Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis.

BACKGROUND: Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation. METHODS: We studied EZH2 expression in 409 patients with colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy. RESULTS: EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P=0.041) and high proliferation (>or=40%; P=0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P=0.001), but not among those who were treated by surgery alone (P=0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P=0.046), but not in patients with low proliferation (P=0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55). CONCLUSION: Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.

Oligodendroglioma. Histologic evaluation and prognosis.

All oligodendrogliomas registered in Norway during a 25-year period (1953-1977) were studied to establish the frequency of different histologic features and to compare them with survival data of the patients. The minimum observation time was five years. The original tumor specimens from 208 patients were independently reexamined by two pathologists. The characteristic oligodendroglioma of this series was of medium cell density (53% of lesions), with moderate nuclear atypia, with vascular endothelial proliferation (53%), calcification (56%), with from one to five mitotic figures per ten high power fields, and without microcystic degenerative changes (58%). Subpial tumor cell infiltration, perivascular lymphocytic infiltration and local leptomeningeal invasion were present in a minority of cases. In 11 cases autopsy material was the only source of diagnosis. Microcysts, necrosis, and cell density were the only histologic features of prognostic significance. Subpial infiltrative growth was of suggestive prognostic value. There was no significant association between the number of mitotic figures and survival. Vascular endothelial proliferation, calcification, pronounced nuclear atypia, perivascular lymphocytic infiltration and local leptomeningeal invasion were of no significant prognostic value. Age at operation did not alter these conclusions, neither did sex nor duration of preoperative symptoms.

Tissue sampling and histological grading in colorectal cancer. Are routine sections representative?

Microscopical sections from 50 colorectal adenocarcinomas were examined to test the representativity of routine sections with regard to histological grade. Point-counting of drawings of microscopical fields from randomly selected parts of whole-tumour specimens formed the basis for estimates of volumetric relationships between parts of the tumours exhibiting well, moderately and poorly differentiated glands. An overall histological grade was assigned to each tumour, and was compared with the grade obtained by examining a limited number of routine sections from the same tumour. It is concluded that if superficial and deep parts of the tumours are included, and provided that the sections measure at least 2-3 cm, colorectal adenocarcinomas may be graded with sufficient accuracy on the basis of one or two routine sections.

The extent and clinical significance of adenomyotic lesions in the uterine wall. A quantitative assessment.

This report presents an attempt to assess quantitatively the extent of adenomyotic lesions in hysterectomy specimens from women with symptoms suggesting adenomyosis (n = 14) and from women operated on for other reasons (n = 12). The specimens were cut into 5 mm-thick slices in which adenomyotic lesions were localized and counted microscopically. Nineteen uteri contained from 1 to 890 lesions. The distribution of lesions was mostly focal and patchy. More than half of the cases with adenomyotic lesions would have remained unrecognized if only the slice from the axial plane had been examined. Seventy-two per cent of the lesions were found in the posterior wall. Leiomyomas were found in 68% of the uteri with adenomyotic lesions. As adenomyotic lesions were observed with equal frequency in patients with and without pelvic pain, and as the degree of adenomyotic involvement did not correlate with complaints of pain, the significance of adenomyotic lesions as a cause of gynecological symptoms may be questioned.

Degree of differentiation in colorectal adenocarcinomas: a multivariate analysis of the influence on survival.

Three hundred and sixty eight resected colorectal adenocarcinomas were graded (WHO) retrospectively and the results correlated with estimated length of patient survival. In 30 (82%) of the tumours more than one degree of differentiation was found. Histological grade significantly influenced survival time when other explanatory variables such as tumour site and stage, age, and sex were adjusted for. The results suggested that three degrees of differentiation (well, moderate, and poor) are sufficient for the grading of colorectal carcinomas, and that grading should be based on the predominating degree of differentiation represented in the primary tumour.

Fibroepithelial polyps of the vagina: are they old granulation tissue polyps?

AIMS: To study the nature of fibroepithelial polyps of the vagina. METHODS: Sixty five fibroepithelial polyps of the vagina and 64 granulation tissue polyps diagnosed over 15 years were reviewed histologically. RESULTS: Cytologically benign multinucleated stromal cells were present in large numbers in 19 of the fibroepithelial polyps of the vagina (FEPV). Only one polyp contained atypical stromal cells, a high mitotic count, and abnormal mitoses and was indistinguishable from a malignant tumour. Immunostaining showed the presence of vimentin and desmin positive mono- and multinucleated stromal cells in FEPV and occasional oestrogen receptor positive nuclei. Desmin positive cells could not be shown in granulation tissue polyps. CONCLUSIONS: FEPV are common lesions with benign mono- and multinucleated fibroblastic stromal cells in which myoid differentiation is often present. FEPV may develop as a result of a granulation tissue reaction after some local injury of the vaginal mucosa. Hormonal factors may modulate the growth of FEPVs. Delayed differentiation of myofibroblastic cells may explain why granulation tissue sometimes does not contract properly but turns into polyps.

Influence of mucinous components on survival in colorectal adenocarcinomas: a multivariate analysis.

Of 534 resected colorectal adenocarcinomas, 165 (31%) contained some mucinous components; these represented the main part of the tumour in 67 (13%). Of the mucin containing tumours, 63 (38%) were in the right colon compared with 50 (13%) of the non-mucinous ones (p less than 0.001). Patients with predominantly mucinous tumours were significantly older than those with non-mucinous tumours, and they tended to present with tumours at a more advanced stage. A multivariate analysis did not show any significant independent prognostic influence of the mucinous component except when this had a predominantly signet ring cell pattern.

Association between invasiveness, inflammatory reaction, desmoplasia and survival in colorectal cancer.

Five hundred and twenty seven colorectal carcinomas were reviewed histologically. A multivariate analysis (Cox) was used to test the prognostic importance of certain histological features (invasiveness, inflammatory reaction, and amount of fibrous tissue) at the tumour edge after allowance had been made for clinicopathological stage, tumour site, and histological type and grade. A poorly defined tumour border, lack of inflammatory reaction, and a pronounced fibrosis (desmoplasia) at the tumour edge were associated with unfavourable stage distributions, but each of these features also had an independent effect on prognosis.

Neuroendocrine differentiation in bronchial carcinomas of classic squamous-cell type: an immunohistochemical study of 29 cases applying the tyramide signal amplification technique.

With regard to the cellular origin of bronchial squamous-cell carcinomas, there are some clinicopathologic and experimental data indicating a link between neuroendocrine (NE) bronchial tumors and the traditionally non-NE squamous-cell carcinomas. Against this background, 29 consecutively resected bronchial squamous-cell carcinomas were examined immunohistochemically (IHC) by means of the specific NE cell marker chromogranin A (CgA), using not only conventional IHC methods, but also the technique with increased sensitivity, offered by the tyramide signal amplification (TSA) procedure. Whereas none of the 29 tumors displayed CgA immunoreactive (IR) cells using the conventional IHC procedure, 10 were found to display a fine granular CgA IR in the neoplastic parenchymal cells using the TSA technique. This incidence is higher than previously reported. However, the CgA IR cells never formed any majority cell population of the neoplastic parenchyma; when present, most of them occurred as micronodules or larger confluent areas in the peripheral most undifferentiated parts of the carcinomatous sheets. Single CgA IR cells were detected only rarely in the spinocellular or keratinized areas. It can be speculated that the observations conform with the recently proposed hypothesis that there is a reservoir of NE progenitor cells in the bronchial mucosa capable of proliferation.

Statistical analysis of clinicopathological features, radiotherapy, and survival in 170 cases of oligodendroglioma.

The postoperative survival time of 170 nonrandomized patients treated for cerebral oligodendrogliomas in Norway from 1953 to 1977 was studied. Survival times were significantly prolonged if postoperative irradiation was performed in addition to surgery (median survival time 26.5 vs. 38 months, p = 0.039). In the group without postoperative radiotherapy, the 5-year rate of survival was 27% compared with 36% in the irradiated patients. The respective survival rates after 8 years were 14% versus 17%; thus, there was little effect on long-term survival. Irradiation appears not to be of benefit after "total" removal. Patients with partly resected lesions appeared to benefit from postoperative radiotherapy; the median survival period after subtotal tumor resection was 37 months with and 26 months without radiotherapy (p = 0.0089). The findings also indicate that irradiation doses between 40 and 50 Gy were as effective as doses between 50 and 60 Gy in increasing the patients' probability of surviving 5 years after subtotal tumor resection. Since the risk of radiation necrosis is proportional to the dose applied, the lower dose is recommended. These conclusions were also valid when adjustments were made for prognostically significant histological and clinical features.

Oligodendroglioma: incidence and biological behavior in a defined population.

The cases of 208 patients with histologically confirmed oligodendrogliomas were studied. The incidence represents 4.2% of all primary brain tumors diagnosed in the Norwegian population over a 25-year period. All of these tumors were cerebral and the majority affected the frontal lobe. The patients' median age at diagnosis was 47 years, with a range from 3 to 76 years; 6% of the oligodendrogliomas occurred in children. The median duration of symptoms before diagnosis was 20.5 months (mean 43 months). Plain skull x-ray films showed calcified deposits in 28% of the tumors. At operation, most of the tumors were poorly defined, without cyst formation, hematoma necrosis, or calcification. The median duration of disease from onset of symptoms until death was 14 months in nine untreated cases. In surgically treated oligodendroglioma patients the median survival time from onset of symptoms was 74 months. The median postoperative survival time was 35 months (mean 52 months). Tumor calcification, as seen on plain skull x-ray films, was associated with a significantly longer survival period. The surgical findings of gross necrosis, gross hypervascularity, and soft tumor consistency were all related to a shorter total duration of disease. Grossly well demarcated lesions were associated with a significantly longer postoperative survival. The length of postoperative survival correlated with the preoperative clinical status. The cumulative proportion of patients surviving 5 years was 0.342. The patient's age and sex did not have a statistically significant influence on survival time. The extent of surgical excision only seemed to play a role when the neurosurgeon considered that he had removed the whole lesion: these patients had a median postoperative survival period 14 months longer than the other oligodendroglioma patients. The ABO blood group of the oligodendroglioma patient was of prognostic value. In particular, patients with blood group A had a distinctly poorer prognosis than patients with O or B blood. The survival data from this unselected series indicate that cerebral oligodendrogliomas have a less favorable prognosis than has generally been believed.

Menometrorrhagia in the perimenopause is associated with increased serum estradiol.

OBJECTIVE: The purpose of this study was to evaluate the possible association between menometrorrhagia and the level of endogenous estrogen in perimenopausal women. METHODS: A prospective controlled study in which 28 perimenopausal women > 40 years presenting with menometrorrhagia were compared with 28 age-matched (+/- 2 years) women with normal cyclical menstrual periods concerning levels of estradiol and follicle-stimulating hormone (FSH). Neither of the two groups had received sexual hormone treatment at least in 2 weeks preceding the hormonal assessment. RESULTS: The serum level estradiol in the patients was significantly higher than in the controls (0.55 nmol/l versus 0.24 nmol/l), whereas FSH was not significantly different between the two groups (21.2 IU/l versus 11.8 IU/l). Twenty of the 28 patients had performed at histologic examination of the endometrium, and 10 of these (50%) had signs of endometrial hyperplasia. No relationship was found between the endometrial histology and the estradiol level. CONCLUSIONS: An association between a high endogenous estradiol level and menometrorrhagia in the perimenopause was demonstrated. This may have implications for the choice of treatment in this group of women. It is proposed that this type of bleeding disturbances should be controlled by progestins only, and not with combined estrogen-progestin treatment. Suppression of the associated hyperestrogenism could be achieved by use of oral contraceptives or GnRH agonists.

Ki-67 as a prognostic marker in adenoid cystic carcinoma assessed with the monoclonal antibody MIB1 in paraffin sections.

The monoclonal antibody MIB1 recognizing the Ki-67 antigen in formalin-fixed, paraffin-embedded tissue was used to study the proliferative activity in 44 adenoid cystic carcinomas of the salivary glands. The antigen expression was compared with clinical factors, histopathological grading, and prognosis. The Ki-67 value was significantly higher in tumors from patients suffering from treatment failure than in nonfailures (P<0.001). The Ki-67 expression was also higher in tumors exhibiting areas more than 30% of the solid growth pattern and higher in sinonasal tumors than in other locations. By Cox regression analysis, Ki-67 more than 4% was the strongest prognostic indicator (P<0.005). Clinical stage and violation of surgical margins were also found to be independent significant prognostic indicators. We conclude that Ki-67 expression estimated by the use of MIB1 is a powerful tool for predicting the short-term prognosis for patients with adenoid cystic carcinoma.

Prognostic significance of nucleolar organizer regions in adenoid cystic carcinomas of the head and neck.

OBJECTIVE: To determine the prognostic use of nucleolar organizing region (AgNOR) counts and clinical and histopathological features in adenoid cystic carcinoma. DESIGN: Argyrophilic staining was applied to ordinary formalin-fixed, paraffin-embedded specimens and evaluated to obtain the mean number of AgNORs and the percentage of nuclei with more than 1 (pAgNOR > 1), more than 2, more than 3, and more than 4 AgNORs. RESULTS: Using the log rank test, the mean AgNOR count showed no correlation with the disease-free period. All pAgNOR parameters exceeding the respective overall mean had poorer prognosis when compared with those below the mean (P = .02). The pAgNOR > 1 appeared as the best discriminator, singling out all treatment failures (P < or = .001). This parameter also showed a high degree of intraobserver and interobserver reproducibility. Stage of the disease, violated resection margins, and presence of the histopathological solid subtype were markers of an unfavorable prognosis. Multivariate analysis by the Cox model showed that pAgNOR > 1 (P < or = .001) and tumor stage (P = .03) were the only statistically significant parameters. CONCLUSIONS: Estimation of pAgNOR > 1 is easy, quick, and highly reproducible. It may become a useful prognostic parameter in adenoid cystic carcinoma, but larger studies should be performed to confirm the reliability of this method.

ABO blood groups, rhesus types, and colorectal adenocarcinoma. A retrospective study of 747 cases.

The distribution of ABO blood groups and Rh types was studied retrospectively in 747 patients with single adenocarcinomas of the large intestine. The distributions were similar to those of healthy blood donors. Rh- patients had a more favourable stage distribution than Rh+ patients. The proportion of patients with localized disease was higher for Rh- patients than for Rh+ patients (66% versus 46%), whereas metastases into regional lymph nodes were more common among Rh+ patients (23% versus 9%). The observed relationship between Rh type and stage distribution suggests that Rh+ patients with colorectal cancer are less protected against tumour spread than Rh- patients, especially with regard to regional lymph node metastases.

Site distribution of colorectal adenocarcinomas. A retrospective study of 853 tumours.

The site distribution of 853 histologically verified colorectal adenocarcinomas diagnosed at a Norwegian regional hospital from 1964 through 1978 was studied retrospectively. There was a notable increase in the annual number of diagnosed tumours from the first to the last 5-year period of the study. No significant change in site distribution could be found. Men had a higher proportion of rectal cancer than women (43% versus 31%) and a lower proportion of tumours of the right and transverse colon (29% versus 38%). Significant differences in site distributions between men and women, however, were found only in the age group above 60 years. Of the colorectal tumours in the present series 20% were within the reach of the examining finger on rectal examination.

Tumour site: a prognostic factor in colorectal cancer? A multivariate analysis.

Data from 753 patients with single adenocarcinomas of the large intestine diagnosed and treated at Trondheim Regional and University Hospital between 1964 and 1978 were studied to determine the influence of tumour site on survival by adjusting for tumour stage, age, and sex. The Cox regression model was used. Although the clinicopathologic stage had the strongest association with prognosis, the tumour site independently influenced the mortality, which increased from the right colon via the transverse/left part of the colon to the rectum.

Histologic confirmation of endometriosis in different peritoneal lesions.

The aim of this study was to compare the macroscopic evaluation of peritoneal abnormalities suspected of endometriosis with the histologic examination of the tissue. Peritoneal biopsies from 152 patients investigated for gynecological problems (94) or undergoing tubal sterilization (58) were taken from macroscopically abnormal peritoneum, and examined for the presence of endometriosis. Endometriosis was histologically confirmed by the presence of both endometrioid glands and stroma. Endometriosis was confirmed in 78 of the patients (51%). If the diagnostic criteria were extended also to include endometrioid stroma lacking glands, but containing iron pigment and/or hemorrhage, 82 patients (54%) were positive for endometriosis. Endometriosis was histologically confirmed in 76% of pigmented lesions, in 57% of clear or red papules, in 12% of peritoneal pockets, and in 16% when only fibrosis or scarring was observed. Half of the samples with confirmed endometriosis exhibited cyclic activity. The reproducibility of the histologic evaluation was satisfactory. A high rate of negative biopsies emphasizes the need of taking biopsies from peritoneal lesions suspected of endometriosis for confirmation of the diagnosis.