Subsequent breast carcinoma risk after biopsy with atypia in a breast papilloma

BACKGROUND: Risk of breast cancer after biopsy demonstrating a papilloma has long been variously interpreted on the basis of histologic pattern of multiplicity of papillomas. METHODS: A nested case control study was performed on women with surgical breast biopsies evidencing papillomas; cases who subsequently developed invasive carcinoma were compared with controls who did not. Presence of atypical hyperplasia (AH) within the papilloma as well as areas of AH in the surrounding parenchyma were evaluated in both cases and controls. The entire cohort (not tested) was separately evaluated for all variables except for atypia within papillomas. RESULTS: The relative risk of invasive carcinoma for women with papillomas containing AH was > 4x that of papillomas without AH within or surrounding the papilloma. This risk may be greater with added atypical hyperplasia outside the papilloma and most strikingly, most of the subsequent invasive carcinomas developed in the same breast and probably near the site of the original papilloma. However, ordinary patterns of epithelial hyperplasia lacking specific features of AH within the papilloma do not add to the risk of subsequent carcinoma development over papillomas without hyperplasia. CONCLUSIONS: This study indicates that women having papillomas with AH have a similar or greater cancer risk than others with specifically defined patterns of atypical hyperplasia within the breast parenchyma (4-5x relative risk). Most importantly, this risk is largely local in the region of the original papilloma.     

Interobserver concordance in discriminating clinical atypia of melanocytic nevi, and correlations with histologic atypia

BACKGROUND: The clinical features attributed to atypical (formerly ?dysplastic") nevi and to the atypical multiple mole melanoma syndrome have been used in clinical practice, as well as experimentally, to assign melanoma risk. Little information is available, however, on the interobserver reliability in assessing those features. OBJECTIVE: Our purposes were to quantify interobserver and intraobserver concordances in recognizing certain atypical characteristics of nevi and to correlate the clinical assessments with the histologic characteristics. METHODS: Three observers evaluated clinical photographs of 100 pigmented lesions (predominantly melanocytic nevi, with some lentigines and seborrheic keratoses) from 95 subjects, of whom 85 were family members of four multiple melanoma kindreds and 10 were spouses. Each lesion was rated for border irregularity, color variegation, surface contour irregularity, pigment diffusion, and macularity versus papularity. Predictions were made as to the histologic diagnoses and presence of melanocytic atypia for those lesions judged to be nevi. RESULTS: The pair-wise concordances before agreement on specific criteria were quantified by kappa statistics, which indicated slight to fair agreement in judging the atypical clinical characteristics; concordances increased to moderate levels after consensus development of criteria for color variegation and assessment of macularity, but agreement on the other features remained limited. Whereas macularity and color variegation did correlate somewhat with higher grades of histologic atypia, correlations were generally low between the clinical and histologic diagnoses. CONCLUSION: There is limited interobserver reliability in the clinical assessment of nevus atypia, although correlations do exist between some atypical characteristics and grades of histologic atypia. Because of the low concordances, the clinical discrimination of the melanoma-associated atypical nevus phenotype should rely more on quantitative aspects of the trait, such as total numbers or maximal sizes of nevi, rather than on the subjective determinations of atypia.     

Impedance of a goat eye lens

Cyclins are essential proteins in cell cycle control, and their deranged expression has been reported to be associated with malignant transformation. Involvement of cyclins in the development of endometrioid carcinomas of the endometrium was studied immunohistochemically using antibodies against both cyclin A and tumor suppressor gene product p53, and their expression was compared with that of Ki-67 antigen. Sixty-two cases of endometrial endometrioid carcinoma and 20 cases of normal endometrium (10 proliferative and 10 secretory phase) were examined. Of the 62 endometrioid carcinomas, atrophic endometrium and hyperplasia were found adjacent to the cancers in 30 and 19 cases respectively. Cyclin A was expressed in < 1% of the glandular cells of normal endometrium in the proliferative phase and in hyperplasia, but was negligible in normal secretory phase and atrophic endometrium. p53 was almost always negative in normal endometrium and hyperplasia. Of the 62 endometrioid carcinomas, 12 tumors (19.4%) overexpressed cyclin A and 21 tumors (33.8%) overexpressed p53 (positive cells > 1%). Cyclin A and p53 were more frequently expressed in poorly differentiated tumors than in well differentiated tumors (cyclin A, p = 0.002; p53, p = 0.016). In addition, cyclin A-positive cells were topographically related to those cells positive for p53 as well as Ki-67. In conclusion, the abnormal expression of cyclin A and p53 is associated with high-grade endometrial endometrioid carcinomas.     

Ataxia-telangiectasia in the Japanese population: identification of R1917X, W2491R, R2909G, IVS33+2T-->A, and 7883del5, the latter two being relatively common mutations

Postmenopausal uterine bleeding is an indication to sample the endometrium for diagnostic purposes. The endometrial brush cytologies of 20 advanced postmenopausal women collected at the time of hysterectomy in order to benchmark the expected morphology of postmenopausal endometrial brushings were reviewed. No women had symptoms or gross findings of primary endomyometrial disease. Endometrium was collected at the surgical pathology laboratory using the Tao Brush and CytoRich Fixative System. After formalin fixation of the uterus, the entire endometrium was embedded for routine histology. Sixteen endometrial brushings and matched endometrial sections showed endometrial atrophy, one brushing showed many ciliated epithelial cells, and three brushings showed focal (less than 10%) epithelial-cell atypia. In two atypias, abnormal endometrial epithelial-cell sheets contained enlarged, clear nuclei with nuclear notches and grooves resembling papillary thyroid cancer. One case showed no histological counterpart to this finding. The other case showed thickening of the pericornual fundic endometrium with cystic glands. The third case with epithelial atypia showed abnormal endometrial-cell sheets with nuclei resembling atypical hyperplasia or type I endometrial adenocarcinoma; corresponding endometrial tissue sections showed rare, irregular glands and back-to-back gland clusters with equivalent nuclear features. Atypical epithelium may be found in atrophic uteri in the absence of gross endometrial thickening. This may be a common event related either to de novo intraepithelial dysplasia in a noncycling endometrium or to hyperplasia that has partly regressed with estradiol withdrawal. This study shows that, in addition to endometrial intraepithelial carcinoma (EIC), isolated atypical glands with morphological and immunohistochemical features of atypical hyperplasia or type I endometrial adenocarcinoma may be found in grossly normal advanced postmenopausal endometrium of asymptomatic patients. This atypical epithelium is readily apparent in endometrial brush preparations, but requires serial sectioning of the endometrium to be demonstrated histologically. We have not established the natural history of this lesion, and in the absence of EIC or gross endometrial thickening indicative of atypical hyperplasia, we do not know whether this degree of epithelial atypia should be an indication for hysterectomy.     

Early diagnosis of adenocarcinoma by endometrial cytologic samples

145 endometrial cytologic samples were taken by Endocyte and they were compared to histologic samples. The diagnostic concordance was 96.55%, proliferative endometrium, secretory endometrium, hyperplastic endometrium and carcinoma were screened and only 2.75% of cases were uncertain. Endometrial cytology is advantageous because Endocyte can be used in the out-clinic without risks for patients.     

Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions

PURPOSE: To assess the interobserver agreement on the diagnosis and classification of cutaneous melanoma. MATERIALS AND METHODS: A set of 140 slides of cutaneous melanoma, including a small subset of benign pigmented skin lesions, were circulated to four experienced histopathologists. The kappa statistic for multiple ratings per subject was calculated using the method described by Fleiss. RESULTS: The kappa value on the diagnosis of cutaneous melanoma versus benign lesions was 0.61. There was some discordance on the diagnosis in 37 of 140 cases (26%). For the histopathologic classification of cutaneous melanoma, the highest kappa values were attained for Breslow thickness (kappa = 0.76) and presence of ulceration (kappa = 0.87). The agreement was generally poor for other histologic features, such as level of dermal invasion (kappa = 0.38), presence of regression (kappa = 0.27), and lymphocytic infiltration (kappa = 0.27). CONCLUSION: Our study suggests considerable disagreement among pathologists on the diagnosis of melanoma versus other pigmented lesions. Tumor thickness and presence of ulceration are the most reproducible histologic features of cutaneous melanoma.     

Usefulness of transvaginal ultrasound and hysteroscopy in diagnosing endometrial hyperplasia and endometrial carcinoma

Modern methods enabling evaluation of endometrium in all phases of the menstrual cycle were presented. Transvaginal ultrasound does not give characteristic pictures. The most frequently observed sonographic features in endometrial hyperplasia and endometrial carcinoma were compared. Most frequently, in 29% we observed the thickening of the endometrium. The enlargement of the uterine body was detected in 27%. The dominant feature in endometrial carcinoma was distortion or lack of medium-focus echo-90%. Different echogenicity was observed in 69% of all cases. Application of hysteroscopy enables us to visualize changed endometrium and also to sample focal lesions for histopathological examination. Endometrial carcinoma was detected in all analyzed cases with application of hysteroscopy and ultrasound. Pathological endometrial hyperplasia was diagnosed by ultrasound only in 44% and with application of hysteroscopy in 84% of all material.     

Endometrial hyperplasias: histology, classification, prognostic significance and therapy

Carcinomas of the endometrium are the most frequent neoplasias of the female genital tract. Precancerous lesions of the endometrium, including simple hyperplasia with and without atypism, complex hyperplasias as well as atypical complex hyperplasias occur 4.5 times more. The existence of hyperplastic or precancerous lesions of the endometrium is well established, but differences in terminology and difficulties in interpretation have complicated the communication between morphologists and clinicians. The risk of a metachronous endometrial carcinoma increases from about 1% in simple hyperplasia to 29-45% in atypical complex hyperplasia. Therapeutic procedures include the gestagen-therapy, depending from age and reproductive status of the women. Atypical complex hyperplasia requires the hysterectomy with bilateral salpingo-oophorectomy to treat a possible simultaneous carcinoma. Transvaginal sonography, hysteroscopy and pulsed Doppler sonography give additional informations and allows to distinguish a pathological from a normal endometrium. These methods may reduce the number of unnecessary diagnostic dilatation and curettage procedures, especially in patients with additionally cardio-vascular and other risk factors. But the histological examination of curettage material is still the "gold standard" for distinguishing between a normal and a pathologic endometrium. The classification and histologic criterias of precancerous lesions of the endometrium is presented and the need for better communication between pathologists and gynecologists is emphasised.     

Clostridium septicum infection and hemolytic uremic syndrome

Ultrasonography of the hip was performed sequentially by two different examiners in 75 infants. The ultrasound strips were reviewed twice by three paediatric orthopaedic surgeons and classified by the Graf method. The intraobserver and interobserver agreement between the interpretations was analysed using simple and weighted kappa coefficients calculated for agreement on the Graf classification and for grouping as normal (types 1A to 2A), and abnormal requiring treatment (types 2B to 4). When examining the same ultrasound strip, intraobserver agreement for the Graf classification was substantial (mean kappa 0.61), but interobserver agreement was only moderate (kappa 0.50). For the grouping into normal and abnormal, the mean kappa value for intraobserver agreement was 0.67 and for interobserver agreement 0.57. Because of the significant differences in agreement between normal and abnormal hips, we analysed a subgroup of those with at least one abnormal interpretation. Intraobserver agreement within this subgroup showed moderate reliability (kappa 0.41), but interobserver agreement was only fair (kappa 0.28). Interpretations of two different strips performed sequentially showed significantly lower agreement with an intraobserver kappa value of 0.29 and an interobserver value of 0.28. In the subgroup with at least one abnormal reading, the intraobserver kappa was 0.09 and the interobserver 0.1. Our findings suggest that both the technique of performing ultrasonography and the interpretation of the image may influence the result.     

Epidemiology of endometrial hyperplasia and adenocarcinoma

In a retrospective study characteristics of 729 climacteric and postmenopausal women with hyperplasia and adenocarcinoma of the endometrium are compared with those of 82 women with atrophic endometrium and 96 women with carcinoma of the cervix. In a prospective study 225 women with glandular-cystic, adenomatous and atypical hyperplasia of the endometrium have been checked by a control-curettage within a period of two months until four years following the first diagnosis. Low parity, disturbances of menstruation with anovulatoric bleedings during fertility period, adipositas, hypertension and diabetes mellitus in climacteric and postmenopausal women indicate a high risk of carcinoma of the endometrium. Hyperplasias of the endometrium in climacteric women cannot be considered as precursors of corpus carcinoma. They are the result of a temporary hormonal dysfunction. Prophylactic hysterectomy, however, should be performed, if adenomatous or atypical hyperplasia appears in older postmenopausal women with the indicators of high risk of endometriumcarcinoma as mentioned above.     

Sinusoidal capillarization of human hepatocellular carcinoma: possible promotion by fibroblast growth factor

Expression of acidic and basic fibroblast growth factors (aFGF and bFGF) and von Willebrand factor (vWF) was immunohistochemically investigated in 55 nodules of human hepatocellular carcinoma (HCC), 15 nodules of adenomatous hyperplasia (AH) of the liver and 10 cirrhotic livers (LC). AH, a putative preneoplastic lesion in the cirrhotic liver, was subdivided into ordinary and atypical types: the former was characterized by little cellular and structural atypia and the latter had some atypia equivocal as to benignity and malignancy. The positive rates of FGF (aFGF and/or bFGF) were as follows: 0% in LC, 20% in AH (ordinary and atypical) and 42% in HCC, whereas the positivity of vWF was 10% in LC, 20% in ordinary AH, 30% in atypical AH and 40% in HCC. There was no correlation between the expression of FGF or vWF and the size of HCC. No correlation was also found between the positivity of FGF and that of vWF in HCC and atypical AH. While vWF was not constantly expressed in the vicinity of FGF-positive HCC cells, capillarized sinusoids were significantly more numerous in FGF-positive cases than in FGF-negative cases (p < 0.01). These data indicate that FGF may be pathogenetically linked to the multistep development of HCC in relation to sinusoidal capillarization.     

Early HCC and adenomatous hyperplasia: evaluation of arterial and portal blood flow with CTA, CTAP, and pathologic correlation

In order to analyze the hemodynamic properties of early hepatocellular carcinoma (HCC) and adenomatous hyperplasia (AH), three lesions (two HCCs, one AH) depicted as hypoattenuating at CTA and iso attenuating at CTAP were correlated with the histopathological findings. The number of normal hepatic arteries in the tumor was lower than in the liver. Degeneration and narrowing of the lumens were also seen microscopically. All tumors showed the replacing growth pattern and had similar numbers of the portal tracts in the tumor to the liver. The decreased number of intratumoral normal arteries is suspected to be a characteristic finding of the early stage of HCC.     

Distinction of basaloid carcinoma of the prostate from benign basal cell lesions by using immunohistochemistry for bcl-2 and Ki-67

The distinction of rare basaloid carcinomas (BC) of the prostate from more common basal cell hyperplasia may be difficult, because basal cell hyperplasia (BCH) may have prominent nucleoli and may appear infiltrative. Using immunohistochemistry, we studied bcl-2 and p53 expression and Ki-67 proliferation index in eight cases of typical BCH, eight cases of BCH with nucleoli, and six cases of BC. Bcl-2 expression (P < .0001) and Ki-67 index (P=.005) were elevated in BC compared with typical BCH or BCH with nucleoli, whereas there was no significant difference between typical BCH and BCH with nucleoli. P53 was not discriminative in separating benign from malignant basal cell lesions of the prostate. Bcl-2 may play a role in the pathogenesis of basal cell lesions of the prostate. Elevated expression of bcl-2 and higher Ki-67 index may aid in the diagnosis of basal cell proliferative lesions of the prostate.     

Adenoid basal epitheliomas of the uterine cervix: a reevaluation of distinctive cervical basaloid lesions currently classified as adenoid basal carcinoma and adenoid basal hyperplasia

A series of 12 adenoid basal carcinomas and three adenoid basal hyperplasias of the cervix were analyzed. The ages of the patients with adenoid basal carcinoma ranged from 30 to 91 years with a mean of 71 years. Pap smear results for 11 of 12 (92%) were abnormal. Almost all patients were asymptomatic. None had a gross cervical tumor. All tumors had typical histologic features of adenoid basal carcinoma, with various degrees of squamous differentiation. Depth of tumor invasion ranged from 2 mm to 10 mm (mean, 4.3 mm; median, 3.7 mm), exceeding 3 mm in six tumors (50%). Tumor volume was >500 mm3 in four tumors (33%). An associated neoplastic squamous lesion was present in 92% of patients, including high-grade cervical intraepithelial neoplasia in 10 cases and microinvasive squamous cell carcinoma in one. Treatment was predominantly surgical, usually after some form of cervical conization; conization alone was performed in three patients. Lymph nodes were removed in five patients; none of 104 nodes had metastases. No recurrence of tumor developed in any patient. Nine patients were alive without disease after 4 to 82 months (mean, 30 months), and three died without disease after 24, 63, and 87 months. The three patients with adenoid basal hyperplasia also were asymptomatic and did not have a gross cervical lesion. Pap smear results for two patients were abnormal. The adenoid basal hyperplasias were incidental, very superficial lesions that resembled small adenoid basal carcinomas. Generally, they were attached to the squamous or endocervical mucosal epithelium; all were less than 0.5 mm in depth. Treatment was hysterectomy in one patient and conization in two. Follow-up was short but uneventful. Our findings, together with those previously reported, indicate (1) adenoid basal carcinoma with typical histologic features is not a malignant neoplasm in that it typically presents in asymptomatic women, usually is discovered after an abnormal Pap smear result due to cervical intraepithelial neoplasia, does not produce a grossly visible lesion, has never metastasized to regional lymph nodes or elsewhere, and has never itself caused death; (2) rare, histologically atypical tumors with distinctly malignant features should not be regarded as adenoid basal carcinoma; and (3) adenoid basal hyperplasia probably is a small adenoid basal carcinoma. We propose the term "adenoid basal epithelioma" to replace adenoid basal carcinoma and adenoid basal hyperplasia, because it better describes the clinicopathologic features of these distinctive lesions and their excellent prognosis and may reduce the likelihood of unnecessarily aggressive treatment.     

Fine needle aspiration biopsy of breast carcinoma in pregnancy and lactation

OBJECTIVE: To delineate the cytomorphologic features seen in cancer of the breast during pregnancy and lactation, to compare them to the cytomorphologic parameters in benign conditions and to determine the feasibility of differentiating features of malignant breast carcinoma from those of benign breast lesions during pregnancy. STUDY DESIGN: The study group consisted of pregnant or lactating women with breast carcinoma and with benign breast lesions who underwent fine needle aspiration (FNA) of the breast lesions. The findings of FNA were reviewed, analyzed, tabulated and correlated with the pathologic diagnosis of the breast biopsies. RESULTS: Eleven patients had malignant cytomorphologic changes, including increased cellularity, multilayering, enlarged and pleomorphic nuclei, single or multiple nucleoli, mitosis and numerous isolated tumor cells. Secretory changes were scanty. The background was foamy and necrotic. FNA of the benign lesions showed a biphasic cell pattern with cohesion; minimal nuclear pleomorphism; single, regular nucleoli; and naked nuclei in a granular background with foamy macrophages. Increased cellularity with nuclear atypia, single cells and a dirty background was seen in benign and malignant conditions. CONCLUSION: The main cytologic features that differentiate breast carcinoma from benign conditions during pregnancy and lactation are crowding and overlapping of nuclei, dyscohesion and enlarged, pleomorphic nuclei with irregular nuclear membranes, coarse nuclear chromatin and mitoses. Pregnancy-related hyperplastic changes with atypia can potentially result in a false positive diagnosis of carcinoma.     

Severe atypical endometrial changes and sequential contraceptive use

Of eight young women, seven had a diagnosis of well-differentiated endometrial adenocarcinoma and one had atypical endometrial hyperplasia. The average age was 40.1 years, with 6.04 years of dimethisterone-ethinyl estradiol (Oracon) sequential contraceptive use. The patients were not typical of those in whom endometrial carcinoma develops. Although these cases do not prove that long-term administration of dimethisterone-ethinyl estradiol causes endometrial adenocarcinoma or atypia, they indicate that it may do so.     

PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma

The two most common types of genetic alterations yet identified in uterine endometrioid carcinoma (UEC) are PTEN mutations and microsatellite instability (MI). Furthermore, MI-positive UECs (defined as tumors with detectable alterations at two or more different microsatellite loci) are significantly more likely to contain PTEN mutations than are MI-negative UECs. To determine whether PTEN inactivation is a relatively early event in endometrial tumorigenesis, we evaluated complex atypical hyperplasia (CAH), the direct precursor to UEC, for the presence of PTEN mutations. Mutations were present in 3 of 11 (27%) CAHs with synchronous UEC and in 4 of 18 (22%) CAHs that were not associated with invasive carcinoma. One case with synchronous CAH and UEC contained a germ-line PTEN mutation. In addition, we evaluated the same series of CAHs for MI. We identified four MI-positive CAHs with synchronous UEC but did not detect the MI phenotype in any CAHs without associated invasive carcinoma. A PTEN-mutant (germ-line mutation) MI-negative CAH was synchronous with a PTEN-mutant MI-positive UEC. These results suggest that mutation of PTEN can be an early event in the pathogenesis of UEC and may precede the development of the MI phenotype in a subset of cases.     

Pathomorphologic characteristics and differential diagnosis of small hepatocellular carcinoma

Recent advances in various diagnostic imagings have made possible early diagnosis of hepatocellular carcinoma (HCC). Grossly, small HCCs of the early stage up to around 1.5 cm in diameter are vaguely demarcated from surrounding liver tissue. Such minute tumors are classified as small HCC with indistinct margins. Histologically, these tumors consist of uniform distribution of well-differentiated cancerous tissues, which are characterized by increased cell density with increased nuclear/cytoplasmic ratio, irregular thin-trabecular pattern with occasional pseudoglandular structure, and frequent fatty and/or clear cell change. In all small HCCs with indistinct margins, varying numbers of portal tracts are contained within the cancerous tissues. None of them represents invasion of the portal vein or intrahepatic metastasis. Thus, small HCC with indistinct margins is considered to be HCC of the earliest stage that can be clinically detected at this moment. Along with the increase of resected small HCCs, hyperplastic lesions such as adenomatous hyperplasia (AH) and atypical AH, which are difficult to differentiate from well-differentiated HCC have also been found. Atypical AH is considered a borderline malignancy. Some focal nodular hyperplasias and liver cell adenomas are also difficult to differentiate from well-differentiated HCC. It should be recalled that some metastatic tumors such as carcinoid tumor, renal cell carcinoma and hepatoid adenocarcinoma also resemble HCC.     

The human lysyl oxidase-related gene (LOXL2) maps between markers D8S280 and D8S278 on chromosome 8p21.2-p21.3

OBJECTIVE: bcl-2 is a protein which prohibits programmed cell death. The purpose of this study was to determine whether bcl-2 staining was related to traditional prognostic factors and/or recurrence in patients with endometrial carcinoma. METHODS: One hundred twenty consecutively surgically treated patients with endometrial carcinoma had their tumors studied immunohistochemically for bcl-2 staining. RESULTS: The mean follow-up of the patients was 53 months with a median of 56 months (range 30 to 68 months). bcl-2 staining was positive in 44.0% of patients with endometrioid carcinomas and in 23. 1% of patients with nonendometrioid carcinomas (P < 0.001). Increasing depth of invasion (P = 0.014), grade (P = 0.011), and FIGO stage (P = 0.018) were each correlated with decreasing bcl-2 staining. bcl-2 staining was positive in 44.1% of patients whose tumors showed no lymphovascular space invasion and in 11.1% of patients with lymphovascular space invasion (P < 0.001). Only 1 of 26 patients with recurrent disease had persistence of bcl-2 staining. Multivariate analysis revealed FIGO stage (P = 0.0051), histologic grade (P = 0.050), and lack of staining for bcl-2 (P = 0.012) to be independent predictors of recurrence. CONCLUSION: bcl-2 persistence is more common in endometrioid than in nonendometrioid adenocarcinomas of the endometrium. It appears to be inversely correlated with the universally recognized prognostic factors of depth of invasion, histologic grade, and FIGO stage. Lack of bcl-2 persistence was an independent predictor of recurrence of disease. This group of patients continues to be followed to determine the role of bcl-2 persistence or lack of persistence as a predictor of 5-year survival of patients with endometrial carcinoma.