An assessment of MAC 387 antibody as a diagnostically useful marker of L1 epithelial antigen expression by lung tumours.

A recent report describing the distribution of L1 epithelial antigen in lung tumours in relation to the histological type claimed that this antigen was a highly reliable marker of squamous cell carcinoma. Our study was designed to test this claim and to examine the potential of this antigen in the typing of lung tumours in biopsy specimens. A total of 143 lung tumours were typed according to the WHO classification and examined immunohistochemically for L1 epithelial antigen expression using commercially available monoclonal mouse anti-human myeloid/histiocyte antigen (MAC 387). Positivity was found in 46 of 55 squamous cell carcinomas (84 per cent), 12 of 27 adenocarcinomas (44 per cent), 15 of 16 adenosquamous carcinomas (93 per cent), 10 of 15 large cell carcinomas (67 per cent), none of 20 small cell carcinomas, and none of 10 carcinoid tumours. Of those tumours expressing L1 epithelial antigen, most showed a patchy pattern of positivity. From this study it is clear that detection of L1 epithelial antigen by MAC 387 antibody is not specific for squamous cell carcinomas, but it may have a limited use in the diagnosis of small cell carcinomas and carcinoid tumours as these are consistently negative.     

Squamous differentiation in primary urothelial carcinoma of the urinary tract as seen by MAC387 immunohistochemistry

Squamous differentiation (SqD) is variably present in urinary tract tumours, but its significance remains unclear. In this study, SqD was assessed by immunohistochemistry using the monoclonal antibody Mac387 in 145 urothelial tumours (bladder, n = 115; renal pelvis, n = 30). Mac387 detects the myelomonocytic L1 antigen; a member of the calgranulin family shared by epithelial cells and keratinocytes. L1 antigen was shown in SqD in urothelial carcinomas of the bladder or the renal pelvis, including 11 cases with focal SqD unrecognised by conventional analysis. SqD is more frequent in renal pelvic tumours (p = 0.027) and increases with grade/stage mainly in bladder carcinoma (grade, p = 0.05; stage, p = 0.005). Stage Ta/T1 bladder carcinomas with SqD recurred more (p = 0.021). In conclusion, Mac387 efficiently shows SqD in urothelial tumours.     

Mac387: its non-specificity as a tumour marker or marker of histiocytes

A commercially available monoclonal antibody which detects histiocytes in paraffin sections, Mac387, was reacted with 148 soft tissue sarcomas, 29 carcinomas and 10 malignant melanomas. The soft tissue sarcomas had been previously immunophenotyped. All categories of sarcomas, with the exception of angiosarcomas, were positive. Most showed staining in less than 50% of the tumour cells. Six of 10 adenocarcinomas and three of nine basal cell carcinomas were positive, while squamous carcinomas and malignant melanomas were negative. Normal squamous mucosa and epidermis were also positive. The results of this study suggest that Mac387 is of little value in the differential diagnosis of soft tissue tumours, nor is it a specific histiocytic marker.     

Mac 387 antibody and detection of formalin resistant myelomonocytic L1 antigen.

The murine monoclonal antibody Mac 387 was raised against a purified protein fraction obtained from human monocytes. By immunoblotting experiments, Mac 387 was shown to react with a previously defined antigen called L1; this is a multichain myelomoncytic protein of about 36 Kd which shows sequence homology with the cystic fibrosis antigen. The L1 protein is present in the cytoplasm of virtually all resting peripheral neutrophils and monocytes; it is also variably expressed on the plasma membrane of these cells, possibly as a secretory product. Because the L1 antigen is resistant to denaturation by formalin, its tissue distribution can be studied in routinely processed biopsy material. In a wide variety of specimens Mac 387 was shown by immunohistochemical analysis, to produce a cytoplasmic staining pattern concordant with that of a well defined polyclonal antibody to the L1 antigen. Cytoplasmic reactivity was obtained with granulocytes and infiltrating macrophages but generally not with several categories of dendritic cells. In addition, squamous epithelium of mucous membranes was strongly positive, in contrast to normal epidermis.     

Expression of the epithelial L1 antigen as an immunohistochemical marker of squamous cell carcinoma of the lung

The distribution of epithelial L1 antigen was evaluated in 139 bronchogenic carcinomas which had been classified by a panel of pathologists according to the WHO recommendation of 1981. L1 was not found in three large cell and 13 small cell carcinomas, but it was expressed by tumour cells in 67 of 69 squamous cell carcinomas (97%), in three of four adenosquamous carcinomas (75%), and in three of 49 adenocarcinomas (6%). The staining for L1 antigen was more diffusely distributed in the positive adenocarcinomas than in the squamous cell carcinomas. Its expression in squamous cell carcinomas was typically confined to relatively small tumour cell groups and never included a complete specimen. Semi-quantitative estimation of the immunostaining showed no clear relationship to the degree of differentiation and scores for proliferation, but L1 expression was negatively related to nuclear aberration (P less than 0.025) and malignancy scores (P less than 0.002). The good agreement between morphological classification and expression of L1 makes this a valuable marker in the diagnosis of lung carcinomas.     

鼻咽癌癌旁柱状上皮鳞状化生过程中上皮性标志物表达的变化

采用免疫组化方法，应用一组抗癌胚抗原（ＣＥＡ）、上皮膜抗原（ＥＭＡ）和不同分子量细胞角蛋白的抗体，对７８例鼻咽癌癌旁上皮的上皮性标志物的表达进行了研究。结果表明，柱状上皮的储备细胞和鳞状上皮的基底细胞的上皮性标志物表达不同。在柱状上皮的鳞状化生过程中，一方面是柱状上皮的储备细胞增生并转化为鳞状上皮的“基底细胞”；另一方面，这些“基底细胞”按照正常鳞状上皮的分化程序，分化并发育成鳞状上皮，但仍保留储备细胞的一些分化特征。因此，鳞化上皮与正常被覆鳞状上皮在上皮性标志物表达上仍存在一些差异。     

Increased expression of cytokeratins 8, 18 and vimentin in the invasion front of mucosal squamous cell carcinoma

The immunohistochemical expression patterns of cytokeratins 8 and 18 and vimentin were examined in frozen sections of 120 human mucosal squamous cell carcinomas with special emphasis on the topological distribution in the tumour. This was done in order to evaluate in squamous cell carcinoma a particular expression pattern observed recently by us in transitional cell carcinoma of the urinary tract and designated as an ‘interface phenomenon’;. This phenomenon implying maximum expression of cytokeratins 8 and 18 at the tumour front, and to a lesser extent also in areas of intratumorous stroma contact, was also found in about 50 per cent of the squamous cell carcinomas examined. It was even found for vimentin, which contrasted with transitional cell carcinoma. The percentages of occurrence of the phenomenon varied for the different sites of origin of the tumour. Tumour grade did not influence the results. These findings further support the idea that invasive carcinoma cells interacting with the stromal micro-environment display a characteristic intermediate filament phenotype that deviates from the pattern expected on the basis of their direction of differentiation. These changes might eflect phenotype involved in invasive, migrating, and proliferating activities.     

Cytokeratin expression in non-neoplastic oesophageal epithelium and squamous cell carcinoma of the oesophagus

The expression of cytokeratins (CK) 19, 8, 18, 13, 10 and 7 was examined in 35 cases of squamous cell carcinomas of the oesophagus (10 well-differentiated, 13 moderately-differentiated, and 12 poorly-differentiated) and the adjacent mucosa by means of a panel of monoclonal antibodies on frozen sections. The study was undertaken to assess the pattern of expression of these keratins in oesophageal tumours and its relation to the degree of differentiation. The normal oesophageal epithelia expressed CK19 in 86%, CK18 in 17% and CK13 in 14% of cases. CK8, CK10 and CK7 immunoreactivity was not observed. The tumours expressed CK19 in 86%, CK8 in 46%, CK18 in 97%, CK13 in 83%, CK10 in 34% and CK7 in 29% of cases. Thus, the so-called simple epithelial markers CK18 and CK19 occurred in the majority of oesophageal squamous cell carcinomas. CK13 (the so-called non-keratinizing squamous epithelial marker) was only infrequently demonstrated in the non-neoplastic oesophageal mucosa, and its expression was more frequent in carcinomas. CK10 was not demonstrated in non-neoplastic mucosa, but was mostly associated with well-differentiated carcinomas. We therefore conclude that the pattern of expression of cytokeratins in oesophageal carcinomas is different from that in normal oesophageal epithelia and varies with differentiation.     

Immunodetection of GLUT1, p63 and phospho-histone H1 in invasive head and neck squamous carcinoma: correlation of immunohistochemical staining patterns with keratinization

Immunodetection of GLUT1, p63 and phospho-histone H1 in invasive head and neck squamous carcinoma: correlation of immunohistochemical staining patterns with keratinizationAims : To examine invasive head and neck squamous carcinomas for expression of GLUT1, a glucose transporter and marker of increased glucose uptake, glycolytic metabolism and response to tissue hypoxia; p63, a p53 homologue that is a marker of the undifferentiated proliferative basaloid phenotype; and phospho-histone H1, a marker of activation of the cell cycle-promoting cyclin-dependent kinases 1 and 2. Methods : Routinely processed slides from 34 invasive squamous carcinomas, including 25 with intraepithelial components, were immunostained with anti-GLUT1 (Chemicon), anti-p63 (4A4, Santa Cruz), and antiphospho-histone H1 (monoclonal 12D11). Results : In keratinizing carcinomas, all three markers were most commonly immunodetected peripherally, with loss of expression in central keratinized zones. In contrast, in non-keratinizing carcinomas, p63 and phospho-histone H1 expression was most commonly observed throughout tumour nests and anti-GLUT1 stained in a pattern suggestive of hypoxia-induced expression ('antistromal' staining), in which cells at the tumour-stromal interface were GLUT1- and cells in central, perinecrotic zones showed progressive induction of GLUT1. Intraepithelial components also displayed basal and 'antibasal' GLUT1 staining patterns, homologous to the pro- and antistromal patterns in invasive carcinoma; basal patterns in intraepithelial lesions appeared to be more predictive of keratinizing invasive carcinoma and antibasal intraepithelial staining more predictive of non-keratinizing poorly differentiated carcinomas. Conclusions : Keratinizing and non-keratinizing squamous carcinomas differ in expression patterns of GLUT1, p63 and phospho-histone H1. In the former, all three markers were typically suppressed in conjunction with keratinization; in the latter, GLUT1 expression was more likely to occur in a hypoxia-inducible pattern and expression of p63 and phospho-histone H1 was unsuppressed. GLUT1 expression patterns in intraepithelial lesions may be predictive of the differentiation status of the associated invasive carcinoma.     

Involucrin, a marker of squamous and urothelial differentiation. An immunohistochemical study on its distribution in normal and neoplastic tissues

Involucrin is a soluble protein precursor of the cross-linked envelope present in the submembranous zone of human stratum corneum, and subsequently demonstrated in stratified squamous epithelia. The immunoperoxidase technique was used to assess the distribution of involucrin in 107 normal and 318 abnormal tissues. With few exceptions, involucrin was restricted to squamous epithelia, urothelium, some skin appendages and thymic Hassall's corpuscles. In normal squamous epithelium and normal urothelium, staining was most intense in the superficial layers where it was concentrated at the cell periphery and gradually decreased toward the basal layer. This orderly staining pattern was maintained in benign squamous and urothelial lesions and in grade I papillary urothelial carcinomas. Higher grade papillary urothelial carcinomas, infiltrating urothelial and squamous carcinomas, and in situ urothelial and squamous carcinomas demonstrated abnormal staining patterns for involucrin that are described. Foci of squamous differentiation in adenocarcinomas and other epithelial malignancies stained intensely for involucrin. Brenner tumours of the ovary and Walthard rests of the fallopian tube, lesions of uncertain histogenesis but possibly urothelial-related, also stained for involucrin. Results of this study suggest that involucrin is a sensitive and specific marker for squamous and urothelial differentiation, staining patterns for involucrin may be helpful in distinguishing benign from malignant urothelial and squamous lesions, and presence of involucrin may be helpful in determining the histogenesis of selected lesions.     

Immunohistochemical staining patterns of keratins in normal oesophageal epithelium and carcinoma of the oesophagus

To clarify the keratin staining patterns of invasive carcinoma of the oesophagus, 22 cases of formalin-fixed paraffin-embedded surgical specimens were examined immunohistochemically with the labelled streptavidin biotin method using a panel of six different monoclonal anti-keratin antibodies. The antibody reacted adequately when antigen was retrieved in a microwave oven, and the relationship between morphological characteristics and keratin reaction patterns was analyzed in carcinomas and compared with adjacent histologically normal epithelium. In the normal oesophageal epithelium, AE3 and CK8.12 labelled all layer of cells, KS-1A3, E3 and KL1 labelled suprabasal cells, and LL002 selectively labelled the basal cells. In squamous cell carcinomas, AE3, CK8.12, KL1 and LL002 labelled almost all the tumour cells regardless of their differentiation, E3 only labelled keratinized cells, while marked decrease or loss of KS-1A3 staining was seen in all cases examined. Therefore, the characteristic profile of squamous cell carcinoma was a strong and diffuse expression of keratin 14 and 16, strong but localized expression of keratin 17, and loss of keratin 13 expression. Undifferentiated carcinoma totally lacked all keratin reactivity. The findings suggested that the neoplastic epithelial cells showed different keratin reactivity and distribution compared to normal oesophageal epithelium. In addition, histologically normal epithelium, dysplasia and carcinoma-in-situ adjacent to or overlying carcinoma expressed keratin 14.     

Cytokeratin 14 expression in epithelial neoplasms: a survey of 435 cases with emphasis on its value in differentiating squamous cell carcinomas from other epithelial tumours

AIMS: The tissue distribution of cytokeratin 14 (CK14) in epithelial neoplasms is not well defined. We have evaluated 435 cases of epithelial neoplasm of various origins with cytokeratin 14 monoclonal antibody with special attention to possible use in differential diagnosis. METHODS AND RESULTS: Immunohistochemistry (ABC-HRP method) was performed for detection of CK14. We found that the expression of cytokeratin 14 was generally restricted to: (i) the majority of cases of squamous cell carcinoma regardless of origin (67/74) and degree of differentiation; (ii) neoplasms with focal squamous differentiation, including endometrial, and ovarian adenocarcinoma, malignant mesothelioma and transitional cell carcinoma; (iii) thymoma (8/8); (iv) myoepithelial components of salivary gland pleomorphic adenoma (3/4); and (v) oncocytic neoplasms, including thyroid Hurthle cell adenoma (1/1) and salivary gland Warthin's tumour (2/2). CONCLUSION: CK14 protein is a useful marker in differential diagnosis of squamous cell carcinomas.     

Expression of epithelial and neural antigens in small cell and non small cell lung carcinoma

Seventy-one lung carcinomas from 66 different patients were stained with a panel of monoclonal antibodies. Twenty-nine were small cell lung carcinoma (SCLC), 15 adenocarcinomas, 17 squamous carcinomas and 10 large cell carcinomas. Three of the monoclonal antibodies recognize different cytokeratins, three recognize other epithelial antigens and one recognizes a neural antigen. Both formalin-fixed and cryopreserved tumours were studied using an indirect immunoperoxidase method. 23/29 SCLC reacted with all but one of the antibodies which recognize epithelial antigens. This staining was similar to that seen in non small cell lung carcinomas (NSCLC) and provides further evidence that SCLC are true epithelial tumours. All but one of the SCLC stained with the antibody recognizing a neural antigen. This antibody did not stain squamous or adenocarcinomas. However, four of the large cell carcinomas stained well with this antibody, suggesting that SCLC and some large cell carcinomas share a common pathway of differentiation. There were variations of staining seen both within and between tumours. This has obvious implications if immunotargetting with monoclonal antibodies is to be used diagnostically or therapeutically.     

The distribution of cytokeratin antigens in the kidney and in renal tumours

The distribution of cytokeratin antigens during embryogenesis of the kidney and in 57 renal tumours has been studied using immunocytochemical techniques. A polyclonal antiserum to epidermal prekeratins and the monoclonal antibodies CAM 5.2 and PKK1 have been used to identify cytokeratins of different molecular weights. The ureteric bud-derived structures expressed large molecular weight cytokeratins. The tubular component of the kidney expressed cytokeratins detected by CAM 5.2 and PKK1. During glomerular development there was transient expression of low molecular weight cytokeratins by the visceral glomerular epithelium but in the adult kidney only the parietal epithelium expressed cytokeratins. Tubules in nephroblastomas contained low molecular weight cytokeratins but the blastema did not. Some ureteric bud-derived structures were identified in six nephroblastomas. Renal carcinomas expressed low molecular weight cytokeratins. Four collecting duct carcinomas were studied; these all expressed the large molecular weight cytokeratins found in collecting duct epithelium. These results indicate that the cytokeratin phenotype of renal tumours is unchanged from that of the normal epithelial cells.     

New monoclonal antibodies recognizing epidermal differentiation-associated keratins in formalin-fixed, paraffin-embedded tissue. Keratin 10 expression in carcinoma of the vulva

Two monoclonal antibodies (MAb) specific for differentiation-related epidermal keratins have been developed. They represent specific molecular probes for different stages of epidermal differentiation. Antibody DE-K10 is chain-specific for cytokeratin polypeptide no. 10 (56.5 kD) expressed in all suprabasal layers of the epidermis. Antibody DE-SCK is specific for modified stratum corneum keratins and thus represents a marker for the terminal step of epidermal differentiation. Since the epitopes identified by both antibodies are preserved in formalin-fixed, paraffin-embedded tissue sections, these antibodies can be used for retrospective studies of differentiation in various pathological processes. We have used antibody DE-K10 to study the cytokeratin 10 expression in 26 stage II or III vulvar squamous cell carcinomas. Preliminary data suggest an increased risk of recurrence in cytokeratin 10 negative tumours.     

Monoclonal antibody JC1: new reagent for studying cell proliferation.

AIM: To characterise a newly developed mouse monoclonal antibody JC1 which recognises a nuclear antigen present in proliferating cells in normal tissues and neoplastic lesions, and which is absent in resting cells. METHODS: The methodology was established using a representative range of frozen sections from normal tissues and from certain tumours which were immunostained with antibodies Ki67 and JC1. The molecular weight of the antigen recognised by JC1 was obtained by western blot analysis and this was compared with that of Ki67. IM-9 cell lysates containing Ki67 derived plasmids were also tested with JC1 antibody. RESULTS: Biochemical investigation indicated that the antigen recognised by JC1 gives two molecular weight bands of 212 and 123 kilodaltons, which is distinct from the well characterised anti-proliferation monoclonal antibody Ki67 (395-345 kilodaltons). In addition recombinant Ki67 protein is not recognised by JC1. Immunohistological reactivity was seen in areas known to contain numerous proliferating cells such as lymphoid germinal centres, splenic white matter, cortical thymocytes and undifferentiated spermatogonia. In tumours many cells from adenocarcinomas, oat cell carcinomas, squamous cell carcinomas of lung, and seminomas were labelled by JC1 with a distribution and proportion similar to that seen with Ki67. In normal tissues the only apparent difference was in testis where JC1 stained a considerably greater number of cells than Ki67. In all cases studied the new antibody showed nuclear reactivity only. JC1 did not show any cytoplasmic crossreactivity with squamous cells as is frequently seen with Ki67. CONCLUSION: Antibody JC1, which recognises a nuclear antigen present in proliferating cells, should provide a useful adjunct to Ki67 as a marker of proliferation especially in those cases such as squamous cell carcinomas where a Ki67 index cannot be determined.     

Differences in the ARID‐1 alpha expressions in squamous and adenosquamous carcinomas of uterine cervix

AT‐rich interactive domain 1A (ARID1A) is a tumor suppressor gene involved in chromatin remodeling which encodes ARID1A (BAF250a) protein. Recent studies have shown the loss of ARID1A expression in several types of tumors. This retrospective study was designed to evaluate the differences in tissue expressions of ARID1A in a spectrum of cervical neoplasms. Cervical intraepithelial neoplasms, invasive squamous or adenosquamous carcinomas were identified in 100 patients recently diagnosed as cervical neoplasms based on pathology databases. In this series, there were 29 low‐ and 29 high‐grade cervical intraepithelial neoplasms, 27 squamous cell carcinomas, and 15 adenosquamous carcinomas. Mean age of the patients was 47.8 ± 13 years (20–80 years). It was determined that the expression of ARID1A was statistically significantly down‐regulated in adenosquamous carcinomas when compared with non‐invasive or invasive squamous cell carcinomas (p = 0.015). Lower levels of the ARID1A expression were detected in cases with adenosquamous carcinomas (60%), low‐ or high‐grade squamous intraepithelial lesion (SIL) (31%), and squamous cell carcinomas (18.5%). Our findings have demonstrated the presence of a correlation between ARID1A expression and adenomatous differentiation of uterine squamous cell carcinomas. Therefore, ARID1A gene may suggestively have a role in the pathogenesis of cervical adenosquamous carcinomas.     

Immunohistochemistry of cytokeratin proteins in squamous and transitional cell lesions of the urinary tract.

Expression of low and high molecular weight cytokeratin proteins was investigated immunohistochemically in a variety of transitional and squamous epithelial lesions of the urinary tract with and without schistosomiasis. The monoclonal antibodies used were CAM 5.2 and NCL5D3 for low, PK 63 and 121 for high, and MAK 6 for a broad range of intermediate molecular weight cytokeratins. On staining with CAM 5.2 and NCL5D3, urothelial hyperplasias (n = 12) and grades 1 (n = 5) and 2 (n = 10) papillary transitional cell carcinomas showed labelling patterns quite distinct from carcinoma in situ (n = 4) and non-papillary grades 2 (n = 6) and 3 tumours (n = 3). Among squamous lesions only focal positivity was obtained in 14 of 22 moderate to poorly differentiated squamous cell carcinomas. By contrast, PK 63 and 121 stained squamous lesions exclusively. MAK 6 stained the whole range of urothelial and squamous lesions with the exception of squamous metaplasias. Polyclonal antikeratin adequately labelled spindle cell areas of high grade tumours. The distinctive staining patterns given by these or similar antibodies may help in the identification of squamous metaplasia and in diagnosing tumours of the urothelium.     

Drug-induced toxic epidermal necrolysis and pancytopenia: a puzzling association

The molecular mechanisms involved in the pathogenesis of toxic epidermal necrolysis (TEN) remain not fully understood. We report a unique case of antibiotic-induced TEN developed in a patient who also suffered from prolonged severe methotrexate-induced pancytopenia. The objective of the study was to explore the nature of the cutaneous inflammatory infiltrate and the density in dermal dendrocytes (DD). Immunohistochemistry was used to identify activated T lymphocytes (CD45R0), monocyte-macrophages (Mac 387, CD68), DD (Factor XIIIa), and Langerhans cells (CD1a). The proliferation marker (Ki67) and the antibody to Fas receptor (CD95R) were also used to assess the distribution of the germinative pool of keratinocytes and the FAS-related apoptotic process, respectively. Numerous Factor XIIIa+ DD were present in the papillary dermis with only sparce perivascular CD45RO+ T lymphocytes and scattered CD68+ or Mac 387+ macrophages. Double immunostainings revealed that a minority of Factor XIIIa+ DD co-expressed the CD68 glycoprotein (a marker of phagocytic activity). No cells co-expressed factor XIIIa and Mac 387 immunoreactivities. CD45RO+ T lymphocytes, CD68+ and Mac 387+ macrophages were absent in the epidermis. The expression of CD95R was present although restricted to the basal keratinocytes, while the L1-protein (Mac 387+) was diffusely present in the epidermis. Langerhans cells (CD1a+) were sparce, but normal in distribution. The presence of a great number of Factor XIIIa+ DD without any possible recent recruitment from bone marrow suggests that these cells differentiated from resident cells of the skin. Indeed, there was no co-expression of Factor XIIIa and L1-protein, thus showing the absence of recruitment from monocytes. The simultaneous over-expression of Factor XIIIa and CD68 in some DD indicates some phagocytic activity. In view of the absence of inflammatory cells in the epidermis, keratinocytes appeared responsible for their own destruction through CD95-mediated and/or calcium-dependent apoptotic pathways. This finding entails that TEN treatments should target the keratinocyte metabolism rather than the circulating inflammatory cells which presumably play a limited role, if any, in the epidermal destructive process.     

Distinct expression profiles of p63 variants during urothelial development and bladder cancer progression

The TP63 gene, a member of the TP53 tumor suppressor gene family, can be expressed as at least six isoforms due to alternative promoter use and alternative splicing. The lack of p63 isoform-specific antibodies has limited the analysis of the biological significance of p63. We report a novel set of well-defined antibodies to examine p63 isoforms in mouse and human urothelium during embryogenesis and tumor progression, respectively. We provide evidence that basal and intermediate urothelial cells express p63 isoforms, with the TAp63 variant the first to be detected during development, whereas umbrella cells are characterized by a p63-negative phenotype. Notably, we report that p63-null mice develop a bladder with an abnormal urothelium, constituted by a single layer of cells that express uroplakin II and low molecular weight cytokeratins, consistent with an umbrella cell phenotype. Finally, analysis of 202 human bladder carcinomas revealed a new categorization of invasive tumors into basal-like (positive for ΔNp63 and high molecular weight cytokeratins and negative for low molecular weight cytokeratins) versus luminal-like (negative for ΔNp63 and high molecular weight cytokeratins and positive for low molecular weight cytokeratins) phenotypes, with ΔNp63 expression associated with an aggressive clinical course and poor prognosis. This study highlights the relevance of p63 isoforms in both urothelial development and bladder carcinoma progression, with ΔNp63 acting as an oncogene in certain invasive bladder tumors.