Gregory F. Sterrett

Adenocarcinoma in situ of the endocervix.

The current study examines 1) the sensitivity of detection and 2) sampling and screening/diagnostic error in the cytologic diagnosis of adenocarcinoma in situ (AIS) of the cervix. The data were taken from public and private sector screening laboratories reporting 25,000 and 80,000 smears, respectively, each year.

Histological grading in breast cancer: interobserver agreement, and relation to other prognostic factors including ploidy

Summary Sections of neoplasms from 76 female patients with primary operable carcinoma of the breast were independently assessed by 2 pathologists for histological features and assigned a grade score. Relative disagreement rates between pathologists were estimated by use of a log‐linear model and found to be similar to those reported by many other groups, but higher than that reported by acknowledged experts. Tumor grade was related to nuclear DNA content as measured by static cytometry, inversely related to oestrogen receptor status and provided some additional prognostic information but, in this small series of patients, did not correlate with short‐term survival as closely as other prognostic indicators such as ploidy, tumor size or the extent of lymph node involvement. Patients with Grade III tumors had a particularly poor prognosis, however, there were few patients allotted to Grade III (poorly differentiated tumors), and survival differences between Grades I and II were small; in short‐term followup, used alone, grading separated out only a small proportion of patients into useful prognostic groups. This preliminary study emphasizes the need for a careful approach to the use of grading of breast carcinomas in the routine histopathology laboratory. Demonstration of higher levels of interobserver agreement, or concordance with experts in the field, will be necessary before our grading can be incorporated into a prognostic index useful for patient management.

A diagnosis of malignant pleural mesothelioma can be made by effusion cytology: results of a 20 year audit

Aims: Cytological diagnosis of malignant pleural mesothelioma (MPM) is controversial, but has been used in our institution for over 30 years. To assess the role of effusion cytology in mesothelioma diagnosis we conducted an audit of pleural fluid cytology results over a 20 year period (1988–2007). Methods: Pleural samples were received from 6285 patients; data linkage with Western Australian Cancer and Mesothelioma Registries demonstrated that 815 of these patients had a diagnosis of MPM. Cytological examination of a pleural effusion specimen had been performed in 517 (63%) of these 815 patients. Results: Definitive cytological diagnosis of MPM was made in 377/517 cases, resulting in an ‘absolute’ sensitivity of 73%. An additional 66 patients were diagnosed as atypical/suspicious, resulting in a ‘complete’ sensitivity of 86%. If only biopsy/necropsy proven cases are considered, the absolute sensitivity is 68% and the complete sensitivity is 82%. There were no false positive diagnoses of malignancy; two patients with metastatic adenocarcinoma were initially diagnosed as MPM, prior to the availability of specific mesothelial markers, resulting in a positive predictive value of 99%. Conclusions: Effusion cytology is an inexpensive, minimally invasive procedure which should be included in the diagnostic work-up of cases of suspected MPM.

Can CD34 discriminate between benign and malignant hepatocytic lesions in fine-needle aspirates and thin core biopsies?

Distinguishing well differentiated hepatocellular carcinoma (HCC) from benign hepatocellular lesions is a well recognized problem in fine‐needle aspiration (FNA) cytology. The endothelial cell marker CD34 is negative in normal hepatic sinusoids and stains vessels diffusely in HCC. This feature is useful in distinguishing benign from malignant hepatocytic lesions in histological specimens, although benign lesions may show focal positivity for CD34 confined to periportal and periseptal areas. In this study, we assess the role of CD34 in cell block and thin core biopsy material from benign and malignant hepatocellular lesions, and compare it with reticulin staining.

Detection of p53 gene mutation by rapid PCR-SSCP and its association with poor survival in breast cancer.

We examined the association between mutation of the p53 gene and survival in a large cohort of breast cancer patients. Using a rapid, non‐isotopic single‐strand conformation polymorphism (SSCP) method we screened for mutations in exons 4–10 of the p53 gene in 375 primary breast cancers from patients with a median follow‐up of 57 months. Mutations were found in 19% of tumours. Statistically significant associations were found between p53 mutation and histological grade, hormone receptor status, ploidy and S‐phase fraction. No association was found between p53 mutation and axillary lymph node involvement, histological type, tumour size, vascular invasion or patient age. In univariate survival analysis, p53 mutation was strongly associated with poor prognosis. This was maintained in the lymph node‐negative and hormone receptor‐positive patient subgroups. In multivariate analysis, p53 mutation was associated with poor survival independent of lymph node status, estrogen receptor status and S‐phase fraction. Our results demonstrate the feasibility of using a rapid and simple polymerase chain reaction‐SSCP screening procedure to detect p53 gene mutation in breast cancer for the provision of prognostic information. Int. J. Cancer 74:642–647, 1997.© 1997 Wiley‐Liss, Inc.

Mesothelial cell differentiation into osteoblast- and adipocyte-like cells.

Serosal pathologies including malignant mesothelioma (MM) can show features of osseous and/or cartilaginous differentiation although the mechanism for its formation is unknown. Mesothelial cells have the capacity to differentiate into cells with myofibroblast, smooth muscle and endothelial cell characteristics. Whether they can differentiate into other cell types is unclear. This study tests the hypothesis that mesothelial cells can differentiate into cell lineages of the embryonic mesoderm including osteoblasts and adipocytes. To examine this, a functional assay of bone formation and an adipogenic assay were performed in vitro with primary rat and human mesothelial cells maintained in osteogenic or adipogenic medium (AM) for 0–26 days. Mesothelial cells expressed increasing levels of alkaline phosphatase, an early marker of the osteoblast phenotype, and formed mineralized bone‐like nodules. Mesothelial cells also accumulated lipid indicative of a mature adipocyte phenotype when cultured in AM. All cells expressed several key osteoblast and adipocyte markers, including osteoblast‐specific runt‐related transcription factor 2, and demonstrated changes in mRNA expression consistent with epithelial‐to‐mesenchymal transition. In conclusion, these studies confirm that mesothelial cells have the capacity to differentiate into osteoblast‐ and adipocyte‐like cells, providing definitive evidence of their multipotential nature. These data strongly support mesothelial cell differentiation as the potential source of different tissue types in MM tumours and other serosal pathologies, and add support for the use of mesothelial cells in regenerative therapies.

Gastrointestinal stromal tumours (GISTs): a clinicopathological and molecular study of 66 cases

Aims: Predicting the clinical behaviour of gastrointestinal stromal tumours (GISTs) is difficult and criteria delineating benign from malignant cases are not firmly established. The aims of this study were to define the clinicopathological and molecular features of 66 GISTs, and to determine whether any specific parameters were associated with patient outcome. Methods: Archival cases of GIST from two major teaching hospitals in Western Australia were studied. Inclusion criteria for the study were: (1) appropriate morphology, (2) CD117 positivity, (3) adequacy of pathological material for study, and (4) exclusion of other tumour types on the basis of immunophenotypic and/or ultrastructural features. Expression of CD117, CD34, S100 protein, keratin (using broad spectrum MNF116), &agr;‐smooth muscle actin (SMA) was determined by immunohistochemistry. PCR and single strand conformation polymorphism (PCR‐SSCP) analysis were used to screen for mutations in exons 11 and 9 of c‐kit. Results: There were equal numbers of males and females with a mean age at diagnosis of 60 years, followed up for a mean of 54 months. Thirteen patients (21%) had died of GIST by the end of the study. Tumours were mostly located in the stomach (67%) and small intestine (SI; 25%). The cell types were pure spindle (68%), pure epithelioid (12%) and mixed epithelioid/spindle (20%). c‐kit mutations were found in 69% of GISTs, with the large majority (91%) occurring in exon 11. Size >10 cm, tumour necrosis and pure epithelioid cell morphology each were the only factors significantly associated with adverse survival (p=0.038, and p=0.047 and p=0.028, respectively). Mitotic activity >5/50 HPF showed a definite trend association with adverse survival, but unlike some other studies, did not achieve statistical significance (p=0.067). c‐kit mutations were more frequent in small intestinal GISTs (p=0.05) and in those with pure spindle cell morphology (p=0.023) but were not associated with patient outcome. Conclusion: In this study, size >10 cm, necrosis and/or pure epithelioid cell morphology correlated significantly with adverse survival. Mitotic activity showed a strong association with survival but this did not reach statistical significance. c‐kit mutations occurred mainly in GISTs of the SI, and in purely spindle cell tumours. While the mutation status did not associate with patient outcome in this series, this remains a controversial issue, and further studies are needed to assess whether the type of mutation affects response to tyrosine kinase inhibitor therapy in metastatic GISTs. CD117 staining of any mesenchymal lesion of the gastrointestinal tract should be mandatory for accurate classification. PCR‐SSCP analysis is a fast, sensitive and relatively inexpensive method of analysing c‐kit mutations, which may be important prognostically and also of therapeutic relevance in the assessment of new tyrosine kinase inhibitor therapies.

Adenocarcinoma in situ of the uterine cervix: screening and diagnostic errors in Papanicolaou smears.

Little attention has been given to the reasons for failure to detect adenocarcinoma in situ (AIS) of the uterine cervix in Papanicolaou (Pap) smears. In the current study, the authors examined a series of screening or diagnostic errors in cases in which the final histologic diagnosis was either AIS or AIS combined with a high‐grade squamous intraepithelial lesion (AIS + HSIL).

Medullary carcinoma of the thyroid

A preoperative diagnosis of medullary carcinoma of the thyroid (MCT) allows for the investigation of associated multiple endocrine neoplasia/pheochromocytoma, and definitive surgery without the need for frozen section. Criteria for cytodiagnosis are well known but variable patterns of presentation may cause diagnostic difficulty.

Adenocarcinoma of the cervix

Although hormone receptor status is an important prognostic indicator in adenocarcinoma of the breast and the endometrium, few studies have investigated the expression and clinical significance of estrogen receptor (ER) and progesterone receptor (PgR) in adenocarcinoma of the cervix.