Cushing's disease arising from a clinically nonfunctioning pituitary adenoma

A 49-yr-old woman with a large pituitary tumor leading to visual loss and galactorrhea-amenorrhea was submitted to transcranial pituitary surgery, when a clinically nonfunctioning pituitary adenoma was partially removed. Histopathology and immunohistochemistry confirmed the diagnosis of “non-secreting atypical adenoma”. At that time, serum and urinary free cortisol were normal, with low T4 levels and hyperprolactinemia. The patient was discharged on thyroxine and bromocriptine and treated with conventional radiotherapy. Two years later, she presented high free urinary cortisol levels and a positive ACTH response to desmopressin testing on dexametasone 2 mg overnight. A pituitary biopsy confirmed aggressive growth as well as positive immunoreactivity for ACTH, p53, Ki-67, and c-erb-B2. The patient was then treated with radiosurgery on ketoconazole therapy. The overall clinical, laboratory, and pathological data suggest a transition from a clinically nonfunctioning to a hypersecreting ACTH-producing tumor. Putative mechanisms of tumor transformation and the possibility of a silent corticotropinoma evolving into clinical Cushing's syndrome are discussed.     

Therapeutic implications of accurate classification of pituitary adenomas

Recent data suggest that 1 of 5 individuals in the general population is affected with a pituitary adenoma. Many of these neoplasms are clinically non-functioning adenomas that may be small and clinically undetected or may present as mass lesions; others are hormonally active and cause significant morbidity due to the metabolic effects of hormone excess (e.g., acromegaly and cushing's disease). In either case, they can grow and invade adjacent anatomic structures. Tumors with similar clinical features are morphologically heterogenous and detailed comprehensive classification of pituitary adenomas is important to predict specific clinical behaviors and genetic changes that serve as targets for therapy. We provide a practical approach to clinical diagnosis and highlight the pitfalls in the classification of these common neoplasms.     

CD markers in pituitary adenomas

Immunostaining of CD markers in normal pituitary cells has been reported, but a study of these markers in pituitary adenomas has not been done. The expression of CD 3, CD 8, CD 15, CD 20, CD 30, CD 43, CD 45R0, CD 45 R, CD 79 α, and VS-38c was investigated in a collection of 65 pituitary adenomas of various types. CD 3 was present in 75%, CD 8 in 18.5%, CD 15 in 12.3%, CD 20 in 66.1%, CD 30 in 10.8%, CD 43 in 10.8%, CD 45 RO in 72.3%, CD 45 R in 16.9%, CD 79α in 0% and VS-38 c in 44.6%. Densely granulated GH cell adenomas expressed CD 3, CD 20, CD 45 RO, and CD 45 R, but no other markers. Sparsely granulated GH cell adenomas showed CD 3, CD 8, CD 20, CD 43, and CD 45 RO. Mixed GH/prolactin cell adenomas contained CD 3, CD 8, CD 20, CD 30, CD 45RO, CD 45 R, and VS-38c. Mammosomatotroph cell adenomas were positive only for CD 3, CD 8, CD 20, CD 43, and CD 45 RO. Prolactin cell adenomas expressed CD 3, CD 8, and CD 20. ACTH cell adenomas showed CD 3, CD 15, CD 20, CD 30, CD 45 RO, CD 45 R, and VS-38c. TSH cell adenomas contained CD 3, CD 8, CD 15, CD 20, CD 45 RO, and VS-38c. Gonadotroph cell adenomas were positive for CD 3, CD 8, CD 20, CD 45 RO, CD 45 R, and VS-38c. Alpha-subunit-only adenomas expressed CD 3, CD 8, CD 15, CD 20, CD 30, CD 45 RO, and VS-38c. Plurihormonal adenomas contained CD 3, CD 8, CD 20, CD 30, CD 43, CD 45 RO, CD 45 R, and VS-38c. Oncocytic adenomas were positive for all markers except CD 45 RA and CD 79 α. We conclude that the spectra of different adenoma types expressing CD markers varies greatly and that significant correlations do not exist, although noninvasive adenomas appear to express CDs more frequently than invasive adenomas. We have no clear-cut explanations for the various expressions and suggest that it may be a sign of local interactions between the immune system and pituitary adenomas.     

垂体腺瘤p53蛋白表达及其意义

目的：研究突变型ｐ５３癌基因在垂体腺瘤中的表达。方法：应用免疫组化ＡＢＣ法检测６４例垂体腺瘤（复发组３１例，非复发组３３例），６例正常垂体、２例垂体瘤中ｐ５３蛋白表达阳性，非复发组中有２例ｐ５３蛋白表达阳性，两组差异有显著性。２例垂体癌ｐ５３蛋白强阳性表达，６例正常垂体无阳性表达。ｐ５３蛋白在不同激素类型垂体腺癌中的阳性表达率差异无显著性。结论：ｐ５３蛋白高表达与少数垂体腺癌在潜在恶性及复发有关，     

Different expression of Bcl-2 protein in gastric adenomas and carcinomas

In order to cast light on the possible role of bcl-2 protein (Bcl-2) expression In gastric tumorigenesis, 33 cases of gastric adenomas and carcinomas originating from the same stomachs were immunohistocnemically investigated for Bcl-2 protein (Bcl-2) expression, accumulation of p53 protein and cell proliferation as determined by the KI-67 labeling index (LI). Bcl-2 expression was detected in 24/33 (72.7%) adenomas and in 6/33 (18.2%) carcinomas, the difference being statistically significant (P=0.0O01). Only 4 of 33 (12.1%) cases exhibited expression in both adenoma and carcinoma lesions in the same stomachs. ImmunoreactMty was decreased in areas of cellular and structural atypia in adenoma lesions ( P <0.008), and appeared to be positively linked to the tumor progression and the degree of differentatlon in carcinomas, although It did not reach statistical significance. Accumulation of p53 protein was rare In the adenomas but was found in 15/33 (45.5%) of carcinoma lesions, with a significant dissociation from Bcl-2 immunoreactivity. No apparent relation between Ki-67 U and either adenoma grading or carcinoma typing was noted, although average KI-67 LI of the highest labeling areas in carcinomas was statistically higher than in adenomas ( P =0.0001). These results indicate that the regulation of Bcl-2 expression may differ between gastric adenomas and carcinomas, may be correlated with tumor dlfferentiathre features. In addition, p53 accumulation may play an Important role in the onset of malignancy.     

Grading of pituitary adenomas in acromegaly

Summary In a series of 284 adenomas from cases of acromegaly we studied major morphological variables using light microscopical techniques and compared them with immunocytochemical and clinical results.Using our semiquantitative estimations many inter-relationships were observed. We established the density of secretory granules, nuclear pleomorphism and the rate of occurrence of multinuclear tumour cells, as essential features of tumour differentiation. Mitotic activity and invasive growth patterns did not reveal clear dependences.Immunocytochemical analysis of 105 cases showed growth hormone (GH) in nearly all adenomas (98%), prolactin in 68%, and LH in 40%. The other hormones (ACTH, FSH, and TSH) were present at a much lower rate. Monohormonal GH-adenomas were found in only 29% of our cases.Many different combinations of hormone content could be demonstrated without any relationship to morphological or clinical data. From the linear correlations and advanced method of semiquantitative evaluation, the granular density of the tumour cells is the most useful variable for subclassification and grading of pituitary adenomas in acromegaly.This publication contains results from the doctorthesis submitted by M. Riedel (Hamburg 1984)     

Clinical significance of Ki-67 labeling index in pituitary macroadenoma

The aim of our study was to investigate the correlation of the proliferative activity of pituitary neoplasms with clinical characteristics and recurrences. Tumor specimens were obtained from 44 consecutive patients with pituitary macroadenomas who underwent surgery between July 1998 and August 2003. Specimens were immediately fixed in 10% buffered formalin and then embedded in paraffin. The Ki-67 antigen was assessed by immumohistochemical analysis using the monoclonal antibody. We investigated the correlation of the Ki-67 labeling index with the following clinical and radiological characteristics: sex, age, presence or absence visual field defect, tumor classification, maximal tumor diameter, Hardy's classification, type of tumor, invasiveness, and recurrence. Our study suggests that the clinical characteristics such as visual field defect and recurrence are correlated with the high Ki-67 labeling index. No statistical differences were observed in the Ki-67 labeling index in relation to the following characteristics: sex, age, tumor classification, maximal tumor diameter, Hardy's classification, type of tumor, and invasiveness into the sphenoid sinus or cavernous sinus.     

Sparsely granulated prolactin cell adenomas of the pituitary gland

Summary The possible relationship between the preoperative plasma prolactin levels of patients having a sparsely granulated prolactin cell adenoma of the pituitary gland and the morphology of the tumors was studied by means of quantitative electron microscopy. To this end, a number of ultrastructural variables were chosen which are generally regarded to be indicative of cellular activity and which could be determined in a quantitative or semiquantitative way. These variables were determined in 19 adenomas from 17 patients and plotted against the corresponding prolactin levels. It appeared that marked endocrine activity was associated with a small number of granules per cell, a high frequency of exocytosis, and a marked development of the rough endoplasmic reticulum. Granule size and development of Golgi apparatus and lysosomes were not at all, or only poorly correlated with the plasma hormone levels. Finally, the number of mitochondria per cell showed a totally unexpected inverse correlation with endocrine activity. Due to the close mutual correlation existing between several of the variables investigated, combining them in a multivariate analysis did not significantly improve the correlation with the hormone level.     

Plurihormonal pituitary adenomas: immunostaining of all pituitary hormones is mandatory for correct classification

AIMS: We studied the clinicopathological characteristics of plurihormonal pituitary adenomas. METHODS AND RESULTS: The study material included 167 plurihormonal adenomas, which consisted of 31% of the surgically removed pituitary adenomas that we collected during a 12-year period. The mean age of patients with plurihormonal adenoma was 45.7 years (range 13-75 years). There were 86 men and 81 women. All tumours were fully classified by immunohistochemical staining for seven pituitary hormones or subunits. Thirty immunohistochemical subtypes of plurihormonal adenomas were recognized. Hormonal symptoms were present in 70% of patients, while serum hormonal levels were increased in 89% of patients. Most patients had symptoms related to only one of the hormones and only 7% of patients had symptoms related to two hormones. The most common hormonal symptom was acromegaly (50%); symptoms related to hyperprolactinaemia ranked second (20%). Double immunostaining of all the possible combinations of the hormones was performed in 30 selected tumours, and they all showed mixtures of hormones in individual adenoma cells in any hormonal combinations studied. The latter finding supported the view that plurihormonal adenomas are monomorphous adenomas. CONCLUSIONS: Plurihormonal adenomas are common pituitary adenomas. Immunohistochemical staining of all pituitary hormones is mandatory for correct classification.     

Human pituitary gonadotroph adenomas: Relationship between gonadotropin immunoreactivity and clinicopathologic findings

Clinically nonfunctioning pituitary adenomas are generally seen in middle-aged and older patients, and most of them may be gonadotropin-immunoreactive adenomas, that is, gonadotroph adenomas. Our aim was to clarify the relationships between the gonadotropin immunoreactivity, patient age, sex, and microscopic features in 68 gonadotroph adenomas with special reference to either gonadotropin-immunonegative or intensively immunopositive adenomas. There were 68 patients with gonadotroph adenomas (mean age 54.7 yr) in the study, including 39 men (mean age, 52.8 yr) and 29 women (mean age, 57.4 yr). The adenomas were diagnosed on the basis of immunoreactivity for gonadotropins (β-subunit of follicle-stimulating hormone: β-FSH; β-subunit of luteinizing hormone: β-LH; and the α-subunit of the pituitary glycoprotein hormone: α-SU) by the avidin-biotin peroxidase complex (ABC) method or by the characteristic histological feature of a perivascular or pseudorosette pattern, that is, the cells aligned polarity directed toward the capillaries. Fifty-four adenomas (79%) were positive for one or more gonadotropin subunits and β-FSH was the most common subunit encountered (47/68, 69%). In men β-FSH immunoreactivity was similar among all age groups, whereas in women, it was significantly less frequent in patients who were 50 yr or older, compared to younger patients. Gonadotropin-immunonegative adenomas were seen in 4 men (mean age, 46.8 yr) and 10 women (mean age, 61.5 yr). Among the 22 women aged 50 or over, β-FSH was negative in 12 tumors (55%), whereas in men of the same age group, it was negative in 3 of 26 tumors (12%). The reason for this reduced frequency is not clear, but the postmenopausal state and associated changes in the systemic endocrine state may play a role. Adenomas that were intensively positive for β-FSH showed an unusual morphology other than the characteristic perivascular pattern, regardless of the patients' age and sex; the tumor cells had abundant vacuolated cytoplasms and were arranged in a sheet-like pattern. Electron microscopically, these cells with abundant cytoplasm had well-developed Golgi complexes, suggesting an enhanced activity of gonadotropin synthesis, and these adenomas seem to be endocrinologically, if not clinically, functioning. The results indicate that gonadotroph adenomas may vary from functioning adenomas with intense immunoreactivity and unusual histology to immunonegative and less functioning adenomas, which are more frequent in women 50 yr or older.     

Immunohistochemical analysis of tumor angiogenic factors in human pituitary adenomas

Microvessel density (MVD) has been studied in a number of neoplasias, and apparently, there is a relationship between angiogenesis and tumor progression, response to treatment, and outcome. In pituitary adenoma, the association between MVD and vascular endothelial growth factor (VEGF) with tumor behavior has been described, but correlation with other angiogenic factors such as fetal liver kinase 1 (Flk-1) or proliferative markers is unknown. We investigated MVD, VEGF, and its receptor Flk-1 expression in 60 human pituitary adenomas: 13 growth hormone cell adenomas, 7 prolactin cell adenomas, 5 corticotroph cell adenomas, 2 thyrotroph cell adenomas, and 33 nonfunctioning adenomas (30 gonadotroph cell adenomas and 3 null cell adenomas). We performed immunohistochemistry for CD34, Ki-67, VEGF, and Flk-1. To evaluate MVD, we used 2 methods: the number of vessels per square millimeter and the Chalkley method. Immunohistochemistry results were correlated, as well as with clinicopathologic factors. Adenomas with higher MVD were thyrotroph cell adenomas (299.9 +/- 87.5), and those with lower MVD were prolactin cell adenomas (168.6 +/- 63.3; P = .45, analysis of variance). We found a trend toward higher MVD in the adenomas of older patients (P = .142), but no difference was found regarding sex, extrasellar extension, or Ki-67 (P > .05). However, extrasellar extension was nearly significant when the Chalkley method score was high (P = .056). Low expression of VEGF was seen predominantly in prolactin cell adenomas, and high in nonfunctioning adenomas, or in cases of older patients (P < or = .032). Flk-1 score correlated with VEGF (P = .006). High expression was observed in nonfunctioning adenomas, cases presenting at older ages, and with extrasellar extension (P < or = .022). Our study shows that VEGF and Flk-1 are widely expressed in pituitary adenomas, predominantly in nonfunctioning adenomas and those presenting at older ages. Moreover, Flk-1 is associated with a more aggressive phenotype, and it may have potential therapeutic interest.     

Correlation between PCNA expression and AgNOR dots in pituitary adenomas

Nucleolar organizer regions are segments of DNA associated with argyrophilic proteins (AgNORs). Our previous findings showed that the number, the area, and the intranuclear localization of AgNOR dots differ according to tumor aggressiveness and to the hormone-immunopositivity of pituitary adenomas. Proliferating cell nuclear antigen (PCNA) is a nuclear protein, whose expression is correlated with cell proliferation. The aim of the present paper was to examine PCNA-labeling indexes in pituitary adenomas and to correlate them with AgNOR dots in various immunohistochemical types of the tumors. Histological slides from 32 pituitary tumors and one normal pituitary were silver-stained and analyzed with a computerized system for microscopic image analysis. We found that the percentage of PCNA-positive cells did not differ significantly among examined groups of monohormonal adenomas. However, tumors immunopositive for α-subunit (α-SU) showed a significantly higher (p<0.05) PCNA index than adenomas immunonegative for that unit. PCNA index in recurrent tumors was significantly higher than in primary adenomas. There was a moderate positive correlation between the PCNA index and the mean area of AgNOR dots and a similar correlation between the PCNA index and the area of the biggest dot in the nucleus. The obtained results reveal that the PCNA indexes and estimated parameters of AgNOR dots differ according to tumor aggressiveness.     

p53 and Ki-67 immunoreactivity and nuclear morphometry of 'carcinoma-in-adenoma' and adenoma of the gall-bladder

Twenty lntramucosal tumors of ‘carclnomaln-adenoma’ and 43 ademas (39 pylorlc gland type, 4 Intestinal type) of the gall-bladder were studied to establish more precise histo-logical criteria of carcinoma or adenoma In cases of ‘carcinoma In pyforic gland type adenoma’, to compare carcinoma In adenoma with pure, that Is, without adenomatous components, carcinoma, and to confirm the benign nature of spin-dle cell fd in the adenomas. Ki-67 and p53 immunostaining and nuclear morphomety were used. Eight pure intramucessl cancers were used as controls. The formalin-fixed, paraffln+mbedded sections were stained with p53 and Ki-67 antibodies. Splndle cell foci were observed only In the adenoma area of the pyloric gland type, wlth a frequency of 23% In 39 adenomas, and of 45% in 20 tumors of carclnoma-lrradenoma. Ki-67 staining was negative in 129 of 130 spin-die cell foci examlned, regardless of their size, and positive in only one focus (550 pm in size, Ki-67 Index 0.2%). All of the spindle cell foci were negative for p53 stain. The Ki-67 positive index was 36.6 ± 5.6% In the 8 pure carcinomas, and 12.5 ± 1.9% in the cancer areas of 16 tumors with carcinoma-in-adenoma, while it was 7.9 ± 1.7% in the adenoma areas of 16 tumors with carcinoma-in-adenoma and 4.9 ± 0.5% in the 32 pure pyloric gland adenomas. The p53-protein over-expression was found in seven of eight pure intramucosal cancers, and in one of 16 cancer components of carclnoma-in-adenoma. However, it was not found in any of 16 adenoma components of carcinoma-in-adenoma, and 35 adenomas. Cells of the cancer tissue of carcinoma-In-adenoma showed a significantly larger nuclear area and a larger nuclear minor axis than those of the pyloric gland type adenomas, as well as other architectural and cytologic abnormalities differing from the features of adenomas. These results suggest that clustered spindle cells do not indmte a malignant transformation of adenoma cells and that carcinomas in carcinoma-in-adenoma are dtfferent from pylorlc gland type adenomas In terms of morphology and proliferative activity. Moreover, the results of the present study indicate that carcinomas In carcinoma-ln-adenoma are lower In malignancy than pure carcinomas, and that their genetic abnormaltty may differ from that of pure carcinomas.     

p53 and Ki-67 immunoreactivity and nuclear morphometry of 'carcinoma-in-adenoma' and adenoma of the gall-bladder

Twenty Intramucosal tumors of ‘carclnoma-ln-adenoma’ and 43 adenomas (39 pylorlc gland type, 4 Intestinal type) of the gall-bladder were studied to establish more precise hlsto-loglcal criteria of carcinoma or adenoma in cases of ‘carcinoma in pylorlc gland type adenoma’, to compare carcinoma in adenoma with pure, that is, without adenomatous components, carcinoma, and to confirm the benign nature of spindle cell foci in the adenomas. Ki-67 and p53 immunostaining and nuclear morphometry were used. Eight pure intramucosal cancers were used as controls. The formalin-fixed, paraffin-embedded sections were stained with p53 and Ki-67 antibodies. Spindle cell foci were observed only in the adenoma area of the pylorlc gland type, with a frequency of 23% in 39 adenomas, and of 45% in 20 tumors of carclnoma-Jn-adenoma. Ki-67 staining was negative in 129 of 130 spin-die cell foci examined, regardless of their size, and positive in only one focus (550 μm in size, Ki-67 index 0.2%). All of the spindle cell foci were negative for p53 stain. The Ki-67 positive index was 36.6 ±5.6% in the 8 pure carcinomas, and 12.5 ±1.9% in the carcinoma area of 16 tumors with carci-noma-in-adenoma, while it was 7.9± 1.7% and in the adenoma areas of 16 tumors with carcinoma-in-adenoma and 4.9 ± 0.5% in the 32 pure pyloric gland adenomas. The p53-protein overexpression was found in seven of eight pure intramucosal cancers, and in one of 16 cancer components of carcinoma-in-adenoma. However, it was not found in any of 16 adenoma components of carcinoma-in-adenoma, and 35 adenomas. Cells of the cancer tissue of carcinoma-in-adenoma showed a significantly larger nuclear area and a larger nuclear minor axis than those of the pyloric gland type adenomas, as well as other architectural and cytologic abnormalities differing from the features of adenomas. These results suggest that clustered spindle cells do not indicate a malignant transformation of adenoma cells and that carcinomas in carcinoma-in-adenoma are different from pyloric gland type adenomas in terms of morphology and proliferative activity. Moreover, the results of the present study indicate that carcinomas in carcinoma-in-adenoma are lower in malignancy than pure carcinomas, and that their genetic abnormality may differ from that of pure carcinomas.     

MGMT启动子与垂体腺瘤侵略性行为及ADC值的相关性研究

目的 探讨垂体腺瘤O-6-甲基鸟嘌呤DNA甲基转移酶(MGMT)启动子甲基化状态与肿瘤侵略性行为及ADC值的相关性.方法 采用前瞻性研究,选取我院2019年01月至2020年08月收治的垂体腺瘤的患者,所有患者术前接受MRI检查(平扫+增强+解剖弥散),术后对肿瘤组织标本进行苏木精-伊红(HE)染色、免疫组化检查,通过...     

Alpha-subunit-producing pituitary adenomas

Summary Immunohistological techniques demonstrate the alpha-subunit of glycoprotein hormones in the majority of endocrine-inactive, undifferentiated pituitary adenomas and pituitary oncocytomas. In about one-fifth of endocrine-active adenomas, the alpha-subunit is produced in combination with either adrenocorticotropic hormone or prolactin, and it is found in combination with growth hormone in about half of those adenomas causing acromegaly.Pure alpha-subunit-producing, endocrine-inactive adenomas characteristically have small secretory granules that are destroyed by direct osmium fixation, but are well preserved after prefixation with glutaraldehyde. As only a few atypical prolactinomas show similar secretory granules, and as they display a positive reaction for the alpha-subunit only exceptionally, this ultrastructural feature can serve as a guide to differentiate such adenomas.     

Clinicopathological correlations in pituitary adenomas

Pituitary adenomas are common neuroendocrine neoplasms arising from adenohypophysial cells. Recent progress in our understanding of pituitary tumorigenesis as well as pathways involved in molecular cytodifferentiation of the adenohypophysis has impacted on the classification of pituitary adenomas. The detailed comprehensive classification of pituitary adenomas is now well recognized to reflect specific clinical features and genetic changes that predict targeted treatments, as well as prognostic information for patients with pituitary adenomas. Therefore, the clinical responsibility of pathologists is not only limited to the distinction of pituitary adenomas from other sellar lesions, but also to provide a comprehensive subtype classification using appropriate ancillary tools. In this article, we highlight an approach to clinical diagnosis and pitfalls in the classification of these common neoplasms.     

Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas

Pituitary adenomas sometimes progress after surgery and can be locally invasive. Ki-67 and p53 expression are referred to as indicators of aggressive behavior in the World Health Organization Classification of Endocrine Tumors. The real value of these markers including an appropriate threshold for Ki-67 labeling index correlating with tumor progression is controversial. We identified 24 consecutive pituitary adenomas from patients who required surgery for recurrence within 5 years of their first procedure and 31 consecutive adenomas with no evidence of postsurgical progression within 5 years of first surgery. Case selection was based upon availability of complete clinical information, blocks, and slides for study. Immunohistochemistry for Ki-67 revealed that the tumors without progression had a proliferation index of 0.41% +/- 0.01% (mean +/- SEM) (n = 31) (range, 0.08%-1.2%) and the first biopsy from those tumors which progressed had a mean proliferation index of 1.45% +/- 0.09% (mean +/- SEM) (n = 24) (range, 0.1%-10.6%) (P = .01). With the use of ROC analysis, a threshold level of Ki-67 expression greater than 1.3% predicts progression with a high specificity. The group with progression had a higher proportion of nonfunctioning tumors (P < .005, chi(2)). There was no significant difference between the 2 groups with regard to invasion, suprasellar extension, size, tumor type, postoperative radiotherapy, extent of resection, sex, and age. Ki-67 labeling index was an independent predictor of progression (multivariate analysis, P < .011). p53 was positive in 12.5% of cases with surgical progression and in 9.6% of cases without progression, but the difference was not significant (P = .7; chi(2), 0.11).     

Clear cell change in colorectal adenomas: its incidence and histological characteristics

AIMS: The aim of our investigation was to clarify the histological characteristics and biological significance of clear cell change in colorectal adenomas. METHODS ANID RESULTS: We found three cases (0.086%) of tubular adenomas with clear cell change in a review of 3486 cases of colorectal adenoma. These three cases occurred in male patients and were located in the left-sided colon. To investigate the nature and biological significance of the clear cells, we conducted histochemical staining (periodic acid-Schiff (PAS) with or without diastase digestion, alcian blue pH 2.5) and immunohistochemical staining (using antibodies against carcinoembryonic antigen (CEA), alpha-fetoprotein, p53 protein and Ki67 antigen) and also mitotic counts. Histologically, the changed area was characterized by pyknotic and randomly arranged nuclei with PAS-negative clear and vacuolated cytoplasm. Immunoreactivity for CEA was diffuse and strong in the clear cells, but not in the tumour cells in the ordinary portion of the adenomas. The Ki67 labelling index and the mitotic activity were both higher in the clear cell portion than in the ordinary portion. CONCLUSIONS: This is the first study to indicate the incidence of clear cell change among colorectal adenomas. It has confirmed high proliferative activity within the clear cell portion of colorectal adenomas.