Combined double CK5/P63 stain: useful adjunct test for diagnosing pulmonary squamous cell carcinoma

Increasing demand for accurate differentiation of pulmonary squamous cell carcinoma (SQCC) from other subtypes can be challenging for pathologists. This is more so in fine-needle aspirations (FNA) since the sample is small and SQCC may show degenerative changes and necrosis that distort the cellular features. Immunohistochemistry (IHC) is a valuable adjunct, and CK5/6 and P63 immunoreactivity is found to be basically restricted to SQCC. In our study, we evaluated the efficiency of CK5/P63 double staining in the diagnosis of pulmonary SQCC in cell blocks (CB) of lung FNA. We used a cohort including 24 CB of lung SQCC and 34 CB of lung adenocarcinomas (ADC). IHC was performed for CK5/P63 double stain. Seventeen of 24 (70%) lung SQCC were positive for the double stain CK5/P63. Two (8%) were positive for CK5 alone and two (8%) were positive for P63 alone. Thus, a total 19 of 24(79%) SQCC of the lung were positive for CK5 and P63 each. In ADC, no immunoreactivity was detected for CK5 alone or combined CK5/P63. Three of 34(8%) ADC were positive for P63. This first study of double staining of CK5/P63 in FNA CB shows a sensitivity of 70% and specificity of 100% for SQCC of the lung. When each marker staining alone is included, the sensitivity for CK5 and P63 increases to 79% each. This double stain can help in the diagnosis of pulmonary SQCC with an accuracy of 88% and a positive predictive value of 100%.     

Primitive neuroectodermal tumors, embryonal tumors, and other small cell and poorly differentiated malignant neoplasms of the central and peripheral nervous systems

Many different types of small cell, embryonal, and poorly differentiated neoplasms originate within the central and peripheral nervous systems. Because appropriate treatment is based on a correct diagnosis, the surgical pathologist must be familiar both with basic characteristics of each of the numerous entities as well as the spectrum of morphologic features that each may display. The nosology and nomenclature of these tumors have a rich and varied history. One basic distinction is between primitive neuroectodermal tumors of the central nervous system (cPNETs) and primitive neuroectodermal tumors of the peripheral nervous system (pPNETs), which are clinicopathologically and genetically distinct. Among the cPNETs are medulloblastoma, pineoblastoma, cerebral neuroblastoma, ependymoblastoma, medulloepithelioma, primary rhabdomyosarcoma, and atypical teratoid/rhabdoid tumor, whereas the pPNETs comprise the more differentiated end of a spectrum of neoplasms that include skeletal and extraskeletal Ewing's sarcoma.     

p63 Expression in olfactory neuroblastoma and other small cell tumors of the sinonasal tract

Olfactory neuroblastoma (ONB) is a rare neoplasm of the head and neck region that is included in the differential diagnosis of other sinonasal tract malignancies. We studied the usefulness of using p63 as an aid in the diagnosis of ONB and other tumors of the sinonasal region. The specimens were 14 ONBs; 4 nasopharyngeal carcinomas (NPCs), nonkeratinizing subtype; 2 NPCs, undifferentiated subtype; 10 sinonasal undifferentiated carcinomas (SNUCs); 7 malignant melanomas; and 2 extranodal natural killer (NK)/T-cell lymphomas. We observed p63 expression in 5 ONBs (36%), 4 nonkeratinizing NPCs (100%), 1 undifferentiated NPC (50%), 2 SNUCs (20%); 0 malignant melanomas (0%); and 1 extranodal NK/T-cell lymphoma (50%). While all cases of NPC with positive staining for p63 showed strong and diffuse immunoreactivity, the ONB, SNUC, and lymphoma cases with positive immunoreactivity showed only focal staining for p63. No p63 expression was observed in malignant melanoma. We think p63 is a useful marker to help distinguish nonkeratinizing or undifferentiated NPC subtypes from various sinonasal tract malignancies. In particular, p63 helps distinguish nonkeratinizing and undifferentiated NPC subtypes from SNUC.     

Ultrastructure of squamous epithelium in esophageal dysplasia and squamous cell cancer

Electron microscopic examination of the oesophageal squamous cell carcinoma revealed the presence in the tumour of both undifferentiated and differentiated squamous cells. Keratinocytes appeared and the signs of keratinization were more pronounced in the cytoplasm of differentiated cells. Dysplastic changes were observed at the periphery of the primary node. Two main variants of dysplasia (dark-cell and clear-cell) were distinguished, this at the ultrastructural level being the reflection of the direction of differentiation and the degree of cell maturity in the dysplastic foci. With the exception of few cases with a cell polymorphism in the foci of a severe dysplasia, dysplastic changes of the squamous epithelium were characterized by a monotonous ultrastructural cell composition. The dysplastic cells were distinguished by a degree of differentiation and high synthetic activity.     

Expression of the TSLC1 adhesion molecule in pulmonary epithelium and its down-regulation in pulmonary adenocarcinoma other than bronchioloalveolar carcinoma

TSLC1 (tumor suppressor in lung cancer-1) is an adhesion molecule of the Ig superfamily that binds homophilically and mediates cell-cell interactions. Originally, TSLC1 was cloned as a candidate tumor suppressor from the genomic region that frequently exhibits loss of heterogeneity in human non-small-cell lung cancer (NSCLC). However, there have been no studies on TSLC1 expression in normal lungs or NSCLC. Here we show that pulmonary epithelial cells express TSLC1 and its expression levels are often decreased or lost in primary pulmonary adenocarcinoma, a major histologic type of NSCLC. Immunohistochemistry revealed that TSLC1 was localized at cell-cell boundaries of all columnar epithelial cells in mouse embryonic lungs of 10.5 and 13 days postcoitus. Similar staining patterns were observed in bronchiolar and alveolar epithelial cells of adult human lungs, suggesting a physiologic role for TSLC1 in interactions of these cells. Next we performed Western blot analyses of TSLC1 in 47 primary pulmonary adenocarcinomas and judged each tumor as either decreased or nondecreased by comparing TSLC1 expression levels of the tumor with the levels of normal lungs. The expression profiles had a significant relation to histologic subtypes but not to other clinicopathologic parameters. Sixteen bronchioloalveolar carcinomas (BACs) were all judged nondecreased, while 19 of 31 (63%) adenocarcinomas other than BAC were judged decreased (p < 0.0001). Immunohistochemistry of tumors judged nondecreased revealed that not only BAC cells but also tumor cells in lepidic growth components of adenocarcinomas other than BAC expressed TSLC1 on their lateral plasma membranes. These tumor cells are considered less invasive because they proliferate in a lepidic growth pattern along alveolar walls. Thus, the present results not only support the hypothesis that TSLC1 is a tumor suppressor of NSCLC but also suggest that preserved integrity of TSLC1 may contribute to less invasive phenotypes of lepidic growth tumor cells.     

Primary epithelial neoplasms and other epithelial lesions of the appendix (excluding carcinoid tumors)

Epithelial tumors of the appendix range from low-grade mucosal-based tumors which, when confined to the appendix, have an excellent prognosis but, once outside the appendix, have a fair prognosis and often a prolonged disease course, to high grade invasive carcinomas that are rapidly fatal. Low grade mucinous neoplasms may rupture and spread to the peritoneum as pseudomyxoma peritonei, and the nomenclature of these tumors has been the subject of considerable disagreement among pathologists; the designation "low grade appendiceal mucinous neoplasm" has recently been proposed for reasons discussed herein. Demonstrating rupture of these neoplasms may require particularly diligent gross and microscopic evaluation as the rupture site often heals over leaving only subtle evidence of its presence. Invasive adenocarcinomas are often mucinous and may also spread to the peritoneum. Against this backdrop, the clinical and pathologic features of low grade appendiceal mucinous neoplasms and mucinous adenocarcinomas, as well as other types such as typical colorectal type and signet-ring cell type, are reviewed. In addition, emerging entities, serrated polyps and serrated adenomas, whose significance is only beginning to be understood, are considered. Retention cysts, hyperplastic polyps, and diffuse mucosal hyperplasia, although not necessarily neoplastic, are reviewed here as they may enter into the differential diagnosis of appendiceal mucinous neoplasms.     

Chromosomal aberrations in premalignant and malignant squamous epithelium

Biopsies of oropharyngeal cancer were screened for chromosomal imbalances by comparative genomic hybridization (CGH) performed on 22 primary tumors and morphologically nonmalignant surrounding mucosa. The aim was to determine early chromosomal changes of tumor development and to draw conclusions on the mechanisms leading to multiple tumors. The most prominent chromosomal imbalances observed were over representations of genomic material on 3q, 15q, 8q, and 11q and losses on 9p, 3p, and 11q. In morphologically normal mucosa collected at 1 cm from the primary tumor border (M1), amplifications on 15q and 21q were most frequent. Far fewer gains and losses were found in M1 than in the primary tumor (average 2.2 vs. 6.9). Gains dominated over losses, but a tendency toward an increasing proportion of losses in the primary tumor (PT) was observed (ratio of gains to losses: PT, 4.75; M1, 6.3). Almost all the imbalances in M1 were detected in the primary tumor. No chromosomal alterations were identified with CGH in tissue samples dissected at 2 cm from the primary tumor (M2). In all samples, dysplastic morphologic changes decreased with distance from the primary tumor, which correlates with the observed lower level of genetic changes. We suggest that gains of genetic material on 15q and 21q are early events in malignant progression of squamous cell carcinoma, followed by gains on 3q, 8q, and 11q, and losses on 3p and 9p at later stages. Based on our cytogenetic data, we discuss the monoclonal model followed by lateral epithelial spread as an explanation of multiple head and neck squamous cell carcinomas.     

Ectopic stratified squamous epithelium in bovine jejunum

An adult dairy cow developed acute fatal diarrhoea. Necropsy provided no aetiological or morphological cause of the diarrhoea but incidental post-mortem findings included well-circumscribed areas of jejunal squamous epithelium. The cause of this unusual heterotopia is not known, but the lesion may have been of embryological or metaplastic origin.     

Radiologically-determined diameter, pathologic diameter, and reactive zone surrounding pulmonary neoplasms: implications for transthoracic fine-needle aspiration of pulmonary neoplasms.

To determine the relationship between radiologically determined tumor diameter and true pathologic tumor diameter and correlate radiologically determined diameter with the size of reactive zone surrounding pulmonary neoplasms, radiographs and surgical pathology specimens were obtained from 57 patients with pulmonary neoplasms. The tumor size on plane films and CT-scans was measured, as was the size of the neoplasm on gross specimen and surgical pathology slide. The width of the reactive zone was also measured on H&E stained microscopic slides. These findings were correlated along the histopathologic type of neoplasm present. On average, the reactive zone represented approximately 11% of the overall diameter of the neoplasm. However, there was considerable variation in this percentage, with reactive zone thickness varying between 2% and 48% of total tumor diameter. Bronchioloalveolar cell carcinomas generally lacked a reactive zone, while the other types of carcinomas frequently contained reactive zone. Approximately half of all carcinomas displayed a reactive zone of 1 mm in thickness or more. The present study demonstrates that a majority of carcinomas contain a reactive zone. This reactive zone is of variable thickness, but in approximately 50% of carcinomas it is at least 1 mm in thickness. The thickness of the reactive zone represents approximately 11% of total tumor diameter. Diagn. Cytopathol. 1999;21:250-252.     

Subependymomas: clinicopathologic study of 14 tumors, including comparative MIB-1 immunohistochemical analysis with other ependymal neoplasms.

BACKGROUND: Subependymomas are uncommonly encountered ependymal tumors, which are important to distinguish from ordinary ependymomas because of their generally better prognosis. OBJECTIVE: To review the clinicopathologic features and MIB-1 labeling indices (marker of cell proliferation) of 14 subependymomas. DESIGN: Retrospective review of 14 subependymomas encountered in a tertiary care setting. RESULTS: Fourteen ependymomas presenting in 8 men and 6 women between the ages of 18 and 78 years (mean, 53.6 years) comprise the study group. The most common clinical presentations included ataxia (n = 4), dizziness/vertigo (n = 3), nausea/vomiting (n = 3), headaches (n = 3), and incidental finding at autopsy (n = 2). Tumor locations included fourth ventricle (n = 7), lateral ventricle (n = 4), third ventricle (n = 2), and thoracic spinal cord (n = 1). Eight patients underwent gross total resection, and 4 had subtotal resection. Tumors were characterized by clustering of cell nuclei arranged against a fibrillary background. Focal cystic degeneration was seen in 10 tumors, hemosiderin deposition in 8 tumors, sclerotic vessels in 8 tumors, calcifications in 5 tumors, and focal nuclear pleomorphism in 2 tumors. Mitotic figures, vascular endothelial proliferation, and necrosis were not seen in any of these tumors. Cell proliferation marker MIB-1 labeling indices (percentage of positive staining tumor cells) ranged from 0 to 1.4 (mean, 0.3). In comparison, 13 myxopapillary ependymomas had labeling indices ranging from 0 to 5.5 (mean, 1.1). Thirty-nine low-grade ependymomas had MIB-1 labeling indices of 0.1 to 5.4 (mean, 1.1). Fourteen anaplastic/malignant ependymomas had MIB-1 labeling indices ranging from 0.4 to 34.0 (mean, 12.8). One subependymoma was treated with radiation therapy. Six patients were alive with no evidence of tumor at a mean follow-up of 94.4 months. Two patients were alive with residual tumor (follow-up of 4 and 53 months). Two patients died with tumor at 0.67 and 43.4 months. One patient was lost to follow-up, 1 is a recent case, and 2 were incidental findings at autopsy. None of the patients developed tumor recurrence. CONCLUSIONS: Subependymomas are generally low-grade lesions, as evidenced by their benign clinical course and low MIB-1 labeling indices. Compared with other ependymal tumors, subependymomas have the lowest rate of cell proliferation as evidenced by MIB-1 immunostaining.     

The p63 gene in EEC and other syndromes

Several autosomal dominantly inherited human syndromes have recently been shown to result from mutations in the p63 gene. These syndromes have various combinations of limb malformations fitting the split hand-split foot spectrum, orofacial clefting, and ectodermal dysplasia. The p63 syndrome family includes the EEC syndrome, AEC syndrome, ADULT syndrome, limb-mammary syndrome, and non-syndromic split hand/foot malformation. The pattern of heterozygous mutations is distinct for each of these syndromes. The functional effects on the p63 proteins also vary between syndromes. In all of these syndromes, the mutation appears to have both dominant negative and gain of function effects rather than causing a simple loss of function.     

应用组织芯片研究p63及其同系物在肺癌中的表达

目的研究p63蛋白及其同系物TAp63、△Np63在肺癌组织中的表达,并初步探讨其生物学意义。方法选取183例肺癌、30例肺良性病变的石蜡标本,应用组织芯片技术和免疫组织化学方法观察三种蛋白在肺良、恶性病变中的表达情况。结果p63蛋白及其同系物map63、△Np63三者在肺鳞状细胞癌、腺癌、细支气管肺泡癌、小细胞癌的表达具有一致性（r〉0．75,P〈0．01）,且在鳞状细胞癌中的表达率均高于其它类型（P〈0．01）;在鳞状细胞癌中△Np63表达率（74．6％）略高于map63（67．2％）,但无统计学意义（P〉0．05）。三种蛋白的表达与患者性别、年龄、肿瘤分化程度、肿瘤大小、有无淋巴结转移及临床分期不相关（P〉0．05）。p63、TAp63及△Np63在肺癌旁组织或肺良性病变的肺泡上皮细胞和支气管纤毛柱状上皮不表达,而只表达于支气管上皮的基底细胞和支气管腺的肌上皮细胞。结论p63基因在不同类型的肺癌中作用不同,在鳞状细胞癌的发生发展中起着重要的作用。两种同系物map63和△Np63在鳞状细胞癌中也呈高表达,其机制有待研究。p63可作为肺鳞状细胞癌与其它类型癌鉴别的重要依据。     

Diagnostic utility of P63 and CD10 in distinguishing cutaneous spindle cell/sarcomatoid squamous cell carcinomas and atypical fibroxanthomas

The pathologic distinction of atypical fibroxanthomas (AFXs) from cutaneous spindle cell/sarcomatoid squamous cell carcinomas (SCSCCs) may occasionally pose a significant diagnostic challenge, given the substantial clinicopathologic overlap between these lesions. Recent studies indicate that p63 and CD10 are expressed in significant proportions of SCSCC and AFX, respectively. The purpose of this study is to investigate the utility of CD10 and p63 in distinguishing cutaneous SCSCCs and AFXs. The immunohistochemical expression of p63, CD10, cytokeratin AE-1/3, cytokeratin 5/6 and a cytokeratin cocktail (Kermix) was evaluated in an archived group of 23 AFXs and 10 SCSCCs. CD10 was positive in 18/23 AFXs (78%), with most demonstrating strong and/or diffuse staining. Three of 23 AFXs (13%), all negative for cytokeratins, showed focal and weak nuclear staining for p63. Two of 23 AFXs (9%) demonstrated very focal or weak staining for only one cytokeratin; in both cases, p63 and CD10 were negative. One AFX was negative with all immunostains. CD10 was positive in 6/10 SCSCCs (60%), with half demonstrating strong and/or diffuse staining. P63 was positive in 9/10 SCSCCs (90%), with most demonstrating strong and diffuse staining. One SCSCC was negative for p63, but positive with two cytokeratin immunostains. In conclusion, the expression of any of the cytokeratins evaluated herein significantly distinguished AFX from SCSCC. CD10 used in isolation, however, was not useful in making this distinction (positive in 18/23 AFXs versus 6/10 SCSCCs, p=0.4). The addition of CD10 to a panel that includes p63 did not provide any additional information to that obtained from the latter alone. Overall, the most effective combination to distinguish AFX from SCSCC was p63 and cytokeratin AE-1/3. Positivity for both p63 and cytokeratin AE-1/3 was seen in 9/10 SCSCCs (90%) and was not observed in any of the 23 AFXs (p<0.0001). The usefulness of CD10 in this differential diagnosis is limited.     

Synchronous and metachronous tumors in patients with hematological neoplasms

The study has indicated the relatively frequent occurrence of secondary tumors in hematological patients. These tumors may be both synchronous and metachronous. They generally occur in different periods after chemo- and/or radiotherapy. A secondary hematological tumor that is unilinear or heterolinear more commonly develops. The authors have not found a correlation between the intensity of the therapy and the occurrence of a secondary tumor and the impact of elderly age on the shorter occurrence of a secondary pathological process.     

Ubiquitous p63 expression in human esophageal squamous cell carcinoma

p63, a recently identified member of the p53 gene family, plays an important role in human tissue functions. We examined the pattern of p63 expression in human esophageal squamous cell carcinomas including early-stage cancers, and its clinicopathological significance. Immunoreactivity for p63 was detected in 96.9% (63/65) esophageal squamous cell carcinomas. Diffuse p63 expression was seen in 75.4% (49/65). p63 was detected not only in the in situ carcinomatous components or intramucosal carcinomas, but also in the invasive carcinomatous parts of the p63-positive cases. There were no significant correlations between p63 expression and clinicopathological features, such as depth of tumor invasion, tumor differentiation, lymph node metastasis and venous/lymphatic invasion. We also analyzed the relationship between p63 and p53 expression in esophageal squamous cell carcinomas. These results suggest that the p63 gene, as well as the p53 gene, play a major role in the carcinogenesis of human esophageal squamous cells and in the growth of the carcinoma.