Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer

Invasive cervical carcinomas almost invariably carry extra copies of chromosome arm 3q, resulting in a gain of the human telomerase gene (TERC). This provided the rationale for the development of a multicolor fluorescence in situ hybridization (FISH) probe set as a diagnostic tool for the direct detection of TERC gains in Pap smears. We previously used this probe set to show that cervical intraepithelial neoplasia (CIN) 2 and CIN3 lesions could be distinguished from normal samples, atypical squamous cell of undetermined significance (ASCUS) and CIN1, with a sensitivity and specificity exceeding 90%, independent of the cytomorphological assessment. In the current study, we explored whether gain of 3q and amplification of TERC could predict progression from CIN1/CIN2 to CIN3 and invasive carcinoma. We applied our probe set to a series of 59 previously stained Pap smears for which repeat Pap smears and clinical follow-up were available. The samples included CIN1/CIN2 lesions that progressed to CIN3 (progressors), CIN1/CIN2 lesions that regressed spontaneously (regressors), and normal Pap smears from women who subsequently developed CIN3 or cervical cancer. Here, we show that progressors displayed a gain of 3q whereas none of the regressors showed this genetic aberration. These data suggest that 3q gain is required for the transition from CIN1/CIN2 to CIN3 and that it predicts progression. Of note, 3q gain was found in 33% of cytologically normal Pap smears from women who were diagnosed with CIN3 or invasive cervical carcinoma after a short latency. The sensitivity of our test for predicting progression from CIN1/CIN2 to CIN3 was 100% and the specificity, ie, the prediction of regression, was 70%. We conclude that the detection of 3q gain and amplification of TERC in routinely collected Pap smears can assist in identifying low-grade lesions with a high progression risk and in decreasing false-negative cytological screenings.     

Association between micronucleus frequency and cervical intraepithelial neoplasia grade in Thinprep cytological test and its significance

A micronucleus is an additional small nucleus formed due to chromosomes or chromosomal fragments fail to be incorporated into the nucleus during cell division. In this study, we assessed the utility of micronucleus counting as a screening tool in cervical precancerous lesions in Thinprep cytological test smears under oil immersion. High risk HPV was also detected by hybrid capture-2 in Thinprep cytological test smears. Our results showed that micronucleus counting was significantly higher in high-grade squamous intraepithelial lesion (HSIL) and invasive carcinoma cases compared to low-grade squamous intraepithelial lesion (LSIL) and non-neoplastic cases. Receiver operating characteristic (ROC) curve analysis revealed that micronucleus counting possessed a high degree of sensitivity and specificity for identifying HSIL and invasive carcinoma. Cut-off of 7.5 for MN counting gave a sensitivity of 89.6% and a specificity of 66.7% (P = 0.024 and AUC = 0.892) for detecting HSIL and invasive carcinoma lesions. Multiple linear regression analysis showed that only HSIL and invasive cancer lesions not age, duration of marital life and number of pregnancy are significantly associated with MN counting. The positive rate of high risk HPV was distinctly higher in LSIL, HSIL and invasive cancer than that in non-neoplstic categories. In conclusions, MN evaluation may be viewed as an effective biomarker for cervical cancer screening. The combination of MN count with HPV DNA detection and TCT may serve as an effective means to screen precancerous cervical lesions in most developing nations.     

Fine needle aspiration cytology of benign breast lumps: a review of experience with 651 cases

A detailed cytomorphologic study was done on fine needle aspiration smears from 651 benign breast lumps. Cytological categorization enabled the distinction of proliferative from non-proliferative and infective lesions in the majority of the cases. Lumpectomy provided the histological diagnosis in 584 cases, most of which were proliferative lesions. Gross cystic disease and fibroadenoma were the most common lesions encountered. Microcysts with apocrine change, sclerosing adenosis, proliferative disease without atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ were associated with the dominant lesion in many of the cases. In all these cases, retrospective analysis of the cytological smears was done in an attempt to identify cytological features which may indicate these lesions.     

Stereotactic fine needle aspiration biopsy (SFNB) of breast: preliminary results in Perth with the TRC mammotest machine. Cytological aspects.

Stereotactic fine needle aspiration biopsy (SFNB) was carried out on 404 mammographically detected impalpable breast lesions from 389 women between October 1988 and January 1990. Seventy-three lesions were excised, and 38 were carcinomas. Thirty-six of the 38 carcinomas had been diagnosed as atypical, suspicious or malignant by cytology; in the remaining 2 only fat and fibrous tissue were present in smears. The sensitivity of cytological diagnosis in detecting malignancy was therefore 94.8% (36 of 38 cases). A cytological diagnosis of malignancy was made in 23 cases (5.7%) and in 5 (1.2%) the findings were suspicious of malignancy. All of these were confirmed as carcinoma histologically; the predictive value of a positive cytological diagnosis was therefore 100%. In 32 cases (7.9%) the cytological findings were atypical but inconclusive. Twenty-three of these lesions were excised, and 8 proved to be carcinoma (34.8%). No case assessed radiologically and cytologically as benign has subsequently proven to be malignant. Twenty-two of 28 cases of invasive carcinoma were given an unequivocal cytological diagnosis of malignancy; 2 were suspicious of malignancy, and in 3 the findings were atypical but inconclusive. Of the 10 pure duct carcinoma-in-situ (DCIS) lesions, (26.3% of the cancers) 1 was diagnosed cytologically as malignant, 3 as suspicious of malignancy, and 5 as atypical. The sensitivity of SFNB in detecting DCIS lesions was therefore similar to invasive carcinomas, but cases of DCIS were more likely to be given a suspicious or atypical diagnosis rather than a definite diagnosis of malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Undetected invasive lobular carcinoma of the breast: review of false-negative smears

Analysis of a series of 34 fine-needle aspirations (FNA) from 28 patients with invasive lobular carcinoma (ILC) was undertaken. The false-negative smears were reviewed to reveal the cause of such a relatively frequent error. This was a retrospective study and comparison between the cytological and pathological findings in a series of 34 FNA. Three cases were excluded without sufficient material. Twelve cases were positive, nine suspicious of malignancy, and 10 were considered false-negatives. In a second analysis of this later group, one was reclassified as carcinoma, two reconsidered without sufficient material for diagnosis, and the remaining seven, still considered negatives, constituted the core of this study. Of these seven, there were none with hypercellular smears and in six there was a predominance of fat-tissue fragments. The scarce epithelial component showed honeycomb-flat sheets in four, loose clusters in three, small and tight clusters with irregular limits in six, and more than 10% of isolated epithelial cells (noncohesive cells) in one case. "Staghorns" were undetected and myoepithelial cell nuclei were very scarce in all cases. Some nuclear enlargement was detected in one, angulated nuclear contour in three, and nuclear crowding was present in five. All seven had fine, homogeneous chromatin, without prominent nucleoli. Cytoplasmic limits were undefined in all but one (6/7) and occasional cytoplasmic vacuolization was detected in two. Hypocellular smears with few, small, and dense groups (but always with more than 10 groups in at least one smear) can be related with ILC. In these cases, further studies are recommended to exclude malignancy. The loose cluster and flat sheets identified in four cases represent a benign epithelial hyperplasia mixed with the ILC.     

43例腮腺Warthin 瘤的细针穿刺细胞学分析

目的：探讨腮腺腺淋巴瘤的细针穿刺细胞学特点。方法：收集并复习43例腮腺腺淋巴瘤，每例均备有巴氏染色、HE染色涂片及细胞块。结果：43例均发现嗜酸性细胞及淋巴细胞，40例发现细胞碎屑，9例发现带有淋巴间质的嗜酸性细胞乳状结构，35例发现巨噬细胞，5例出现鳞状上皮化生，3例发现肥大细胞。结论：腺淋巴瘤是腮腺的常见肿瘤，细针穿刺一般可以作出准确诊断，但应注意与多形性腺瘤、腺样囊腺癌、腺泡细胞癌、慢性腮腺炎、淋巴上皮囊肿、鳞癌鉴别。     

Atypical ductal hyperplasia and atypia of uncertain significance in core biopsies from mammographically detected lesions: correlation with excision diagnosis

AIMS: To assess: (1) the prevalence of reporting of atypical ductal hyperplasia (ADH) and intraductal atypia of uncertain significance (AUS) in a series of core biopsies from mammographically detected lesions, (2) the proportion of cases where excision revealed breast carcinoma, and (3) whether any diagnoses should be revised on review. METHODS: Breast core biopsy reports from the Sir Charles Gairdner Hospital Breast Assessment Centre for the years 1999-2000 were retrieved. Slides from cases reported as ADH or AUS were reviewed as well as slides from the excision biopsies. RESULTS: There were 1048 core biopsies from 911 women. Breast carcinoma was diagnosed in 197 samples (18.8%) including 88 with invasive carcinoma (8.4%), 109 with ductal carcinoma in situ (DCIS) (10.4%). Three biopsies (0.3%) 'suspicious' of invasive carcinoma proved to be so. Of 52 samples (5.0%) with a diagnosis of ADH or AUS, 46 were excised, showing seven invasive carcinomas, 15 DCIS, 11 ADH, two lobular carcinoma in situ (LCIS), nine fibrocystic change (FCC), one mucocoele-like lesion and one fibroadenoma. The 22 malignancies represented 47.8% of the excised lesions. On review, seven of the 52 original core diagnoses were downgraded to benign hyperplasia. Five underwent excision, revealing two FCC, one complex sclerosing lesion, and two incidental lesions unrelated to the mammographic abnormality, including a microscopic tubular carcinoma and a focus of LCIS. In one case reviewed as unsatisfactory, excision showed invasive carcinoma. Lesions of particular interest included a case of high-grade DCIS with local regression in the core biopsy (so-called 'bumt out DCIS'), and one case diagnosed on excision as micropapillary ADH, where the review diagnosis was micropapillary DCIS. CONCLUSIONS: ADH and AUS were reported in 5.0% of biopsies. There was a high rate of carcinoma (47.8%) in subsequent excisions. Very few diagnoses were revised on review. Current protocols for excision of lesions with a 14-gauge core biopsy diagnosis of ADH/AUS appear justified. Literature review suggests that vacuum-assisted core sampling with 11-gauge needles will not remove the need for excision. Further study of local regression of DCIS and micropapillary lesions will be worthwhile.     

Papillary cystic type of acinic cell carcinoma of parotid: fine needle aspiration cytological features of a high grade variant with oncocytic metaplasia

A 60-year-old female developed a right parotid swelling six months after surgery for intra-oral squamous cell carcinoma. Fine needle aspiration (FNA) cytological smears showed dissociated large and small pleomorphic tumour cells with abundant mitoses and oncocytic features. A cytological diagnosis of parotid acinic cell carcinoma (ACC) was made. Histological study of the subtotal parotidectomy specimen showed a papillary cystic variety of acinic cell carcinoma (ACC-PCV). FNA cytological features in this case of ACC-PCV differs from the two previously reported cases in that it showed prominent oncocytic and high grade features and absence of papillary pattern in the cytological smears. ACC-PCV is an uncommon tumour and knowledge of its varied FNA cytological features is important for the diagnosis of this neoplasm.     

Histological precision of stereotactic core biopsy in diagnosis of malignant and premalignant breast lesions

The reliability of stereotactic core biopsy in the diagnosis of malignant and premalignant breast lesions was assessed in comparison to excision biopsy in patients with non-palpable suspicious breast lesions detected in a mammography breast screening programme. Fifty-two cases of malignancy and nine of atypical ductal hyperplasia were diagnosed on the programme during the two year period July 1993 to June 1995; two patients did not have excision biopsy. Stereotactic core biopsies and representative sections from 59 excision specimens from the same patients were assessed ‘blind’ by one pathologist. All 51 cancers diagnosed on stereotactic core biopsy were confirmed to be malignant on excision biopsy. There was 96% concordance between stereotactic core biopsy and excision biopsy for the diagnosis of invasive or in situ cancer, and 78% concordance for the type of cancer. The stereotactic core biopsy and excision biopsy diagnoses were: invasive ductal carcinomas (39 on stereotactic core biopsy vs. 33 on excision biopsy), mucinous carcinomas (1 vs. 2), invasive lobular carcinomas (3 vs. 8), and in situ carcinomas (8 vs. 8), two of which had invasive cancer present only in the stereotactic core biopsy. Of the nine cases of atypical ductal hyperplasia diagnosed on stereotactic core biopsy, eight had an excision biopsy, six showed low nuclear grade in situ or invasive cancer, one had a 3mm focus of high grade invasive ductal cancer and one was atypical ductal hyperplasia. In the invasive ductal carcinoma group stereotactic core biopsy underestimated tumour grade: in nine cases (31%) the cancer at excision was of a higher grade. Stereotactic core biopsy is a reliable alternative to excision biopsy in the diagnosis of breast cancer, however, stereotactic core biopsy may underestimate tumour grade in invasive ductal carcinoma and may not differentiate between invasive ductal carcinoma and lobular carcinoma. It is recommended that the diagnosis of atypical ductal hyperplasia on stereotactic core biopsy be followed by excision biopsy, as stereotactic core biopsy underestimates the presence of cancer in this group.     

Exfoliative cytology of adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix

Cervical scraping smears from two cases of histologically confirmed adenoma malignum of the uterine cervix were reviewed. In one case, several irregular sheets of benign-appearing glandular cells with slightly enlarged nuclei, conspicuous nucleoli, and clear cytoplasm were found. In the other case, in addition to sheets of benign-appearing glandular cells, there were clustered malignant glandular cells with prominent nucleoli. The sheets of benign-appearing glandular cells in both cases displayed wispy cytoplasmic extensions or “tails.” Cytologic differential diagnosis with other glandular lesions of the cervix such as clear cell carcinoma, microglandular hyperplasia, diffuse laminar glandular hyperplasia, tubal metaplasia, and well-differentiated invasive or in situ adenocarcinoma is briefly discussed. © 1995 Wiley-Liss, Inc.     

Ki-67 staining in histological subtypes of breast carcinoma and fine needle aspiration smears.

Thirty four cases of invasive breast carcinoma were analysed for heterogeneity of Ki-67 reactivity in a tumour, and proliferative activity in various histological subtypes was compared. The growth factions determined in areas of central and peripheral tumour were the same. Mucinous and lobular carcinoma showed lower Ki-67 activity than ductal carcinomas. When ductal carcinomas were subdivided according to their dominant growth pattern, the carcinomas with a solid or comedo growth pattern showed the highest proliferative activity. These results largely confirm data from previous cell kinetic studies on the incorporation of radioactively labelled thymidine. A correlation between the growth fraction determined by Ki-67 in fine needle aspiration smears and cryostat sections of corresponding tumours was shown, implying that the immunostaining of cytological smears gives a reliable impression of the growth fraction of a tumour and may therefore be used in prospective studies.     

Papillomas and atypical papillomas in breast core needle biopsy specimens: risk of carcinoma in subsequent excision

We sought to define the risk associated with papillomas and atypical papillomas in breast core needle biopsy specimens from a series of approximately 8,500 biopsies performed during 8 years. From a total of 62 papillary lesions (including papillomas and atypical papillomas), 40 (65%) had histologic follow-up. Overall, 15 (38%) of 40 patients had ductal carcinoma in situ (12 cases) or invasive carcinoma at excision (3 cases). Eight cases diagnosed as papilloma had benign follow-up. Slides were available for review in 38 cases and reclassified into benign papilloma with florid hyperplasia and no or minimal atypia (18 cases), papilloma with separate foci of atypical ductal hyperplasia (7 cases), and severely atypical papillomas "suspicious" for papillary carcinoma (13 cases). Carcinoma was identified in 0 (0%), 2 (29%), and 12 (92%) cases, respectively. We conclude that while atypical papillary lesions and papillomas with associated atypical ductal hyperplasia in breast core needle biopsy specimens are associated with a risk of carcinoma, lesions diagnosed as papilloma or papilloma with no or minimal atypia are benign and do not need to be excised.     

Cytopathological changes in human cervix and endometrium following prolonged retention of copper-bearing intrauterine contraceptive devices

Since 1971, cytological evaluation of cervical smears and endometrial aspirates was carried out in 604 women wearing CuT200 intrauterine contraceptive devices (IUDs) for periods ranging from 6 mo to 15 yr. No cases of cervical neoplasia or endometrial carcinoma were encountered, even after continuous use of the device for 15 years. Dysplastic cervical smears were, however, found in 45 postinsertional smears, and endometrial hyperplasia was detected in seven aspirates; in no cases was the dysplasia or hyperplasia higher than of moderate degree. Thirty-nine of the 45 women with postinsertional dysplastic smears were followed for 3-4 yr; in no case did the lesion progress to a higher grade or to frank malignancy. However, persistence and recurrence of dysplasia were seen in 10 women, necessitating removal of the IUDs. The incidence of cervical dysplasia and endometrial hyperplasia was found to be much higher when the IUDs had been changed than when the original devices were worn continuously. The rate of removal of IUDs because of persistent or recurring dysplasia was also much higher in the former group. Since no pregnancies were reported in any of the women wearing the original device for as long as 15 yr, we do not advocate the practice of changing the device at the end of 3 yr for maintaining contraceptive efficacy as recommended by the manufacturers; instead, we recommend the uninterrupted retention of the original device for periods not longer than 5 yr in view of occurrence of endometrial hyperplasia in two 6-yr wearers.     

Oral pemphigus vulgaris: Liquid‐based cytological findings and pitfalls

Pemphigus vulgaris (PV) is a chronic autoimmune bullous disease characterized by the formation of suprabasal cleavage and acantholysis. As this disease almost always affects the oral mucosa, conventional cytological smears of oral lesions can be used for the initial diagnosis of PV. We report two cases of PV that were initially diagnosed based on cytological smears of an oral sample. As atypical squamous cells were present even in the liquid‐based cytological (LBC) smears of the oral lesion in these two cases, this ultimately led to the misinterpretation of squamous cell carcinoma. These findings demonstrate that cytological mimicry of oral PV can occur in malignant cases when there is an absence of appropriate clinical information.     

Cytohistomorphological grading of breast carcinoma with special reference to apoptotic rates and lymph node metastasis

To analyze the significance of comparative evaluation of cytohistomorphological grading of infiltrating ductal carcinoma with specific reference to lymphnode metastasis status and apoptotic index. 50 patients who underwent FNAC and mastectomy for infiltrating ductal carcinoma were included in the study. Concordance between cytological and histological grades was calculated. Cytological smears were also evaluated for apoptotic rates and lymph node metastasis and then compared with the histological grades using regression analysis. Histological and cytological grades were comparable and statistically significant difference was found in the lymphnode metastasis rate and apoptotic index in the three cytological grades of the tumor. Moreover, by considering the apoptotic rates, the sensitivity of cytological grading significantly rose in relation to histological grade. With histological grade taken as the standard, cytology was found to be comparable but less sensitive for grading infiltrating ductal carcinoma. However, by considering lymphnode status and apoptotic rates as calculated on cytology, the sensitivity of cytological grading rose significantly in relation to histological grade. Therefore, apoptotic index incorporated with cytological grade may provide relevant information on the aggressiveness of invasive ductal carcinoma of breast and could be a useful parameter to take into consideration when selecting neo-adjuvant therapy.     

False-positive squamous cell carcinoma in cervical smears: cytologic-histologic correlation in 19 cases

Cytologic features of squamous intraepithelial lesions (SIL) can mimic those of invasive squamous-cell carcinoma. We compare and correlate the cytological findings of 19 false-positive squamous-cell carcinomas with follow-up cone biopsies or hysterectomy specimens to define which type of dysplasia is more prone to diagnostic errors on cervical Papanicolaou (Pap) smears. Out of 128 patients diagnosed with invasive squamous-cell carcinoma from 1994-2000, 19 (14.8%) with follow-up cone biopsies or hysterectomy specimens were false-positive cases, showing only cervical intraepithelial neoplasia (CIN). We reviewed tissue sections from these 19 cases of CIN for cytologic features of squamous-cell carcinoma, such as markedly pleomorphic and/or dysplastic squamous cells, necrosis, and nucleoli. Twelve of 19 patients (63%) were menopausal. The mean age was 50.5 yr. On review of cervical smears, 18 cases qualified for the cytologic diagnosis of squamous-cell carcinoma, keratinizing type, and one case qualified for squamous-cell carcinoma, nonkeratinizing type. Pleomorphic and/or keratinizing dysplasia was found in 15 out of 19 patients (79%), necrosis within superficial endocervical glands in 9 out of 19 patients (47%), and conspicuous nucleoli in 12 out of 19 patients (63%). One or more of these changes were seen in all but 2 patients (89%). Endocervical gland involvement was present and extensive in 18 of the 19 cases (94%). The mean age was older than expected for SIL (50.5 vs. a reported 40), and matched the mean age found in patients with invasive squamous-cell carcinoma. Pleomorphic and/or keratinizing dysplasia involving endocervical glands may exhibit the cytologic features of squamous-cell carcinoma on cervical Pap smears.     

The transition from hyperplasia to invasive carcinoma of the breast

The multistep model of carcinogenesis in the breast suggests a transition from normal epithelium to invasive carcinoma via non-atypical and atypical hyperplasia and in situ carcinoma. Within the breast, these proliferations are heterogeneous in their cytological and architectural characteristics. This review considers the evidence supporting a precursor role for these preinvasive lesions. Copyright © 1999 John Wiley & Sons, Ltd.     

Cytological grading of breast neoplasia and its correlation with histological grading

Cytological grading of breast cancer is not well established despite histological grading having gained a strong foothold. In our study we have analyzed 50 cases of breast carcinoma which included invasive ductal carcinoma, invasive lobular carcinoma, mucinous carcinoma, stromal sarcoma, apocrine carcinoma, papillary carcinoma. Papanicolaou smears were graded according to established Hunt's, Simplified Black and Modified Black grading systems. They were then compared with the Scarff Bloom Richardson grading system. Simplified Black grading system has been recommended for cytological grading of breast neoplasia because of its lucidity and its reproducibility. Cytological grading of breast neoplasia is important for neo adjuvant chemotherapy and also for predicting the prognosis of the patient on FNAC alone. Incorporation of other parameters like apoptosis and bcl-2 is also recommended.     

Epithelial proliferations of ductal type

The diagnosis of ductal proliferations requires analysis of both architectural and cytological features. Architectural characteristics of conventional ductal hyperplasia include persistence of the duct lumen as peripheral, crescent shaped spaces; streaming of cells; formation of irregular, slit-like fenestrations; and "maturation." Hyperplastic ductal cells exhibit indistinct cell borders, irregular placement of nuclei, irregular nuclear shapes, granular chromatin, and uniform small nucleoli. The cells do not show polarization or dishesion. Low-grade ductal carcinoma in-situ exhibits both architectural and cytological atypicality. The architectural atypicality takes two forms: the formation of cribriform spaces or their variants and the regular arrangement of cells. The former reflects the polarization of the carcinoma cells and the latter their dishesion. Cytological atypicality includes distinct cell borders; smoothly contoured, oval or round nuclei; homogeneous chromatin; and inconspicuous nucleoli. Atypical ductal hyperplasia shows low-grade cytological atypicality but lacks the architectural atypicality of ductal carcinoma in situ. Proliferations lacking cytological atypicality do not merit the diagnosis of atypical ductal hyperplasia whatever their architectural characteristics. Although not usually necessary, immunohistochemical staining for high molecular weight keratin can help resolve difficult cases. Current evidence does not support the belief that conventional ductal hyperplasia represents an obligate precursor to ductal carcinoma in situ.