin of biliary and metastatic carcinomas. We investigated the expression of CK7 and CK20 in inflammatory, metaplastic and neoplastic conditions of the bile ducts, and evaluated possible relationships between the CK expression pattern and extrahepatic bile duct/gallbladder carcinomas (EBDCs) or intrahepatic bile duct carcinomas (IBDCs). We used immunohistochemistry for the investigation of 48 formalin-fixed, paraffin-embedded specimens grouped as: A) lithiasic or inflamed surgically resected extrahepatic bile ducts/gallbladders: all were CK7+/CK20+; B) percutaneous liver biopsies from patients with chronic hepatitis C primary biliary cirrhosis and primary sclerosing cholangitis: all were CK7+/CK20-; C) EBDCs: all were CK7+/CK20+, except for two cases which were CK7-/CK20-; D) IBDCs: all were CK7+/CK20-, except for one case showing CK20 positivity. Metaplastic changes were seen only among specimens in groups A and C: in these cases, CK20 was either focally or diffusely expressed. Our study suggests that the expression of cytokeratins under specific stimuli can be different from normal tissues, and that sometimes CK20 expression can be related to and precede the occurrence of metaplastic alterations.

CD10 and HHF35 actin in the differential diagnosis between Collagenous spherulosis and adenoid-cystic carcinoma of the breast.

Collagenous Spherulosis (CS) and Adenoid-Cystic Carcinoma (AdCC) of the breast consist of cribriform proliferations of epithelial and myoepithelial cells with an immunophenotypic overlap of some myoepithelial markers, such as p63 and smooth muscle actin (SMA). To our knowledge, CD10 and HHF35 actin have not been assessed in the differential diagnosis of these two breast lesions. We performed an immunohistochemical study on 6 cases of CS and 9 cases of AdCC. We found CD10, muscle-specific actin (HHF35), Estrogen and Progesterone receptors (ER and PR) to be strongly expressed in CS, but not in AdCC; C-kit was diffusely positive in AdCC and scanty in CS; SMA, p63 and Cytokeratine 5/6 (CK5/6) were positive in both. Our results also confirm that AdCC could be true basal-like neoplasia, probably arising from a basal stem line tending to divergent differentiation toward CK5/6/C-kit+, ER/PR-, epithelial basal-like cell type, and toward a myoepitelial-like cell type, with an incomplete SMA/p63+, CD10/HHF35- immunophenotype. By contrast, CS is a reactive, benign proliferation of two well-differentiated cell types: epithelial (ER/PR+, C-kit-) and myoepithelial cells with a complete immunophenotype including CD10/HHF35 positivity. Our study highlights the usefulness of CD10 and HHF35 in the differential diagnosis and helps to understand the histogenesis of the two lesions.

Glut-1 expression and in situ CD1a/CD57 immunologic deficit in keratoacanthoma and squamous cell carcinoma of immunocompetent patients.

It is not easy to reach a differential diagnosis between keratoacanthoma (KA) and squamous cell carcinoma (SCC) and furthermore there is still considerable discussion about the relationship of these 2 tumors with immunity. To facilitate such a diagnosis, we assessed the Glut-1 antibody, reported to be strongly and diffusely expressed in SCC but never assessed in KA. We studied 43 lesions of immunocompetent patients: 17 SCCs, 13 typical KAs (tKAs), and 13 atypical KAs (aKAs), with histologic features of SCC in less than 30% of the lesions. In tKA, Glut-1 stained only the basal layers of the squamous nests (basal pattern) whereas in SCC the squamous nests were randomly and diffusely stained (diffuse pattern). In aKA, a biphasic pattern was observed, with the typical KA areas showing the basal pattern and the SCC-like areas showing the diffuse pattern. Glut-1, therefore, helps to distinguish tKAs from SCCs and highlights the intermediate aKA group, supporting the hypothesis of a progression from KA to SCC. Finally, we used CD1a, CD57, CD4, CD8, CD3, and CD20 antibodies to assess whether or not the progression might be related to an in situ immunologic deficit. Significant differences were found both in CD1a+ cells, more numerous in tKA than in SCC and in CD57+ cells, more numerous in tKA than in aKA and in SCC. This suggests a local immunological failure in aKA and SCC, probably related to the action of UV rays, leading us to consider KA as a model for the study of the interaction of skin cancer and immunity.

Differing expression of metalloprotease and of adhesion molecules in signet-ring cell and intestinal colorectal carcinoma.

BACKGROUND: Pure signet-ring cell colorectal carcinoma (SRCC) is an infrequent and highly malignant histological variant of colorectal cancer (CRC), while it is present as a histological component in colorectal carcinomas more frequently. MATERIALS AND METHODS: The aim of this work was to widen the knowledge of the biological factors involved in the pathogenesis and aggressiveness of SRCC by the identification and evaluation of possible molecular abnormalities. By means of immunohistochemistry the expression of the proteolytic degradation enzyme matrix metalloprotease (MMP)-1, that is a collagenase specifically degrading collagens I, II, III and of the adhesion proteins E-cadherin, beta-catenin and fibronectin which are usually involved in the carcinogenesis of conventional colorectal tumours was investigated. RESULTS: SRCCs showed a significantly greater MMP-1 expression compared to the ordinary intestinal colorectal cancer (ICRC) and a significantly reduced E-cadherin, beta-catenin and fibronectin expression. CONCLUSION: The biological aggressiveness and strong metastatic behaviour of SRCC could be due to high MMP-1 and low expression of the adhesion molecules.

The pathology of bladder cancer: An update on selected issues.

OBJECTIVE: To achieve a closer relationship between urologists and pathologists and to use a common language and identical objectives in the pathology of bladder cancer. METHODS AND RESULTS: Special emphasis was given to an analysis of the new World Health Organization (WHO) grading system, to the interpretation of the last Tumour-Nodes-Metastasis staging rules, and to identifying new markers of prognostic significance in clinical practice. A consensus was achieved on the main points. CONCLUSIONS: The 2004 WHO grading system must become acceptable to clinicians, perhaps by a minimal modification of the present terminology. Simple transurethral resection-biopsy should be expressed in terms of clinical rather than pathological staging. Although there are substantial improvements, no new markers can be recommended for routine use in histopathology at present.

Sarcomatoid carcinoma of urinary bladder: immunohistochemical study of an uncommon case.

A case of sarcomatoid carcinoma of the bladder is reported herein. Immunohistochemical staining with human pancytokeratin antibody was negative, while vimentin staining was strongly positive, suggesting a diagnosis of sarcoma of the bladder. Further immunohistochemical analysis revealed positivity for AE1/AE3 cytokeratins, permitting a correct diagnosis of sarcomatoid carcinoma of the bladder. It can be difficult to distinguish between sarcomatoid carcinoma, undifferentiated carcinoma and sarcoma, particularly if the biopsy specimens are of small size. In rare cases, sarcomatoid tumors may express epithelial markers different from those revealed by human pancytokeratin staining.