Multiparameter flow cytometric analysis of neoplasms of the central nervous system: correlation of nuclear antigen p105 and DNA content with clinical behavior

Analysis of the DNA content of various solid tumors and hematological malignancies may provide useful prognostic information. To date, however, there has been a striking lack of correlation between DNA content in neoplasms of the central nervous system and clinical behavior. Simultaneous quantitation of DNA content and proliferation-associated nuclear antigen (p105) by flow cytometry was performed on paraffin-embedded tissues representing three major groups of central nervous system neoplasms--1) 21 astrocytic tumors, 2) 13 pituitary tumors, and 3) 19 meningiomas--and the results were correlated with clinical behavior. All 4 well-differentiated gliomas were diploid, while 3 of 9 anaplastic astrocytomas and 1 of 8 glioblastomas had a demonstrable aneuploid peak. Three of 13 pituitary tumors had an identifiable aneuploid peak, while only 2 of 19 meningiomas had an aneuploid DNA content. Cell-cycle analysis of the malignant gliomas revealed a significantly higher proliferative index (PI, %S + G2M) compared with the well-differentiated astrocytomas (P less than 0.05). Within the subgroup of diploid anaplastic astrocytomas, however, extended patient survival appeared to be associated with a higher PI. For diploid pituitary adenomas, the PI was consistently lower in the 3 tumors that recurred than it was in the remaining 8 adenomas. Nuclear antigen quantitation of diploid tumors showed a wide range of p105 expression in G0G1 cells, suggesting that, within each tumor, the cells are heterogeneous with respect to proliferative activity. Aneuploid nuclei of glial tumors showed enhanced expression of p105 relative to diploid cells of the same specimen. In pituitary tumors, the median G2M/G0G1 fluorescence ratio for p105 was significantly higher (P less than 0.05) for the 3 diploid recurrent tumors than for those that did not recur. These data support the assumption that the aggressive clinical course of malignant glial neoplasms may be related to an abnormal DNA stemline and/or an alteration in cell proliferative activity. Cell cycle analysis and measurement of p105 by this technique may provide information useful from both a prognostic standpoint and in directing adjuvant therapy.     

Is intestinal metaplasia a necessary precursor lesion for adenocarcinomas of the distal esophagus,gastroesophageal junction and gastric cardia?

Adenocarcinoma of the distal esophagus and gastroesophageal junction are believed to arise in Barrett's esophagus with intestinal metaplasia. Whether adenocarcinoma can arise in columnar lined esophagus without intestinal metaplasia is in doubt. Whether adenocarcinoma of the gastric cardia arises in intestinal metaplasia of the gastric cardia is also in doubt. We aim to evaluate the relationship of size and stage of adenocarcinoma of the distal esophagus, gastroesophageal junction and gastric cardia to intestinal metaplasia and other types of columnar epithelium. Seventy-four patients who had esophagogastrectomy for adenocarcinomas in this region were examined histologically to assess the frequency of residual intestinal metaplasia in the surrounding epithelium. Tumors without residual intestinal metaplasia were evaluated for the presence of other columnar epithelia and correlated with tumor size and stage. Cardiac mucosa was present around all tumors. Residual intestinal metaplasia was present in 48 (65%) tumors, including 33/38 (87%) distal esophageal, 10/25 (45%) junctional and 5/11 (45%) gastric cardia tumors. The prevalence of intestinal metaplasia was 100% in all tumors that were less than 1 cm in maximum diameter and all intramucosal tumors. The prevalence of residual intestinal metaplasia decreased with increasing tumor size and stage. These data strongly support the contention that adenocarcinomas of this region, including those in the gastric cardia, arise in intestinal metaplastic epithelium. The absence of residual intestinal metaplasia in larger tumors is the result of tumor overgrowing the intestinal metaplasia from which it arose.     

Filarial infection of the breast.

The breast is a common site of filarial infection in females in Sri Lanka. We report our experience with 13 cases of filarial breast nodules, 12 containing adult worms and the other only microfilariae. In five of these cases the species was identified as Wuchereria bancrofti.     

High intraepithelial eosinophil counts in esophageal squamous epithelium are not specific for eosinophilic esophagitis in adults

OBJECTIVES: The histologic criterion of >20 eosinophils per high power field (hpf) is presently believed to establish the diagnosis of idiopathic eosinophilic esophagitis (IEE). This is based on data that the number of intraepithelial eosinophils in gastroesophageal reflux disease (GERD) is less than 20/hpf. This study tests this belief. METHODS: Pathology records were searched for patients who had an eosinophil count >20/hpf in an esophageal biopsy. This patient population was biased toward adults with GERD who had routine multilevel biopsies of the esophagus. The clinical, radiological, and manometric data and biopsies were studied. RESULTS: Forty patients out of a total of 3,648 reports examined had an eosinophil count >20/hpf in squamous epithelium of an esophageal biopsy. Analysis of these 40 cases indicated that 6 (15%) patients had IEE, 2 (5%) had coincident IEE and GERD, 28 (70%) had GERD, and 2 (5%) each had achalasia and diverticulum. There was no significant difference among these groups in terms of maximum eosinophil number, biopsy levels with >20 esoinophils/hpf, presence of eosinophilic microabscesses, involvement of surface layers by eosinophils, and severity of basal cell hyperplasia and dilated intercellular spaces. CONCLUSION: All histologic features presently ascribed to IEE can occur in other esophageal diseases, notably GERD. As such, the finding of intraepithelial eosinophilia in any number is not specific for IEE. When a patient with GERD has an esophageal biopsy with an eosinophil count >20/hpf, it does not mean that the patient has IEE.     

Multiple granular cell tumors of the gastrointestinal tract with subsequent development of esophageal squamous carcinoma

Summary A 52-year-old woman initially presented to our medical center with synchronous, submucosal tumors of the esophagus, stomach, and transverse colon. The gastric and colonic tumors were resected, and both displayed infiltrating sheets of polygonal cells with coarsely granular cytoplasm and small vesicular nuclei. The neoplastic cells of both tumors were immunoreactive for S-100 protein. Ultrastructural studies revealed the lysosomal nature of the cytoplasmic granules. Although the esophageal mass was not resected, it was felt that this represented another focus of granular cell tumor of the gastrointestinal tract. Two years later, she presented with disseminated squamous carcinoma of the esophagus. At autopsy, a submucosal granular cell tumor was found adjacent to the squamous carcinoma of the esophagus. To our knowledge, this is the first reported case of synchronous granular cell tumors that involved multiple segments of the gastrointestinal tract, one of which was later associated with a squamous carcinoma of the esophagus.     

Pathological Basis of Gastroesophageal Reflux Disease

Many of the present definitions of Barretts esophagus are based on the dogma that 2 to 3 cm of cardiac mucosa normally line the distal esophagus and proximal stomach. Recent autopsy data refute this dogma. Cardiac mucosa has been shown to be frequently absent from the squamocolumnar junctional zone. When present, its extent is less than 0.5 cm in almost all children and most adults. Cardiac mucosal length increases with age. Patients who have cardiac mucosa are significantly more likely to have abnormal acid exposure in the esophagus as measured by 24-hour pH studies. The length of the cardiac mucosa correlates significantly with the amount of reflux: the greater the length of the cardiac mucosa, the more reflux there is. These new data provide insights into the pathology of gastroesophageal reflux. Normalcy is defined as an esophagus lined by squamous epithelium and a stomach lined by gastric mucosa. Reflux disease is defined by the presence of cardiac mucosa in a junctional biopsy. The severity of reflux disease is quantifiable by the length of cardiac mucosa present. Mutational reflux disease (Barretts esophagus) is defined by the occurrence of intestinal metaplasia in cardiac mucosa and is quantitated by the amount of intestinal metaplasia present. Neoplastic reflux disease is defined as the occurrence of low grade dysplasia, high grade dysplasia, and adenocarcinoma in Barretts esophagus. An attempt is made here to develop a rational grading system for reflux based on these highly objective histologic criteria.     

Retinoic acid receptor-alpha messenger RNA expression is increased and retinoic acid receptor-gamma expression is decreased in Barrett's intestinal metaplasia, dysplasia, adenocarcinoma sequence

BACKGROUND: Expression levels of the retinoic acid receptors (RAR-alpha, RAR-beta, and RAR-gamma) are significantly different in neoplastic tissues compared with non-neoplastic tissues for some tumors. This study investigated whether retinoic acid receptor messenger RNA (mRNA) expression levels are altered in Barrett's esophagus and Barrett's adenocarcinoma tissues. METHODS: Relative mRNA expression levels of the RARs were quantified by using the ABI 7700 Sequence Detector (Taqman) system in Barrett's intestinal metaplasia (n = 15), dysplasia (n = 6), adenocarcinoma (n = 17), and matching normal esophagus tissues (n = 36). RESULTS: RAR-alpha expression was significantly increased, and RAR-gamma expression was significantly decreased, at higher stages in the Barrett's sequence. There was almost complete loss of RAR-gamma expression (relative expression level < or = 1) in a majority (70%) of the dysplasia and adenocarcinoma tissues. There were significant differences in RAR-alpha and RAR-gamma expression in histopathologically normal tissues in patients with cancer versus patients without cancer. RAR-beta expression levels were significantly elevated in adenocarcinoma versus normal esophagus tissues. The RAR expression profile was similar for cancers arising within the esophagus and for cancers arising at the gastroesophageal junction. CONCLUSIONS: RAR mRNA expression levels are significantly different in Barrett's tissues compared with normal esophagus tissues, and these levels are significantly different in Barrett's dysplasia and adenocarcinoma tissues compared with nondysplastic tissues. These results suggest that RAR mRNA levels may be useful biomarkers for this disease and that gastroesophageal junction adenocarcinomas are genetically similar to esophageal adenocarcinomas. These results also suggest that a cancer field is present in the esophagus in patients with cancer and that genetic alterations can precede histopathologic alterations in this disease.