Early cancer and related lesions in the bronchial epithelium in former workers of mustard gas factory

The bronchial epithelium in stepwise transverse sections was examined histologically in 66 male autopsy cases, composed of the groups of 19 mustard gas (MG) ex-workers with lung cancer, 17 MG ex-workers with non-lung cancer, 10 non-MG lung cancer cases, and 20 non-MG non-lung cancer cases. Foci of moderate or severe atypical cellular lesion or dysplasia, or of carcinoma in situ (CIS) in total slides of each group, were counted as 146 in 3,485, 72 in 2,226, 70 in 3,797, and 18 in 4,611, respectively. The relative frequency of moderate or severe dysplasia and CIS in MG exposed non-lung cancer cases resembled that found in lung cancer cases of both MG and non-MG exposed. Seven CIS lesions were detected from among all MG-exposed cases and one CIS was found in a non-MG lung cancer case. Six out of eight CIS examples were adjoined by dysplasia. A multi-variate analysis revealed a significant correlation between the incidence of atypical lesions and MG exposure, though the incidence of atypical lesions was also influenced significantly by age, smoking, and chronic bronchitis. The incidence of atypical lesions was significantly higher in cases of squamous cell lung cancer than those of other histological types, particularly small cell cancer.     

Hyaluronidases and hyaluronan synthases expression is inversely correlated with malignancy in lung/bronchial pre-neoplastic and neoplastic lesions, affecting prognosis

We collected a series of 136 lung/bronchial and 56 matched lung parenchyma tissue samples from patients who underwent lung/bronchial biopsies and presented invasive carcinoma after lung surgery. The lung/bronchial samples included basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma. Matched lung parenchyma tissue samples included 25 squamous cell carcinomas and 31 adenocarcinomas. Immunohistochemistry was performed to analyze for the distribution of hyaluronidase (Hyal)-1 and −3, and hyaluronan synthases (HAS)-1, −2, and −3. Hyal-1 showed significantly higher expression in basal cell hyperplasia than in moderate dysplasia (P=0.01), atypical adenomatous hyperplasia (P=0.0001), or severe dysplasia (P=0.03). Lower expression of Hyal-3 was found in atypical adenomatous hyperplasia than in basal cell hyperplasia (P=0.01) or moderate dysplasia (P=0.02). HAS-2 was significantly higher in severe dysplasia (P=0.002) and in squamous metaplasia (P=0.04) compared with basal cell hyperplasia. HAS-3 was significantly expressed in basal cell hyperplasia compared with atypical adenomatous hyperplasia (P=0.05) and severe dysplasia (P=0.02). Lower expression of HAS-3 was found in severe dysplasia compared with squamous metaplasia (P=0.01) and moderate dysplasia (P=0.01). Epithelial Hyal-1 and −3 and HAS-1, −2, and −3 expressions were significantly higher in pre-neoplastic lesions than in neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic tumor type showed that patients with high HAS-3 expression in pre-neoplastic cells obtained by lung/bronchial biopsy presented a significantly higher risk of death (HR=1.19; P=0.04). We concluded that localization of Hyal and HAS in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, which implied that visualizing these factors could be a useful diagnostic procedure for suspected lung cancer. Finalizing this conclusion will require a wider study in a randomized and prospective trial.     

Proliferative activity in dysplasia, carcinoma in situ and microinvasive carcinoma of the uterine cervix

Proliferative activity of various human uterine cervical lesions obtained by conization was examined by measuring the proportion of mitotic cells including abnormal mitosis and the nuclear DNA content by a microspectrophotometer. Twelve ratios of mitotic cells calculated in the present study showed a step-wise increase from normal squamous cell epithelium through various grades of dysplasia to carcinoma in situ (CIS). The great difference between moderate and severe dysplasia was observed. All ratios in CIS with bulky outgrowth (CIS(b)) were the highest. The nuclear DNA content in various lesions also indicated the great difference between moderate and severe dysplasias in the DNA histograms. Severe dysplasia had a wider distributed DNA histogram without distinct modes similar to those in CIS and the non-invasive areas of the microinvasive carcinoma. These results may suggest that severe dysplasia but not slight or moderate dysplasia is a direct precursor lesion for uterine cervical epidermoid carcinoma.     

Prognostic significance of atypical papillary urothelial hyperplasia

Typical papillary hyperplasia, a recently recognized precursor lesion to low-grade papillary urothelial neoplasms, consists of undulating folds of cytologically benign urothelium. Well-developed, branching fibrovascular cores of a papillary neoplasm are not evident. We have noted lesions with the architectural pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia. We identified 15 cases of atypical papillary hyperplasia (13 males, 2 females, age 55 to 92) with overlying urothelium showing cytologic atypia. Of these cases, 8 (53%) were received in consultation. Of the 15 cases, 8 exhibited overlying flat carcinoma in situ (CIS), 4 had overlying dysplasia, and 3 were transitional between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia. Of these cases, 5 patients had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Concurrent to the diagnosis of atypical papillary hyperplasia, there were 25 different urothelial lesions: CIS (n = 11), papilloma (n = 1), papillary neoplasm of low malignant potential with CIS (n = 1), high-grade papillary urothelial carcinoma (n = 10; 3 with CIS), small-cell carcinoma (n = 1), and infiltrating urothelial carcinoma (n = 1). Of 11 patients with known prior history, 2 had 12 prior urothelial neoplasms (9 low-grade papillary neoplasms, 2 papillary urothelial neoplasms of low malignant potential, and 1 high-grade papillary cancer). Of 10 patients with atypical papillary hyperplasia and a minimum of 1 year of follow-up, 9 had 19 recurrences: CIS (n = 4), papilloma (n = 1), papillary neoplasm of low malignant potential (n = 1), infiltrating urothelial carcinoma (n = 3; 1 with CIS), and high-grade papillary urothelial carcinoma (n = 10; 5 with invasion and 2 with CIS). Whether the papillary hyperplasia had overlying CIS or dysplasia did not affect the correlation with urothelial neoplasms. Immunohistochemical analysis of p53 and Ki-67 expression in 8 cases demonstrated overexpression of p53 (n = 2; 1 with overlying dysplasia and 1 with overlying CIS), and Ki-67 (n = 5; 2 with overlying dysplasia and 3 with overlying CIS). Taken together, these results suggest that atypical papillary hyperplasia is most frequently associated with CIS and high-grade papillary cancer. In some cases, CIS or dysplasia may evolve into atypical papillary hyperplasia, with further progression to high-grade papillary cancer. This process may be analogous to papillary hyperplasia without cytologic atypia progressing to low-grade papillary urothelial neoplasms.     

Pulmonary preinvasive neoplasia

Advances in molecular biology have increased our knowledge of the biology of preneoplastic lesions in the human lung. The recently published WHO lung tumour classification defines three separate lesions that are regarded as preinvasive neoplasia. These are (1) squamous dysplasia and carcinoma in situ (SD/CIS), (2) atypical adenomatous hyperplasia (AAH), and (3) diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIP-NECH). SD/CIS is graded in four stages (mild, moderate, severe, and CIS), based upon the distribution of atypical cells and mitotic figures. Most airways showing SD/CIS demonstrate a range of grades; many epithelia are hard to assess and the reproducibility of this complex system remains to be established. Detailed criteria are, however, welcome and provide an objective framework on which to compare various molecular changes. Alterations in gene expression and chromosome structure known to be associated with malignant transformation can be demonstrated in CIS, less so in dysplasias, but also in morphologically normal epithelium. The changes might be sequential, and their frequency and number increase with atypia. Less is known of the "risk of progression" of SD/CIS to invasive "central" bronchial carcinoma. It may take between one and 10 years for invasion to occur, yet the lesion(s) may be reversible if carcinogen exposure ceases. AAH may be an important precursor lesion for peripheral "parenchymal" adenocarcinoma of the lung: the "adenoma" in an adenoma-carcinoma sequence. There is good morphological evidence that AAH may progress from low to high grade to bronchioloalveolar carcinoma (BAC; a non-invasive lesion by definition). Invasion then develops within BAC and peripheral lung adenocarcinoma evolves. The molecular events associated with this progression are not well understood and studies are hampered by a lack of clear criteria to distinguish high grade AAH from BAC. Nonetheless, as with SD/CIS, the patterns of expression of tumour associated genes are consistent with neoplastic progression. We have little idea of the incidence of AAH in the normal or "smoking" populations. It is found more frequently in cancer bearing lungs, especially in those with adenocarcinoma, and is more common in women. No data are available on the risk of progression of AAH. DIPNECH is an exceptionally rare lesion associated with the development of multiple carcinoid tumours. Almost nothing is known of its biology. Knowledge of these lesions will be crucial in the design and understanding of lung cancer screening programmes, where it is likely that the morphological and, more importantly perhaps, the molecular characteristics of these lesions will provide useful targets for detection and possibly even treatment.     

Consistency of histopathological reporting of laryngeal dysplasia. The Scottish Pathology Consistency Group

AIMS: Clinical management of premalignant and malignant lesions of the larynx is dependent on histopathological evaluation. The Scottish Pathology Consistency Group assessed interobserver variation in the evaluation of laryngeal dysplasia. METHODS AND RESULTS: One hundred laryngeal biopsies ranging from normal to invasive carcinoma were assessed. The overall Kappa result of 0.32 was disappointing. However, agreement on those categories which dictate significantly different management was more favourable. The Kappa figure for mild dysplasia versus severe dysplasia/CIS was 0.7, the Kappa figure for mild dysplasia versus severe dysplasia/CIS and invasive carcinoma was 0.77. The Kappa figure for mild and moderate dysplasia versus severe dysplasia/ CIS and invasive carcinoma was 0.57. An attempt to use a two grade system gave a Kappa figure of 0.52. CONCLUSIONS: Our group had a satisfactory agreement on the distinction of mild from severe dysplasia and on microinvasive carcinoma without any discussion as to histopathological criteria to be used. Clinical management--review endoscopy, repeat cord stripping, radiotherapy and laryngectomy--is in general dependent on histological assessment. Thus the agreement on categories which underpin clinical management is reassuring. However, assessment of moderate dysplasia remains problematic. An attempt to utilize a two grade system--low grade from high grade dysplasia/CIS--may have merit. The implications of the terminology used must be agreed among pathologists and clinicians working closely within clinicopathological cancer groups.     

Glutathione S-transferase π-class as a tumour marker in lingual preneoplastic and neoplastic lesions of rats and humans

Immunocytochemical expression of the π class glutathione S-transferase (GST) was investigated in preneoplastic and neoplastic lingual lesions in a 4-nitroquinoline 1-oxide (4NQO)-induced rat genetic model [Wistar/Furth rats (WF) and Dark-Agouti rats (DA)] and in human surgical material [fibrous polyp, mild to moderate dysplasia, severe dysplasia, carcinoma in situ (CIS), squamous cell carcinoma (SCC)]. Two polyclonal antibodies raised against rat (GST-P) and human (GST-π) antigens were used. In the rat model, DA and WF rats showed contrasting susceptibility to 4NQO, DA rats having a much higher tumour incidence and a significantly shorter survival time than WF rats. While the established lingual SCC in DA and WF rats all expressed GST-P, the number of GST-P⁺ foci in the preneoplastic lingual epithelium was significantly higher in DA (14.5 ± 6.5) than in WF rats (5.5 ± 2.6; P < 0.0001). In contrast, GST-π epithelial staining in human specimens was more variable and the results overlapped in different groups. More frequent nuclear and/or basal cell staining was detected in severe dysplasia, CIS and SCC than in benign and mild to moderate dysplastic lesions. Although the π class GST may be a useful marker for rat lingual carcinogenesis, its value in clinical applications is unclear. GST-π staining patterns and their distribution may be helpful in identifying high-risk lingual lesions in humans.     

AN ALTERED LECTIN BINDING TO MUCUS GLYCOPROTEIN IN GOBLET CELLS OF HUMAN TRACHEOBRONCHIAL EPITHELIUM AMONG FORMER MUSTARD-GAS WORKERS

Lectins, which are well known to have an ability to bind with specific carbohydrate residues of glycoprotein, have been used to examine cellular changes associated with malignant transformation. For the analysis of mucus glycoprotein of goblet cells in the tracheobronchial epithelium, 192 paraffin-embedded sections from 54 autopsy cases including the cases with a history of mustard-gas (MG) exposure were stained with seven plant lectins using PAP method. PNA binding with no neuraminidase treatment as well as BSA-1 binding was observed most frequently in MG-exposed lung cancer cases. The proportion of cases positive for SBA binding in MG-exposed and/or lung cancer cases had a statistical difference from non-MG-exposed non-lung cancer cases. These observations may indicate a large heterogeneity in oligosaccharide chains of mucus glycoprotein and suggest its incomplete or abnormal synthesis, which is most likely to be due to previous exposure to carcinogen, such as MG. ACTA PATHOL. JPN. 37:537–548, 1987.     

Nonneoplastic and nonhyperplastic thymus in myasthenia gravis. An immunohistochemical study with double immunoenzymatic labeling of basement membrane and cellular components

Histologically normal thymus (type A) in patients with myasthenia gravis (MG) was immunohistochemically compared with hyperplastic MG thymus (type B) and normal non-MG thymus. In formalin-fixed, paraffin-embedded sections of ten type A, ten type B, and eight non-MG cases, the thymic epithelium and other cellular components were stained in conjunction with the basement membrane by a double immunoenzymatic method. This technique demonstrated a moderate architectural disturbance in type A thymus, with distended perivascular space (PVS), elongated medullary epithelium, and disrupted basement membrane. These changes were more prominent in type B thymus but were minimal to lacking in non-MG thymus. Compared with those in non-MG thymus, the myoid cells in MG thymuses of both types tended to cluster around the Hassall's corpuscles, with a slight decrease in number in type B but not in type A. B-lymphocytes were present in type B, type A, and non-MG thymuses in that order of abundance; the cells were confined to the medullary parenchyma in the non-MG group but were numerous both in the PVS and medulla in the MG groups. T-lymphocytes were increased in the expanded PVS of type A and B MG thymuses. The number of interdigitating reticulum cells was similar in the three groups, but the cellular distribution was more dispersed in MG thymuses of both types. These findings, although previously described in type B thymus, have not been well recognized in type A thymus. They support the view that a common abnormality (presumably chronic thymitis), differing in degree only, underlies MG thymuses regardless of the presence of follicular hyperplasia.     

An altered lectin binding to mucus glycoprotein in goblet cells of human tracheobronchial epithelium among former mustard-gas workers

Lectins, which are well known to have an ability to bind with specific carbohydrate residues of glycoprotein, have been used to examine cellular changes associated with malignant transformation. For the analysis of mucus glycoprotein of goblet cells in the tracheobronchial epithelium, 192 paraffin-embedded sections from 54 autopsy cases including the cases with a history of mustard-gas (MG) exposure were stained with seven plant lectins using PAP method. PNA binding with no neuraminidase treatment as well as BSA-1 binding was observed most frequently in MG-exposed lung cancer cases. The proportion of cases positive for SBA binding in MG-exposed and/or lung cancer cases had a statistical difference from non-MG-exposed non-lung cancer cases. These observations may indicate a large heterogeneity in oligosaccharide chains of mucus glycoprotein and suggest its incomplete or abnormal synthesis, which is most likely to be due to previous exposure to carcinogen, such as MG.     

Atypical mitoses in elevated dysplasias of the stomach

The number and topographic localization of spontaneously occurring mitotic figures were studied in 22 elevated dysplasias of the stomach. The lesions were divided into 3 equally thick zones. Mitoses occurred in 5 of 7 slight dysplasias, in 7 of 8 moderate dysplasias, and in all 7 severe dysplasias. When present, mitoses were localized to the superficial zone in slight, moderate and severe dysplasias, in the middle zone in some moderate dysplasias, and in almost all severe dysplasias. In the deeper zone, mitoses were seen in one of the moderate dysplasias and in as much as 5 of the severe dysplasias. The number of mitoses were significantly higher in moderate and severe dysplasia, when compared to slight dysplasia. The percentage of atypical mitoses increased gradually from 27% in slight dysplasia to 41% in moderate, and 52% in severe dysplasias. In the adjacent, non-dysplastic gastric mucosa, a 1.5% of atypical mitoses was found. Significantly higher amounts of atypical mitoses were recorded in severe dysplasias, as compared to slight and moderate dysplasias. The results suggest that the various types of elevated dysplasias (slight, moderate and severe) of the stomach may be distinguished, not only by the characteristics of the atypical cells in interphase--as is the case today--but also by the topographic distribution of mitoses and by the difference in percentage of atypical mitoses occurring in these lesions. The possible significance of the mitosis as a biohistological marker of the behaviour of elevated dysplasias of the stomach is discussed.     

Risk of gastric carcinoma in patients with mucosal dysplasia associated with atrophic gastritis: a follow up study.

AIMS: To assess the risk of gastric carcinoma in patients with histologically verified dysplasia and atrophic gastritis of the stomach. METHODS: One hundred and one patients with mild (n = 84), moderate (n = 14), or severe (n = 3) dysplasia among 359 elderly men who smoked underwent gastroscopy because of low serum pepsinogen. Patients with dysplasia were prospectively followed up for an average of four years with repeated gastroscopies and multiple biopsies. RESULTS: Four of the 84 (4.8%) cases of mild dysplasia had progressed to moderate dysplasia during the follow up. Most of the cases of mild dysplasia had resolved spontaneously. No surgical intervention was required. Three of the 14 (21%) cases of moderate dysplasia had progressed to severe dysplasia, but no carcinomas were observed during follow up. Five moderately dysplastic lesions were removed surgically or endoscopically. In two of these five cases, moderate or severe dysplasia recurred. Two of the three severe dysplasias progressed to carcinoma. CONCLUSIONS: In atrophic gastritis progression of mild and moderate dysplastic lesions seems to be a slow process and is rare in mild dysplasia. However, severe dysplasia is highly predictive of subsequent cancer. It is suggested that a five year follow up interval is sufficient in cases with mild dysplasia and two years in those with moderate dysplasia. Local removal of moderate dysplasia is indicated but does not guarantee that the lesion will not progress. Severe dysplasia requires immediate surgical intervention.     

Histological types and significance of bronchial epithelial dysplasia.

Pulmonary epithelium is known to undergo a preneoplastic process prior to the development of lung carcinoma. Squamous dysplasia and atypical adenomatous hyperplasia have been identified and classified as preinvasive lesions of squamous cell carcinoma and peripheral pulmonary adenocarcinoma, respectively. However, these commonly recognized preinvasive lesions do not completely explain the development of all histological types of lung carcinoma. By examining 114 resection lung specimens, we concluded that there are four histological patterns of bronchial epithelial dysplasia based on morphological features (basal cell dysplasia, columnar cell dysplasia, bronchial epithelial dysplasia with transitional differentiation, and squamous dysplasia). The histological patterns were further characterized by immunohistochemistry. Basal cell dysplasia was focally positive for cytokeratin (CK) 17 and 10/13; columnar cell dysplasia was generally positive for CK7, 8, and 18; bronchial epithelial dysplasia with transitional differentiation had a heterogeneous immunoprofile, while squamous dysplasia was positive for CK10/13 and focally positive for CK17. Various degrees of abnormal expression of p53 and Ki-67 were found in the different types of bronchial epithelial dysplasia. The cases were divided into three groups based on degree and extent of bronchial epithelial dysplasia. By Crosstabs McNemar test, the Mann-Whitney U-test (for two independent groups), the Kruskal-Wallis one-way nonparametric ANOVA (for >2 independent groups) and Spearman correlation analysis, the degree and extent of bronchial epithelial dysplasia was shown to be positively correlated with the incidence of bronchogenic carcinoma and multifocal primary lung carcinoma (P<0.05). These findings indicated the following: (1) bronchial epithelium can develop various patterns of dysplasia with abnormal/ambiguous cell differentiation and abnormal expressions of p53 and Ki-67. Thus, these bronchial epithelial dysplastic lesions may represent a preneoplastic process. (2) The degree of bronchial epithelial dysplasia may significantly predispose individuals to bronchogenic carcinoma and multifocal primary lung carcinoma.     

Focal adhesion kinase as a marker of malignant phenotype in breast and cervical carcinomas

Integrins mediate cell adhesion to extracellular matrix and stimulate signals involved in cell proliferation, survival, and migration. Focal adhesion kinase (FAK) is considered the central molecule in integrin-mediated signaling. Previously, FAK has been implicated in invasive tumor behavior based on Northern or Western blot (immunoblot) using total tumor tissue homogenates. We used immunohistochemistry to demonstrate FAK expression in benign cervical epithelium, dysplasia, carcinoma in situ (CIS), and invasive cervical squamous cell carcinomas (SCCs), as well as in benign breast tissue, atypical ductal hyperplasia, and ductal carcinoma in situ (DCIS) and invasive carcinomas of the breast. We also used polymerase chain reaction to analyze whether infection with the high-risk human papillomavirus (HPV) subtypes correlated with FAK overexpression in CIS of the cervix. We found minimal FAK expression in benign cervical and breast epithelium and in low-grade squamous dysplasia (CIN I and CIN I-II) of the cervix, and variable FAK expression in CIS lesions of the cervix (10 of 14 cases). Most of the invasive SCCs of the cervix (13 of 16 cases) and DCIS of the breast (6 of 8 cases) were positive for FAK. Surprisingly, all DCIS of the breast were also strongly positive (7 of 7). Only 3 of 13 cases of atypical ductal hyperplasia were focally positive for FAK. Regardless of the intensity of FAK staining, all CIS of the cervix were positive for either HPV 16 or 18. We conclude that FAK overexpression is not restricted to invasive phenotype, but rather appears to be a marker for malignant transformation.     

Preneoplastic lesions of pulmonary carcinoma

The World Health Organization (WHO) 2004 classification includes 3 categories of pulmonary preneoplastic lesions, including squamous dysplasia and carcinoma in situ (CIS) for squamous cell carcinoma, atypical adenomatous hyperplasia (AAH) for the majority of adenocarcinomas and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) for carcinoids. The distinction of the 3 grades of squamous dysplasia and CIS is mainly based on the degree by which the basal cell zone is expanded, the degree of cellular atypia and the level of mitoses. The category AAH consists of a proliferation of atypical epithelial cells with Clara cells or type 2 pneumocyte features. They grow along the alveolar septae in a lepidic fashion, sometimes reaching into the terminal bronchioles. In contrast to the newly described adenocarcinoma in situ (AIS), AAH is smaller (≤ 5 mm), has a lower cell density and a lower degree of cellular atypia. The putative cancer stem cells of peripheral adenocarcinomas reside in the bronchioloalveolar duct junction, while those of central squamous cell carcinomas are located in the basal cell compartment of the bronchi. This review provides an overview of the current knowledge on preneoplastic lesions of the lungs and their clinical impact.     

EXTRACTION OF FERRUGINOUS BODIES FROM LUNG TISSUE OBTAINED AT SURGERY and AUTOPSY

Ferruginous bodies were extracted quantitatively from 508 patients; operated 242 with lung cancer and 94 with non-lung cancer, and autopsy 51 from hepatomas, 42 from stomach cancers, and 79 from non-cancer diseases. The bodies were divided morphologically into 4 types; 2 types may be from asbestos and the other 2 types from carbon and silicate which were very rarely found. The incidence of the bodies was the highest in hepatoma 96.8, followed by lung cancer 90.8%, non-lung cancer 80%, stomach cancer 76.2%, and non-cancer 74.2% in the years 1975–1981. Distribution of count of asbestos bodies was characteristic in patients with lung cancer, i.e. the cases who had asbestos bodies above 100/5 g of wet lung were found in 36 of 242 patients with lung cancer (14.8%) who were all smokers and 15 of 266 patients with the other diseases (5.6%) with significant difference between the two groups. Moreover, out of 14 patients who had the bodies above 300/5 g of wet lung, 9 were patients with lung cancer and also smoked heavily, and remaining 5 patients with diseases other than lung cancer consisted of 2 heavy smokers, a moderate and a mild smoker, and a non-smoker. These evidences may suggest the existence of some relation between occurrence of lung cancer and low degree of asbestos exposure with addition of smoking.     

Expression of MUC1 and MUC2 mucins and relationship with cell proliferative activity in human colorectal neoplasia

Our previous studies on MUC1 and MUC2 mucin expression in various human neoplasms have found that MUC1 expression is related with a poor outcome whereas MUC2 expression is related with a favorable outcome. In the present study, we examined the alteration of MUC1 and MUC2 antigens on malignant transformation of colorectal mucosa, and also its relationship with cell proliferative activity (Ki-67 labeling index) of neoplastic epithelial cells in 200 adenomas and 58 carcinomas. In the 200 adenomas, we analyzed a total of 400 adenomatous lesions (mild dysplasia, 200 lesions; moderate dysplasia, 153 lesions; severe dysplasia, 47 lesions). MUC1 was expressed in carcinomas (24%) and adenomas with severe dysplasia (4%), but was not expressed in adenomas with mild or moderate dysplasia. MUC2 was expressed in a significantly greater number of adenomas with mild dysplasia (72%) than in adenomas with moderate dysplasia (45%) or severe dysplasia (47%), as well as in the carcinomas (38%; P < 0.0001). The Ki-67 labeling index was significantly lower in the MUC2-positive cases than in the MUC2-negative cases in the adenomas with mild dysplasia (13.6 vs 24.2%; P < 0.0001) or moderate dysplasia (25.7 vs 44.4%; P < 0.0001), and in the carcinomas (32.5 vs 48.4%; P < 0.05). In conclusion, the data from our study indicate that increased MUC1 expression and reduced MUC2 expression may be related to malignant transformation of colorectal neoplasia. We also demonstrated that decreased MUC2 expression, which is correlated with increased Ki-67 labeling, may play an important role in the progression of colorectal adenomatous change.     

Molecular analysis of oral lichen planus. A premalignant lesion?

Oral lichen planus (OLP) is a common mucosal condition that is considered premalignant by some, although others argue that only lichenoid lesions with dysplasia are precancerous. To address the question of whether OLP without dysplasia is premalignant, we used microsatellite analysis to examine 33 cases of OLP for allelic loss at nine loci located on chromosomes 3p, 9p, and 17p. Loss of heterozygosity (LOH) on these three arms occurs frequently in oral tumors, and the presence of these alterations in premalignant lesions suggests that they may play an important role in tumor progression. Results were compared with those observed in oral dysplasias (10 mild, 11 moderate, 16 severe/carcinoma in situ), 22 oral squamous cell carcinomas, and 29 reactive lesions. LOH was present in 6% of OLP, 14% of reactive lesions, 40% of mild dysplasia, 46% of moderate dysplasia, 81% of severe dysplasia/carcinoma in situ, and 91% of squamous cell carcinomas. LOH was detected on only a single arm in OLP and reactive lesions but occurred on more than one chromosome in dysplasia and cancer, and the frequency of this multiple loss correlated significantly with increasing degrees of dysplasia and progression into squamous cell carcinoma (P = 0.0028). Although these findings do not support OLP as a lesion at risk for malignant transformation, such results need to be confirmed by use of other genetic markers as OLP may undergo malignant transformation through genetic pathways different from those of oral dysplasia.     

Gastric epithelial dysplasia: a prospective multicenter follow-up study from the Interdisciplinary Group on Gastric Epithelial Dysplasia.

To assess the evolution of gastric epithelial dysplasia (GED), a prospective multicenter study was based on a protocol of repeated endoscopies and biopsies. To date, 134 cases (0.4% of all patients endoscopically examined in the same period) have been diagnosed as having GED and 80 of those have had an "adequate" follow-up (at least three endoscopies). Mean follow-up time was 18 months. Gastric epithelial dysplasia was mild in 59% of cases, moderate in 25%, and severe in 10%. Six percent of the patients had lesions that were "indefinite for dysplasia." Chronic atrophic gastritis (40%), gastric ulcer (32%), gastrectomy (10%), and polyps (9%) were the most frequently associated lesions. The term "regression" was adopted for GED no longer detectable during follow-up and the term "progression" was used when more severe changes or cancer was detected. Mild GED regressed in 66% of cases, persisted in 15%, and progressed in 19% (three cases to moderate, one to severe, and five to cancer). Moderate GED regressed in 30% of patients, persisted in 30%, and progressed in 40% (one to severe GED and seven to cancer). Severe GED regressed in 12.5% of patients, persisted in 12.5%, and progressed to cancer in 75%. Of the five patients with lesions indefinite for dysplasia, two had no dysplastic changes at follow-up and three had cancer diagnosed. Ten of 21 cases of cancer (48%) were at the early stage. The diagnosis was reached within the first year of follow-up in 14 cases and after 1 year in seven (13 to 39 months). Fifteen of 21 cases of cancer were diagnosed in gastric ulcer patients. In conclusion, GED is an infrequent finding and its biologically neoplastic significance is confirmed by the results of the follow-up study: (1) in its mild form, it tends to regress but adequate subsequent check-ups are mandatory as it may associate with or evolve as cancer; (2) patients with moderate GED require strict follow-up since the lesion shows a higher cancer risk; (3) surgery is indicated for severe GED because gastric cancer develops in 75% of cases; and (4) patients with lesions indefinite for dysplasia should immediately undergo repeat endoscopy and biopsy. Such an approach allows gastric cancer to be detected at an early stage in a much higher percentage of cases than may be expected.     

Potential value of hormone receptor assay in carcinoma in situ of breast

The estrogen receptor (ER) expression of invasive breast cancer has been extensively studied both biochemically and with specific monoclonal antibodies against ER. Relatively few studies have attempted to characterize ER pattern in breast carcinoma in situ (CIS) and in other premalignant lesions. In the current study, the authors investigated the pattern of ER expression in 62 cases of breast CIS, 30 of which had a component of invasive cancer, and 36 cases of atypical hyperplasia. Paraffin sections of formalin-fixed breast tissue underwent enzyme pretreatment to expose nuclear antigenic sites as previously described. Breast tissues then underwent estrogen immunocytochemical assay using specific monoclonal antibodies (Abbott Laboratory, Chicago, IL). The cases were evaluated for heterogeneity, intensity of staining, and percentage of ER-positive cells. An attempt was made to study the relation between the pattern of ER expression, nuclear pleomorphism, and type of CIS. The results of ER immunocytochemical assay showed positive nuclear staining for ER in 75% of the CIS, 73% of CIS with invasive cancer, and 100% of atypical hyperplasias. ER expression in CIS agreed with that in the invasive carcinoma in 29 of 30 cases. This study also suggests that comedocarcinoma has a higher incidence of negative ER expression than the other types of CIS, particularly when it is associated with significant nuclear pleomorphism. There was no significant difference in ER tumor heterogeneity between premalignant and malignant lesions.