Cytologic findings in endometrial hyperplasia

The cytologic findings in 15 endometrial hyperplasias were compared with those of normal endometrium and well-differentiated endometrial adenocarcinoma. Differences in tumor diathesis, hypercellularity, uneven internuclear distance, severe piling up of nuclei, anisokaryosis, nuclear size and macronucleoli were the main cytologic findings that were noted among the three conditions. These features varied in the different types of endometrial hyperplasia. It is not clear that these cytologic findings can be used to cytologically diagnose endometrial hyperplasia because some of the findings involve subjective judgments by different cytologists. Further studies on larger series of cases will be necessary to establish the cytologic criteria for the correct interpretation of endometrial abnormalities.     

Potential of the learning vector quantizer in the cell classification of endometrial lesions in postmenopausal women

OBJECTIVE: To investigate the potential of artificial neural networks for cell identification in endometrial lesions from postmenopausal women. STUDY DESIGN: The study was performed on cytologic material obtained by the Gynoscann endometrial cell samplerfrom 12 cases of atrophic endometrium, 48 cases of hyperplasia without cytologic atypia (18 cases of simple hyperplasia and 30 cases of complex hyperplasia), 12 cases of hyperplasia with cytologic atypia (complex atypical hyperplasia) and 48 cases of adenocarcinoma (30 cases of well-differentiated, 12 cases of moderately differentiated and 6 cases of poorly differentiated carcinoma). From each case approximately 100 cells were examined using a custom image analysis system. A learning vector quantizer (LVQ) identified the collected data. RESULTS: Investigation of cells from Endometrial Alterations with LVQ proved that according to the nuclear characteristics, as expressed by morphometric and textural measures, the endometrial cells from postmenopausal women may be identified as belonging to one of thefollowing three groups: atrophy, hyperplasia without cytologic atypia (simple and complex hyperplasia) and malignant neoplastic lesions (atypical complex and adenocarcinoma). CONCLUSION: The role of nuclear morphologic features in the cytologic diagnosis of endometrial alterations was confirmed. The overlap in thefeature space observed indicates that cell characteristics do not form strictly separate clusters. Thatfact explains the difficulty that morphologists have with the reproducible identification of cells from endometrial lesions in postmenopausal women. Application of LVQ offers a good classification at the cell level and promises to be a powerful toolfor classification on the individual patient level andfor the clarification of the natural history of endometrial pathology.     

Stereotaxic fine needle aspiration cytology of clinically occult malignant and premalignant breast lesions

Stereotaxic fine needle aspiration (FNA) cytology was used to study clinically occult (nonpalpable) breast lesions in 114 consecutive patients with mammographically suspicious findings prior to excisional biopsy. The aspirate contained insufficient material for cytologic evaluation in 15 cases (13.2%), which were histologically diagnosed as benign (7 cases), atypical hyperplasia (7 cases) or carcinoma in situ (1 case). The cytologic findings indicated a benign lesion in 77 cases (67.5%), which were histologically diagnosed as benign (71 cases) or atypical ductal hyperplasia (6 cases). The cytologic sample showed atypia in eight cases (7.0%), which were histologically diagnosed as severe atypical ductal hyperplasia (three cases), carcinoma in situ (one case) or proliferative fibrocystic disease (four cases). In the eight cases (7.0%) cytologically interpreted as probably malignant, histology confirmed six invasive carcinomas, one carcinoma in situ and one fibrocystic disease. Of six cases (4.4%) cytologically reported as malignant, five were histologically diagnosed as invasive carcinoma and one as carcinoma in situ. Overall, stereotaxic FNA cytology reported as malignant or probably malignant 14 of the 15 cases with a histologic confirmation of malignancy, for a sensitivity of 93.3%. Cytology correctly identified 78 of the 83 histologically negative cases, for a specificity of 94.0%. The 16 cases histologically diagnosed as ductal hyperplasia, which carries a high risk for subsequent malignancy, were studied in detail in an effort to define histologic and cytologic criteria for this entity. Using selected histologic criteria, 11 of these cases were graded as showing mild-to-moderate atypical hyperplasia and 5 as showing severe atypical hyperplasia. Three of the latter cases were similarly identified by an analogous cytologic grading; the other two cases had insufficient cytologic samples. The total results in this series of 114 cases support the use of stereotaxic FNA cytology in the diagnosis of these nonpalpable breast lesions, examples of which are illustrated. In particular, it may help to raise the low specificity yielded by mammography alone, which would represent a significant advance for the patient in terms of the accuracy, expediency and reduced cost of diagnosing these lesions.     

Significance of cytologically normal endometrial cells in cervical smears from postmenopausal women

OBJECTIVE: To determine the significance of cytologically normal endometrial cells in cervicovaginal (CV) smears from postmenopausal women over age 55 years. STUDY DESIGN: From January 1995 to January 1998, 220 women had CV smears demonstrating cytologically normal endometrial cells. The menopausal status, hormone replacement therapy (HRT) and information related to subsequent CV smears and endometrial sampling within 12 months of the initial diagnosis was recorded. RESULTS: Eighty-one of the 220 cases (36.8%) had histologic sampling of the endometrium. Thirty-four of 81 (42%) showed no endometrial pathology. Endometrial pathology was identified in 28 of 81 (34%), of which 19 were endometrial polyps (23.4%), 4 were endometrial hyperplasia (4.9%), 4 were endometrial carcinoma (4.9%) and 1 was a leiomyoma (1.2%). Nineteen (23.4%) were insufficient for diagnosis. Ninety-one of 220 women were on HRT, and 129 were not. In the group without HRT, endometrial disease was identified in 22/51 (43%) cases as compared to 6/30 (20%) in the group with HRT (P < .001). Endometrial carcinoma was identified in three (5.8%) cases and one (3.3%) case without and with HRT, respectively. CONCLUSION: Although the finding of normal endometrial cells in Pap smears from postmenopausal women was without any clinical significance in the majority of women in this study, in a small number it was associated with endometrial hyperplasia and carcinoma. Women who were not on HRT had a higher incidence of endometrial pathology.     

The premalignant disease of the endometrium: endometrial intraepithelial neoplasia

The WHO 1994 classification for endometrial hyperplasias is based on the morphologic features of the lesions. This system characterizes the nuclear cytologic morphology as typical or atypical and describes the glandular architectural pattern as simple or complex. The main problem of this classification is the poor reproducibility. Although the predictive value of the atypical category is high, there are many typical hyperplasia cases with cancer progression. Modern molecular data related to endometrial tumorigenesis and precise computerized morphometric analysis have identified the lesion that may be considered as a precursor of endometrioid adenocarcinoma. By definition, this endometrial intraepithelial neoplasia (EIN) is a clonal proliferation of architecturally and cytologically altered endometrial glands which are prone to malignant transformation to endometrioid (type I) endometrial adenocarcinoma. The morphometric basis of EIN diagnosis is the D-score (DS), which is a logical combination of three morphometric features that represent the glandular complexity, glandular volume and cytological alterations. PTEN inactivation and K-ras mutation are the earliest genetic changes that can be revealed in these lesions. Hyperplasia cases that do not fit into the EIN categories are considered as benign or hormonal endometrial hyperplasia. This is the theoretical basis of a new classification system in premalignant endometrial diseases. Retrospective clinical data proved the high predictive value of the EIN scheme, so the decision on therapy can be more established. The reproducibility is excellent with application of precise definitions and PTEN immunohistochemistry. In the "Blue book" published in 2003 the WHO introduces the new morphometric- and molecular-based EIN system, and recommends it as an alternative classification method.     

Diagnostic utility of galectin-3 in aspirates of thyroid follicular lesions

OBJECTIVE: To investigate the expression of galectin-3 in various thyroid follicular lesions, including diffuse hyperplasia, nodular hyperplasia, and benign and malignant follicular neoplasms, to clarify the diagnostic utility of galectin-3 in aspirates of follicular lesions. STUDY DESIGN: A total of 146 follicular lesions diagnosed cytologically, obtained from patients who had undergone thyroidectomy for either benign or malignant nodules, were evaluated using Papanicolaou-stained slides and cell blocks with galectin-3 immunostaining. We primarily categorized the aspirated specimens as benign, indeterminate or suspicious for a follicular neoplasm based on cellularity, architectural arrangement of the follicular cells and presence or absence of colloid. Galectin-3 immunostaining was evaluated according to the proportion and intensity of positively stained cells. Cytologic diagnoses were correlated with the results of galectin-3 and categorized into 3 groups (benign, indeterminate for malignancy, suspicious for malignancy) and compared with the corresponding histologic diagnoses. RESULTS: When the histologic diagnoses were compared with the cytologic diagnoses, the accuracy in the distinction between benign and malignant cases was 79.5% except for 8 cytologically and 3 histologically indeterminate cases. Except for 11 indeterminate cases, there were 18 (12.3%) discrepant cases. False positive cases included 8 of 62 (12.9%) nodular hyperplasias and 1 of 42 (2.4%) follicular adenomas. Of 9 false negative cases, 4 minimally invasive carcinomas and 2 widely invasive carcinomas were included. Three follicular tumors of uncertain malignant potential were cytologically categorized as malignant, and all cases showed positivity for galectin-3. CONCLUSION: Galectin-3 could be used as a useful supplementary marker for cytologic diagnosis, although it was not an absolute marker in determining whether a lesion was benign or malignant.     

Liquid-based endometrial cytology: cyto-histological correlation in a population of 917 women

OBJECTIVE: Liquid-based cytology, because of its capacity to reduce the obscuring factors and to provide thin-layer specimens, represents an opportunity to reevaluate endometrial cytology. In order to assess the utility of the liquid-based method in endometrial diagnosis, we evaluated its accuracy in comparison with histology. METHODS: Nine hundred and seventeen women scheduled for hysteroscopy were enrolled in the study. After providing informed consent, all the women proceeded sequentially to hysteroscopy, endometrial cytology and then biopsy endometrial sampling. RESULTS: Cyto-histological correlations were possible in 519 cases (57%): in 361 (39%) cases the biopsy was inadequate, in 15 (2%) the cytology was inadequate, and in 22 (2%) both were inadequate. At biopsy 25 (3%) women had adenocarcinoma, 5 (1%) had adenomatous atypical hyperplasia and 21 (2%) had simple non atypical hyperplasia. At cytology two adenocarcinomas and one adenomatous atypical hyperplasia were underrated as atypical hyperplasias and as non-atypical hyperplasia; two simple non-atypical hyperplasias were reported as negative; and eight cases were false positive (non-atypical hyperplasia at cytology, negative at biopsy). In our population, the cytology provided sufficient material more often than biopsy (P < 0.04). Sensitivity was estimated at 96%, specificity at 98%, positive predictive value at 86% and negative predictive value at 99%. CONCLUSIONS: We concluded that endometrial cytology may be an efficient diagnostic method. It could be applied to selected patients solely or in association with ultrasonography. The combination of these two noninvasive procedures may improve their diagnostic accuracy and reduce unnecessary hysteroscopies, thereby producing benefits for women and society.     

Digital imaging analysis of normal, hyperplastic and malignant endometrial cells in endometrial brushing samples

Sixty cytologic specimens obtained by endometrial brushing (using the Gynecyte device) were quantitated by digital imaging techniques. These samples included 25 from normal endometria, 6 from persistent proliferative endometria, 14 from cystic or adenomatous hyperplasias and 15 from carcinomas. The morphometric parameters surveyed included mean cell area, nuclear area, perimeter and long and short axes. The amount of hematoxylin dye in the nuclei was expressed by mean transmittance (mean of gray levels) and chromatin index (standard deviation of gray levels). The frequency distributions of cells derived from normal tissue and persistent proliferative endometrium were quite similar. The quantitative parameters of cystic and adenomatous hyperplasia, although intermediate between those of normal endometrium and carcinoma, were closer to the former than to the latter. Using stepwise discriminant analysis of the morphometric parameters, 83% of the specimens were correctly classified into the categories of normal/persistent proliferative, hyperplasia and carcinoma. The accuracy was improved to 88% when densitometric parameters were added. This study demonstrates the potential application of digital imaging techniques to the distinction and classification of normal, hyperplastic and malignant endometrial cells.     

Urinary cytology of tuberculosis of the bladder

The cytologic findings in the urinary sediment of 13 patients with tuberculosis (TB) of the bladder were compared with the histologic findings. TB was cytologically recognized in 11 patients because of the presence of epithelioid and/or Langhans' giant cells. The morphologic deviations of the urothelial cells and the urothelium were classified according to the criteria of Koss. The type I atypical urothelial cells found in ten patients were correlated to the urothelial hyperplasia found at histology; the follow-up data documented the benign reversible nature of the urothelial hyperplasia as the focal expression of the reactive potential of urothelium to various forms of inflammatory processes. The presence of type II atypical urothelial cells reflected moderate and severe atypia of the urothelium at biopsy. In order to assess the reactive, reversible or precancerous nature of these forms of atypia associated with TB, an accurate follow-up is necessary. Since TB of the bladder may cause the presence of atypical cells in the urine, this lesion is of special interest in the differential diagnosis between inflammatory processes and carcinoma.     

Exfoliative-cytologic diagnosis of basal-cell carcinoma, with the use of DNA image cytometry as a diagnostic aid

Eighty-four skin lesions clinically suspected of being basal-cell carcinomas were investigated by exfoliative cytology. Specific criteria were found for the cytologic diagnosis of basal-cell carcinoma. All 37 cases of basal-cell carcinoma were correctly classified cytologically and could be differentiated from the 8 cases of squamous-cell carcinoma. There were no false-positive or false-negative diagnoses. Insufficient cellular material was obtained in 17% of the cases. The technique for collecting exfoliated epidermal cells with a new swab is described. DNA image cytometry was used as a diagnostic aid in doubtful cases. DNA image cytometry showed that 83% of the basal-cell carcinomas had an aneuploid nuclear DNA content.     

Cystosarcoma phyllodes. Diagnosis by fine needle aspiration cytology.

The cytologic features of 10 benign, 2 borderline and 5 malignant phyllodes tumors were studied, and an attempt was made to correlate the cytologic findings with corresponding histologic categories. Seventy-five percent of the benign and borderline tumors were interpreted as benign cystosarcoma phyllodes on fine needle aspiration cytology. Eighty percent of the malignant phyllodes tumors were identified as malignant lesions cytologically. The cytologic features assessed were the epithelial:stromal ratio and morphology of the stromal component, including the degree of atypia, mitotic activity, capillary vessels traversing the stromal fragments, presence of foamy macrophages, histiocytic giant cells and bipolar naked nuclei. A diagnosis of phyllodes tumor was suggested cytologically by the presence of both epithelial and stromal elements; the stroma was present as cellular "phyllodes fragments" and isolated mesenchymal cells. The parameters suggesting malignancy were extreme paucity or absence of epithelial elements and stromal cells in diffuse sheets and clusters less cohesive than normal, with marked stromal atypia and mitotic activity.     

Diagnostic accuracy of liquid‐based endometrial cytology in the evaluation of endometrial pathology in postmenopausal women

C. Remondi, F. Sesti, E. Bonanno, A. Pietropolli and E. Piccione
Diagnostic accuracy of liquid‐based endometrial cytology cytology in the evaluation of endometrial pathology in postmenopausal women Objective: The aim of this study was to compare liquid‐based endometrial cytology with hysteroscopy and endometrial biopsy regarding its diagnostic accuracy in a series of postmenopausal women with abnormal uterine bleeding (AUB) or asymptomatic women with thickened endometrium assessed by transvaginal ultrasound as a screening procedure. Methods: Inclusion criteria were: menopausal status; the presence of AUB and/or thickened endometrium assessed by ultrasound (cut‐off 4 mm); a normal Papanicolaou (Pap) smear; and no adnexal pathology at ultrasound. Exclusion criteria were: previous endometrial pathology; and previous operative hysteroscopy. Of 768 postmenopausal women referred to our general gynaecology clinics, 121 fulfilled the inclusion criteria and were recruited to the trial. Twenty‐one refused to participate. Cytological sampling was carried out by brushing the uterine cavity using the Endoflower device with no cervical dilation and the vial was processed using a ThinPrep® 2000 automated slide processor. The slides were stained using a Pap method. Results: In 98 cases with histological biopsies, endometrial cytology detected five cases of endometrial carcinoma, 10 of atypical hyperplasia and 47 of non‐atypical hyperplasia; 36 cases were negative. In two cases cytology was inadequate because of uterine cervical stenosis. Taking atypical hyperplasia or worse as a positive test and outcome, the diagnostic accuracy of the endometrial cytology was 93.5%, with a sensitivity of 92% and specificity of 95%, a positive predictive value of 73% and a negative predictive value of 99%. All the carcinomas were detected by cytology. Only 42% of women with a positive diagnosis were symptomatic. The cytological sampling was well tolerated by all patients. No complication was registered. Conclusions: Liquid‐based endometrial cytology can be considered an useful diagnostic method in the detection of endometrial pathology as a first‐line approach, particularly if associated with transvaginal ultrasound.     

The cytodiagnosis of well-differentiated neuroendocrine carcinoma. A distinct clinicopathologic entity

Well-differentiated neuroendocrine carcinoma (WDNE) has been recognized as a distinct variant of pulmonary neuroendocrine carcinoma, with characteristic histopathologic and clinical features that separate it from both carcinoid and small-cell carcinoma (SCC). Histologic review of tumors in long-term survivors (greater than two years) with an initial diagnosis of SCC has shown that the majority of these cases are, in fact, better classified as WDNE; the distinction of WDNE from SCC has, therefore, important prognostic and therapeutic implications. A retrospective review of 200 cytologies originally diagnosed as SCC was undertaken in an attempt to characterize the cytomorphologic features of WDNE. The cytologic criteria that distinguished cases of WDNE included polygonal-to-fusiform cells with a variable amount of lacy cytoplasm, oval nuclei with coarsely dispersed chromatin and frequent chromocenters, and mild nuclear and cytoplasmic anisomorphism. The majority of malignant cells were arranged either in acinarlike clusters or in epithelial sheets with evidence of palisading. Twenty-two cases were reclassified cytologically as WDNE and were accurately distinguished from all other neoplastic and SCC cases on repeated double-blind review. Clinical and histologic data confirmed the diagnosis of WDNE in all cases; it can be concluded that SCC and SDNE are cytologically distinct entities.     

Endocyte endometrial smears in the cytodiagnosis of endometrial carcinoma

The cytologic diagnosis of endometrial cancer using material obtained with the Endocyte endometrial sampler was assessed for 874 patients. The samples obtained were smeared directly on slides for fixation and staining; the smears were more difficult to assess than cervicovaginal smears, however, due to the presence of blood, the small size and density of the cells and the flattened three-dimensional architecture of the tissue fragments obtained. Only 8.2% of the samples were classified as inadequate; repeat sampling in some of those cases produced diagnostic material. All 12 cases of carcinoma (including one case in a woman less than 40 years of age) were diagnosed by cytology as malignant; however, the original cytologic sample in one of those cases was inadequate. For the diagnosis of benign versus malignant, cytology had a sensitivity of 92%, a specificity of 100% and predictive value of 100%. Cytology also diagnosed as suspicious the smears from 5 of 13 cases of endometrial hyperplasia and 2 of the 9 cases of endometrial polyps. The cytologic findings for benign and malignant samples are described and illustrated in detail. Relative to other endometrial sampling devices, the Endocyte is inexpensive and was easily used by the gynecologist and well tolerated by the patients, with no complications and minimal discomfort.     

Subcutaneous endometriosis diagnosed by fine needle aspiration cytology

The fine needle aspiration cytology (FNAC) of two patients manifesting cutaneous/subcutaneous endometriosis is presented. Endometrial tissue sampled by the aspiration technique manifested different cytologic characteristics as compared to those of endometrial tissue obtained by standard exfoliative methods. A primary difference was the appearance of the endometrial cells in syncytial clusters in the aspirate, in contrast to the three-dimensional clusters seen in exfoliated material. These cases emphasize the need to include endometriosis in the differential diagnosis of palpable lesions of the abdominal wall, especially in women with healed surgical scars, and the role of FNAC in diagnosing such lesions.     

Cytologic study of noninvasive intraductal papillary-mucinous carcinoma of the pancreas

OBJECTIVE: To examine the cytologic features of noninvasive intraductal papillary-mucinous carcinoma (IPMC) in an attempt to differentiate it cytologically from hyperplasia, invasive IPMC and invasive ductal adenocarcinoma (IDA). STUDY DESIGN: Tumor samples from 23 patients clinically diagnosed with a mucin-producing tumor of the pancreas, including 10 cases of hyperplasia, 10 noninvasive IPMCs and 3 invasive IPMCs, and tumor samples from 21 patients with IDA, were examined cytologically. Cytologic specimens were obtained in various ways, such as by fine needle aspiration, imprint, brushing, vinyl tube aspiration and aspiration from a cannula at endoscopic retrograde cholangiopancreatography. RESULTS: Cytologically, all 10 noninvasive IPMCs exhibited clearly defined cytoplasmic boundaries (+1, ++4, ++ and mainly small nuclei (++7, +++3), with nuclear size and cytoplasm similar to those of hyperplastic cells, and irregular chromatin distribution (+2, ++8) and prominent nucleoli (-2, +4, ++3, +++1), all atypical nuclear features similar to those of invasive IPMC or IDA. There also were small papillary cohesive clusters (-1, +2, ++4, +++3) and euchromatin (+1, ++1, +++8), which were found only in IPMCs. CONCLUSION: The cytologic features of small, malignant nuclei and small papillary cohesive clusters are suggestive of noninvasive IPMC. Furthermore, the addition of clearly defined cell borders and euchromatin and the presence of some goblet cells are more strongly suggestive of noninvasive IPMC.     

Frequency of cytologic features in fine needle aspirates from histologically and cytologically diagnosed fibroadenomas

Identification of key cytologic criteria for various lesions by means of stepwise logistic regression is common today and is often claimed to facilitate cytologic diagnosis. As can be expected, there usually is good agreement between the selected criteria and those given in the cytologic literature. In a study by Bottles et al based on 64 fibroadenomas, stroma, antler horn clusters and honeycomb sheets differentiated fibroadenoma from ductal carcinoma. We applied Bottles's criteria to our fibroadenoma material in order to test their value in clinical cytologic practice. In fine needle aspirates from histologically (cytologically) diagnosed fibroadenomas, stroma was found in 41 (57%), antler horn clusters in 59 (90%) and honeycomb sheets in 62 (81%), which reduced the clinical value of the criteria.     

Goblet-like cells in atrophic vaginal smears and their histologic correlation. Possible confusion with endocervical cells.

The occurrence and origin of goblet-like cells seen between clusters of parabasal cells in atrophic vaginal smears were investigated. The goblet-like cells were cytologically identified in the vaginal smears from 23 (19.2%) of 120 patients whose smears showed an atrophic pattern, but without any inflammatory, dysplastic or malignant changes. Histologically, these cells were found in sections from 6 (18.8%) of 32 elderly women with atrophic vaginal epithelium. The goblet-like cells were situated among the squamous cells of the upper layer of the atrophic squamous epithelium from the vagina to the portio. These goblet-like cells in atrophic smears were initially misinterpreted as endocervical cells, which are regarded as a marker of smear adequacy in the cytologic screening for cancer of the uterine cervix. The correct interpretation of these goblet-like cells in smears from postmenopausal and elderly women is thus obviously important in assessing the adequacy of the sample for the detection of abnormal cells.     

Significance of histiocytes on otherwise-normal cervical smears from postmenopausal women. A retrospective study of 108 cases

OBJECTIVE: To evaluate the significance of histiocytes on normal cervical smears from postmenopausal women and correlate them with endometrial pathology. STUDY DESIGN: Histiocytes were classified into three types. The clinical history was obtained from cytologic and surgical reports. RESULTS: Among 108 cervical smears, 13 had large, foamy histiocytes (type A), 88 had histiocytes resembling superficial endometrial stromal cells (type B), and 7 had variably sized histiocytes alone or in association with inflammatory or multinucleated cells (type C). Endometrial pathology was identified in 13 patients (12.0%): 4/13 with type A histiocytes (2 endometrial adenocarcinomas, 2 endometrial polyps), 8/88 with type B histiocytes (8 endometrial polyps) and 1/7 with type C histiocytes (endometrial polyp). Among 70 patients with no clinical indications for endometrial sampling except for the presence of histiocytes, 4 demonstrated endometrial pathology (all endometrial polyps). In contrast, endometrial pathology was identified in 9/38 with clinical indications for endometrial sampling. Among the 13 patients with endometrial pathology, 9 had a significant clinical history (sensitivity of 69.2%), and 4 had histiocytes as the only indication for endometrial biopsy (sensitivity of 30.8%). CONCLUSION: A significant clinical history is more predictive of endometrial pathology and outweighs the significance of histiocytes as an indication for endometrial biopsy.