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Cytology is an effective method for assessing benign endometrium and for discovering premalignant and malignant endometrial states. In addition, it is useful for diagnosing non-neoplastic abnormalities of the endometrium. This overview compares endometrial cytology to endometrial histology for a variety of benign, abnormal non-neoplastic, and neoplastic conditions; and, discusses both diagnostic criteria and pitfalls in the assessment of endometrial brushings specimens. It also makes an attempt to estimate levels of confidence in endometrial cytodiagnosis. When endometrial brushing is used in conjunction with other diagnostic techniques such as ultrasonography/sonohysterography or hysteroscopy, cytology becomes a sensitive case finding technique that shows good patient acceptance (because of a significant decrease in procedure-associated pain) and high diagnostic yield., (Copyright 2007 Wiley-Liss, Inc.)

With the worldwide acceptance of mechanically assisted, ultrasound guided thin needle biopsy of the prostate gland, prostate fine needle aspiration (FNA) has fallen out of favor with both urologists and cytopathologists. Nonetheless, given today's trend to submit from 12 to 18 core biopsies per patient, prostate FNA remains less expensive, more expedient and more economical than any other sampling method so far developed. This short overview presents prostate FNA as a sensitive, specific and reliable diagnostic modality that should not be dismissed, as an anachronism, from the diagnostic armamentarium of either the urologist or the pathologist., (Copyright 2007 Wiley-Liss, Inc.)

Objective: The objective of the study was to validate a low-cost, liquid-based method for cervical cancer screening., Study Design: We conducted a retrospective, split-sample comparison of 300 liquid-based cervical cytology samples from a group of 150 human immunodeficiency virus-seropositive women and 150 women from low-risk general gynecology clinics whose specimens were screened via standard liquid-based methodology as part of routine care. Residual samples from each specimen were used to prepare a slide using a novel, inexpensive manual membrane method of liquid-based cytology. These slides were screened by a cytotechnologist and abnormal cases were reviewed by a pathologist. Final diagnoses from the manual membrane method of liquid-based cytology slides were compared with the original diagnoses and available cervical biopsy data., Results: There was good overall agreement between the manual membrane method of liquid-based cytology and original cytology diagnoses (76.3% agreement; kappa = 0.52, 95% confidence interval 0.44 to 0.59). Using available biopsy data to determine the accuracy of each method to identify high-grade squamous intraepithelial lesions, the manual membrane method of liquid-based cytology method was found to have a higher sensitivity (71.4% versus 57.1%) and lower specificity (82.1% versus 89.7%). The slightly higher referral rate to colposcopy using the manual membrane method of liquid-based cytology method was limited to women from the low-risk general gynecology clinics (16.7% versus 12.0%, P = .05)., Conclusion: The low-cost manual membrane method of liquid-based cytology cervical cytology method is comparable with a standard commercial method. Consequently, it may be of value in alternative screening strategies in resource-limited settings.

We report a technical improvement upon a previously disclosed manual liquid-based cytology (MLBC) method; and, we use the improved method to prepare slides from residual ThinPrep specimens in order to see how often ThinPrep diagnoses correspond to diagnoses derived from exhaustive examination of their parent sample suspensions. Residual cell suspensions from 500 ThinPrep cases comprising (1) 20 low-grade squamous intraepithelial lesions (LSILs); (2) 200 high risk (HR) negatives and 20 ASC-US; and (3) 260 screening cytology specimens were studied. Institutional review committee guidelines allowed us to know diagnoses by groups of specimens, but did not allow us to know individual patient diagnoses, so we could not perform case-by-case matched outcome-comparisons. Cells were concentrated by conventional centrifugation and sedimented into a polymer gel that was then vortex-mixed and converted into a viscous cell-rich suspension. The cell suspension was smeared between two clean glass slides, which were air-dried and stained with the Papanicolaou stain. Two study-sets were created, comprising one slide from each case. Each of the two study sets was examined by two cytopathologists, and discordant diagnoses were adjudicated. Because of the ambiguity involved in the "atypical" (ASC-US, ASC-H, AGC) diagnosis categories, only outcomes at the level of LSIL or greater were recorded. All MLBC SILs were digitally imaged and abnormal slides plus digital images were sent to the laboratory that provided the residual automated liquid-based cytology (ALBC) suspensions. The final diagnoses were confirmed by the laboratory that provided the residual ALBC specimens. MLBC slides of the 20 LSIL cases afforded 2 high-grade squamous intraepithelial lesions (HSILs) and 18 LSILs. Those of the 200 HR-Negatives showed 3 HSILs and 30 LSILs; and those of the 20 HR-ASC-US showed 3 HSILs and 9 LSILs. MLBC slides of the 260 screening cytology specimens showed 1 Carcinoma, 3 HSILs and 20 LSILs; affording 3 HSILs and 14 LSILs more than originally diagnosed. The MLBC method of this report is useful for preparing cell suspensions for cytological examination. Our analytical method was exhaustive and used nearly all of the cell material that was provided to us for analysis; therefore, we conclude that this approach is useful for determining how well ALBC instruments represent their parent sample suspensions. It appears that "rare events" may be overlooked when limited sample aliquots are analyzed by ALBC instruments, and this probably accounts for our increased discovery of SILs by the MLBC method. Also, SILs often present as aggregates of cohesive cells which, if overlooked or ineffectively transferred to ALBC slides, would not be diagnosed.

This paper focuses on the performance of endocervical curettage (ECC) and intensive endocervical brushing (ECB) (comprising two or more brushings of the endocervix with liquid-based cytology and cell-block examination) in the course of colposcopic examination for abnormal gynecological cytology. To assess their relative effectiveness in disease detection, we reviewed the outcomes of 1,824 colposcopic biopsy collections from women who had an index cytology diagnosis of LSIL or higher. Our intent was to gauge the relative success of ECC and ECB as case-finding procedures in relation to (1) the original cytological diagnosis and (2) the highest (most abnormal) histological diagnosis of the colposcopy study. Our purpose was to determine whether ECB could effectively replace ECC. One thousand five hundred and seven cases of LSILs or higher cases included an ECC along with two or more colposcopic biopsies and 317 cases included an ECB. ECBs were collected into a liquid fixative and processed as both cytology and cell-block specimens; whereas, ECCs were processed according to standard histological techniques. We found that intensive ECB recapitulates the highest diagnosis of the colposcopy study about 5-8 times as often as that of ECC. Moreover, when calculating the proportion of positive outcomes, we found that cases examined with biopsy and ECC discovered fewer women with CIN 2 or higher among both LSIL and HSIL index cytologies as compared with those of cases examined with biopsy and ECB (9.2% vs. 16.8% for LSIL and 63.7% vs. 72.2% for HSIL cases); and, more negative outcomes were seen among women evaluated with biopsy plus ECC than those with biopsy plus ECB (11.3% vs. 8.1% for LSIL and 4.7% vs. 1.4% for HSIL cases). Our findings suggest that the colposcopic study is optimized when it is performed in conjunction with ECB as opposed to ECC, and that intensive ECB may be superior to ECC.

We show that residual cell material from ThinPrep PapTest (Cytyc Corporation, Boxborough, MA) atypical squamous-cells of undetermined significance (ASCUS) cases may be manually reprocessed to triage women into actionable diagnostic categories (HSIL, LSIL, and Negative). Material remaining from each of 358 ThinPrep ASCUS cases was manually reprocessed as two slides, labeled "A" and "B." Interobserver agreement between case contributors (CCs) and three sequential reviewers (SRs) was analyzed with 186 cases (Study 1), and diagnostic reproducibility between SRs was examined with an additional 172 cases (Study 2). In Study 1, CCs classified 33% of cases as LSIL or greater, SRs classified 60% as LSIL or greater, and there was 58% diagnostic agreement between CCs and SRs. No "Negative" case assignment by one group afforded an "HSIL" assignment by the complementary group. In Study 2, there was 95% agreement between SRs A slide and B slide diagnoses with 54% of A slides and 55% of B slides classified as LISL or greater. Again, no "Negative" case assignment to one slide afforded an "HSIL" assignment to the complementary slide. Overall, 12.6% of the 358 cases showed HSIL, and all HSILs by one observer group were ASCUS or greater by the complementary observer group. Using manual reprocessing beyond the 21-day specimen outdate for HPV testing by the Hybrid Capture II High Risk HPV test (HR-HCII; Digene Corporation, Beltsville, MD), many ThinPrep ASCUS cases were reclassified as LSIL or HSIL. The 12.6% HSIL proportion of this study approximated the 11.5% CIN 2 or greater proportion of the ALTS ASCUS arm. Similar to ALTS, manual liquid-based cytology (MLBC) would have referred nearly 60% of women to colposcopy for a definitive diagnosis of HSIL or LSIL without resorting to HPV testing. These data demonstrate that many cases of automated liquid-based cytology (ALBC)-diagnosed ASCUS represent unrecognized SIL, which is present in the ALBC specimen vial at the time the ASCUS diagnosis is rendered., (Copyright 2005 Wiley-Liss, Inc)

We report on the formulation and use of an alcoholic-agar additive solution generally useful for rapid, inexpensive liquid-based cytology slide preparation. Gynecological cytology specimens were collected from 1,000 women. Two hundred fifty aliquots each of CytoRich, CytoRich Red (Tripath Imaging, Inc., Burlington, NC), Preservcyt (Cytyc Corp., Boxborough, MA), and DINA*TRANS (DINA*CYT Corp., Portland, OR) fixatives were used for this study. Fixed cell suspensions from 1,000 women, seen consecutively by a general obstetrics and gynecology practice, were vortex-mixed and transferred into a premeasured amount of alcoholic-agar in test tubes. Test tubes were conventionally centrifuged, cells were trapped in a spontaneously formed agar-gel, and the supernatant solutions were decanted. Vortex-mixing cell buttons caused a rapid gel-to-sol transition, affording viscous cell suspensions that were applied to slides, smeared, and stained using Papanicolaou stains. Slides showed unclumped, monolayered, uniform, random cell-spreads. All of the fixatives afforded crisp presentation of normal and abnormal cells. There was an about 3-fold increase in HSIL+ (0.7-1.8%) and LSIL diagnoses (1.3-4.4%), and a 45% reduction in ASCUS diagnoses (3.3-1.8%), as compared to our cytology laboratory's previous year's patients' statistics with a concurrent 0.2% unsatisfactory rate, due solely to inadequate sampling. This manual method makes liquid-based cytology inexpensive and does not require specialized preparative devices., (Copyright 2001 Wiley-Liss, Inc.)

The blending and use of a metastable alcoholic gel is described. The gel creates durable, uniform suspensions of cells and small aggregates of cells. It allows the random, uniform transfer of virtually any liquid-fixed cytology specimens to a glass slide without the use of specialized devices, proprietary disposables, or adhesive-coated glass slides. The method is inexpensive and can be performed in a timely fashion, not impacting laboratory turnaround times or requiring the specimen to be processed by other laboratories. It empowers cytology laboratories of any size or level of complexity to make slides from readily available commercial cytology fixatives. It allows the total contents of liquid-based cytology specimen vials to be examined, providing a "cytological method" for quality assuring liquid-based cytology samples., (Copyright 2001 Wiley-Liss, Inc.)

Following successful hysterectomy-controlled trials, Tao brush endometrial cytology with liquid fixation was offered to clinicians for office use. This report recounts our first year's cytology and correlative histology outcomes. One hundred thirteen cases were accrued. Correlative tissue examinations comprising Pipelle (Prodimed, Neuilly-en-Thelle, France) biopsy, hysteroscopy and biopsy, dilatation and curettage, and hysterectomy were available at this institution for 59 cases. In 42 cases, cytology diagnoses could be compared to histology diagnoses. Twenty-five of 63 normal brushings were followed up. Fourteen were normal. Eleven Pipelle biopsies of cytologically atrophic endometrium were quantitatively limited and insufficient for diagnosis. Thirty-seven cases were abnormal, and 15 of these showed nuclear anaplasia. Twenty-eight of the abnormal cases were followed up. All correlative tissue examinations confirmed an abnormality. All 15 cases with nuclear anaplasia showed significant histopathology comprising atypical endometrial hyperplasia, endometrial intraepithelial neoplasia (EIN), endometrial intraepithelial carcinoma (EIC), and invasive adenocarcinoma. There were 13 inadequate endometrial brushings. Three cases had insufficient cellular material. The remaining 10 cases were cellular but were chiefly cervical/endocervical samples. Two of the cellular cases resulted from clinicians failing to replace the protective sheath over the brush bristles before removing the Tao brush from the endometrial cavity. The remaining 11 cases resulted from inaccessibility of the uterine cavity due to a tight or stenotic cervix. The Tao brush is a reliable uterine sampling device that performs well as a diagnostic tool for outpatient assessment of the endometrium of women with patent cervices. An advantage of endometrial cytology is that it accurately represents atrophic endometrium, and it is an effective case-finding tool for EIN and EIC. Women with tight or stenotic cervices are poor candidates for endometrial brushing, and may experience pain if the procedure is attempted. Diagn. Cytopathol. 2000;22:186-195., (Copyright 2000 Wiley-Liss, Inc.)

Our purpose was to demonstrate that 17.5-mm liquid-based cytocentrifuge circle-slides made using a Hettich (Andreas Hettich Co., Tuttlingen, Germany) cytocentrifuge are at least as efficacious as conventional smears for detecting cervical abnormalities. One hundred conventional smears were collected with cytobrushes and wooden spatulas from high-risk women. Both devices were then placed into CytoRich Red (AutoCyte, Inc., Burlington, NC). Cells were concentrated from CytoRich Red by centrifugation and suspended in CytoRich Yellow. Two 17.5-mm circle-slides were produced, compared to each other in order to test reproducibility of diagnoses between slides, and compared to conventional slides. Sixty-five normals, three ASCUS, three LSIL, and two HSIL matched. Overall, cytocentrifugation yielded 27 additional findings among 25 cases. Also, it downgraded one conventional ASCUS to normal (immature metaplasia and chronic inflammation) and one conventional HSIL to normal (transitional cell metaplasia). Cytocentrifugation of 14 conventional normals afforded four ASCUS and 10 LSIL. Cytocentrifugation of 11 conventional ASCUS afforded nine LSIL and two HSIL (one with AIS). One HSIL + AIS was found with a conventional HSIL. Cytobrushes and wooden spatulas can be used to collect material for liquid-based cervico-vaginal cytology if they are placed into CytoRich Red. Hettich cytocentrifuge slides were more reliable than conventional smears in presenting well-dispersed, sharply imaged cells, affording greater diagnostic sensitivity and certainty. Compared to previous split-sample studies, three different outcomes were noted: 1) the endocervical component was consistently well-represented; 2) AIS was seen more often in liquid-based slides; and 3) the liquid-based slide did not underdiagnose its conventional companion. The liquid-based preparations downgraded one ASCUS to normal and one conventional HSIL to transitional-cell metaplasia. Histology correlation of these two cases agreed with the liquid-based cytology diagnoses, which validates their specificity. These improvements are ascribed to differences in fixation and processing. The low cost, ease of operation, and reusable chambers of the Hettich cytocentrifuge make it a cost-effective liquid-based cytology instrument, especially for small to intermediate-size laboratories. The claims that this paper makes must be proven by additional studies, and test implementation needs to be scrutinized by appropriate regulatory agencies whose standards may vary from country to country. Diagn. Cytopathol. 2000;22:86-91., (Copyright 2000 Wiley-Liss, Inc.)

Liquid-fixed Tao brush samples showing small quantities (less than 10%) of endometrial epithelial sheets with cancer-like nuclei that are admixed with benign endometrium raise a concern about false-positive cytology interpretations. This paper details 7 cases along with the outcomes of three prior papers that touch on the differential diagnosis of "small amounts of atypical epithelium with cancer-like nuclei." Liquid-fixed, cytocentrifuge-processed Tao brush endometrial samples from 7 women showing "small amounts of atypical epithelium with cancer-like nuclei" were followed up by hysterectomy. Clinical presentations, diagnostic tests, surgical procedures, and tissue outcomes are detailed. Four women had hyperplastic polyps (three with focal atypical complex hyperplasia, and one with focal atypical simple hyperplasia). One had endometrial microcarcinoma. One had p53-positive endometrial intraepithelial carcinoma (EIC). One had endometrial intraepithelial neoplasia (EIN). The differential diagnosis of the index cytological finding, "small quantities of endometrial epithelial sheets with cancer-like nuclei admixed with benign endometrium," includes hyperplastic polyp, EIC, microcarcinoma/EIN, and carcinoma metastatic to the endometrium. Combining endometrial brushing, endovaginal sonography/sonohysterography, and selective immunostaining may be useful for both detecting and sorting out these lesions. Diagn. Cytopathol. 1999;21:378-386., (Copyright 1999 Wiley-Liss, Inc.)

Differential uterine curettage may be performed for the evaluation of abnormal uterine bleeding. The purpose of this study was to test the feasibility of substituting cytological methods for differential uterine curettage to evaluate the entire glandular axis of the uterus and the transformation zone. In order to simulate differential uterine sampling, the endocervix was brushed in 455 uteri from which an endometrial cytology sample had been previously collected. Twenty-five percent of the brushes' cell-sample was examined using two 17.5 mm circle-slides prepared with a Hettich cytocentrifuge. The resulting slides were homogeneous and cellular. They were compared to tissue sections of matched hysterectomy specimens. Endometrial adenocarcinoma was overrepresented in the endocervical cytology preparations. This was ascribed either to prior endometrial collection with "drop-down contamination" of the endocervix and/or to entry of the cytobrush into the endometrial cavity. Otherwise, cytological and histological diagnoses were comparable for squamous and endocervical-adenomatous lesions. Under the conditions of this simulation, endometrial and endocervical brushings appeared to complement each other as case-finding techniques for evaluating abnormal uterine bleeding. Diagn. Cytopathol. 1999;21:419-426., (Copyright 1999 Wiley-Liss, Inc.)

The purpose of the present study was to compare histology outcomes of cytological atypical squamous cells of undetermined significance (ASCUS) to the histology outcomes of cytological low-grade squamous intraepithelial lesion (LSIL). Cases with a cytology diagnosis of ASCUS and LSIL that had correlative histology obtained within 3 mo of the cervico-vaginal smear were accrued from the files of the Cytology and Histology Departments of Mercy Hospital Medical Center (Des Moines, IA). All of the cytology cases were examined by a cytotechnologist, a cytopathologist, and the histopathologist who signed out the biopsy material. The laboratory's benign: ASCUS: LSIL: HSIL + ratio was 94.0%: 3.8%: 1.5%: 0.7% for the time period of this analysis; its ASCUS:SIL proportion was 1.76. Histology correlations to 249 ASCUS cases showed 45 (18%) CIN2s (cervical intraepithelial neoplasm 2) or CIN3s, 134 (54%) CIN1s, and 70 (28%) nonneoplastic biopsies. Ten of 24 (42%) ASCUS cases that showed histological CIN3 and seven of 21 (33%) ASCUS cases that showed histological CIN2 contained atypical immature squamous metaplastic cells, while the remainder showed squamous cells with mature, superficial/intermediate-type cytoplasm. Histology correlations to 576 LSIL cases showed 96 (17%) CIN2s or CIN3s, 397 (69%) CIN1s, and 83 (14%) nonneoplastic biopsies. One hundred forty-six (59%) ASCUS and 424 (74%) LSILs had histological koilocytosis with nuclear atypia (KA); the sole histological finding of KA was seen among 76 (30.5%) ASCUS and 146 (25.3%) LSIL cases. The majority of cytological ASCUS and LSIL cases selected by clinicians for biopsy have histological CIN and a substantial minority show CIN2 and CIN3, which, in the case of ASCUS, is frequently associated with atypical immature squamous metaplastic cells. There is a high prevalence of histological KA among ASCUS and LSIL cases. Diagn. Cytopathol. 21:292-295, 1999., (Copyright 1999 Wiley-Liss, Inc.)

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.

Endometrial intraepithelial carcinoma (EIC) is associated with tumors of high nuclear grade and usually is seen in endometria without complex atypical hyperplasia. Tumor cells oftentimes show an accumulation of mutant p53 protein. This report describes a case of EIC detected by endometrial brush cytology and p53 immunostaining, and confirmed by hysterectomy.

A case of ciliated endometrioid adenocarcinoma of the endometrium, diagnosed by endometrial brush cytology and confirmed by histology, is reported. Features are those of outspoken endometrial adenocarcinoma presenting in a postmenopausal woman with abnormal uterine bleeding. Distinctive characteristics include ciliated neoplastic cells, intracytoplasmic ciliary cysts, complex epithelial stratification, and muscular invasion by malignant ciliated cells in the matched hysterectomy specimen. This report illustrates the merit of linking an easy-to-use liquid fixative with brush-sampling of the endometrium.

Endometrium was obtained by brushing 656 hysterectomy specimens with a MedScand cytobrush (Hollywood, FL) in order to evaluate linking an easy-to-use liquid fixative with brush-sampling of the endometrium, and to determine the fixative's operating characteristics when applied to brush-sampling the endometrium. Liquid-fixed brush-samples yielded 4 to 6 slides per case, and any one slide accurately represented the case diagnosis. Tissue fragments were incidentally collected by the brush in 524 cases (79.9%), were least often obtained from senile and weakly proliferative endometria, and were always obtained from high-grade endometrial hyperplasias and carcinomas. With tissue fragments obtained by brush-sampling, the diagnosis matched that of the hysterectomy endometrium. Cytology alone separated benign endometrium from high-grade atypical hyperplasia and carcinoma, showing that clinical decision-making can be based on endometrial brush cytology collected into a liquid fixative. Furthermore, the addition of tissue-fragment histology increased the diagnostic accuracy of the endometrial brushing procedure to 92.5% overall and 100% for high-grade atypical hyperplasias and carcinomas. At this juncture, we advocate endometrial brushing as a sensitive and generally specific case-finding technique; and perhaps as experience teaches us to distinguish low-grade nonatypical hyperplasias from purely physiological changes of the endometrium, it may become accepted as a definitive diagnostic method. The advantages of examining a liquid-fixed suspension are that 1) because these preparations are homogeneous from slide to slide, with any one slide affording the same diagnosis as any other slide from the same case, the number of slides examined may be greatly reduced, and 2) tissue fragments can be used to quality-control the cytology diagnosis in the majority of cases, especially in cases of endometrial hyperplasia and carcinoma.

Renal hypertension has been reduced to normal levels in the rat with subcutaneous injections of carbon tetrachloride (CCl4). Previous light microscopic evaluation of liver sections demonstrated varying degrees of hepatocellular and hepatic parenchymal injury secondary to CCl4 administration. In normotensive rat populations, saline injections have been shown not to cause hypertension, and the treatment of normal rats with subcutaneous CCl4 did not change their blood pressure over that of noninjected controls. In this study we compare the extent of blood pressure reduction with the degree of CCl4-induced liver injury in the renal-induced, spontaneous hypertensive rat (SHR), and normotensive rat. Statistically significant blood pressure reduction followed CCl4 injection of renal (p less than .01) and SHR (p less than .001) hypertensive animals. The morphological liver injury appeared most sensitively reflected in hepatocellular nuclear atypia. The SHR animals were the most resistant to CCl4 liver damage by chronic CCl4 treatment. There was no measurable effect of CCl4 treatment on the animals as assessed by their activity, rate of development and weight gain. The degree of blood pressure reduction due to CCl4 treatment in the SHR animals was similar to that previously reported in DOCA and renal-induced hypertensive animals.

The preparation and use of an alternate collection device for aspiration biopsy of the prostate is presented. The device is inexpensive and can be constructed from readily available office materials. Its use in conjunction with a liquid-phase collection of cellular products of aspiration biopsy by a backwash technique is described. Following this, a brief discussion of pattern recognition in cytological preparations of benign and malignant prostate epithelial aggregates is presented and illustrated.

The pathologic anatomy of the central nervous system is described in a patient with Apert's syndrome. Multiple developmental anomalies of the brain were noted including disturbances of rhinencephalic organization. The association between maldevelopment of the rhinencephalon and the face is well known. Cranial vault malformations may also be associated with maldevelopment of the rhinencephalon.

Developmental anomalies extrinsic to the extrahepatic biliary tree have been recognized in association with extrahepatic bile duct atresia. Reported are six cases of extrahepatic biliary atresia associated with polysplenia syndrome and two cases associated with splenic hypoplasia. There is a more than chance occurrence of splenic anomalies with anomalies of associated organ systems and extrahepatic biliary atresia. Organ systems most frequently involved were the cardiovascular, gastrointestinal, and respiratory systems.

Aspiration biopsy of the prostate is contraindicated when active prostatitis is present. However, we have found prostatitis in 45.2 percent of 250 consecutive aspiration biopsy specimens, confirming that urologists have difficulty in distinguishing prostatitis from carcinoma on a clinical basis. The epithelial changes accompanying prostatitis also may be confused with carcinoma. We review the microscopic features which distinguish prostatitis from carcinoma. Because 14.1 percent of the patients with prostatitis in this study also had carcinoma, repeat follow-up biopsy is necessary if suspicion of carcinoma persists after adequate therapy for prostatitis.

The histopathologic changes in liver, spleen, and bone marrow of BALB/c mice infected for 6 months with Leishmania donovani are described. Granulomas were the most important histologic lesions found; and the dynamics of their formation, collagen deposition, and resolution in the liver were studied. The number of hepatic granulomas increased until the eighth week and then decreased steadily. In contrast to the liver granulomas, those of spleen and bone marrow do not mature or show collagen deposition. Actual granuloma counts in the liver support the idea that mature granulomas revert to poorly formed ones and finally resolve without scarring. BALB/c mice are suitable for the study of the dynamics of granuloma formation and resolution and the survival of L donovani in an in vivo system. The relevance of these changes to the pathology of L donovani infection in man are discussed.

Aspiration biopsy is a rapid and relatively painless technique for evaluating an abnormal prostate gland. It can be performed on outpatients without anesthesia and is easily tolerated. It sensitivity in detecting cancer is at least equivalent to that of core biopsies, in part because several areas of the prostate may be sampled in a relatively atraumatic fashion. Few complications are encountered. Adequate performance of aspiration biopsy of the prostate requires experience and diligence, both by the urologist, in obtaining adequate specimens, and by the processing laboratory and pathologist, in interpreting these specimens. It is hoped that aspiration biopsy will lead to the early diagnosis of prostatic cancer, effecting lower morbidity, reduced hospital cost, greater ease in performing radical prostatectomy, and more accurate techniques for predicting the prognosis in affected patients.

A perceived disadvantage of fine-needle aspiration biopsy of the prostate is that aspiration biopsies cannot be correlated with current tissue-grading systems. We compared patterns of cellular arrangement among 50 cases of prostate carcinoma studied in histologic and cytologic specimens obtained simultaneously. Cell patterns were independently scored in a semiquantitative fashion on both histologic and cytologic material, and "predicted Gleason scores" were assigned to the cytologic specimens. When carcinomas were classified as well differentiated (Gleason score 2 to 4), moderately differentiated (Gleason score 5 to 7), or poorly differentiated (Gleason score 8 to 10), there was 84 per cent agreement between histology and cytology. In no instance was there overlap between well-differentiated and poorly differentiated adenocarcinoma in the matched specimens. We believe that it is possible to accurately predict tissue patterns of prostate carcinoma and to estimate Gleason scores in aspiration biopsy specimens.

Hodgkin's disease is a malignant neoplasm that shares many histologic features with granulomatous diseases. We have examined 11 cases of Hodgkin's disease, representing the spectrum of histologic types, using transmission electron microscopy and have compared the morphology of Reed-Sternberg cells to that of the developmental stages described for monocyte-macrophage differentiation in vivo. Ultrastructurally, a close parallelism exists between the cells that typify granulomatous inflammation and Reed-Sternberg cells. It is our contention that the heterogeniety among Reed-Sternberg cells in all types of Hodgkin's disease parallels the diversity of the monocyte-macrophage system.

In this rather brief review, we have illustrated and discussed selected examples of dual or multiple differentiation within certain neoplasms. In so doing, we have attempted to present those cases which highlight common diagnostic problems and which have important biologic and clinical implications. We have shown how tumors arising in many organs such as the lung, gastrointestinal tract, and thyroid can simultaneously manifest combined endocrine-nonendocrine differentiation, and we have addressed this phenomenon in relation to the "parent cell of origin" theory. We have emphasized that while many tumors do in fact resemble the tissues in which they arise, the possession of a particular phenotype, such as endocrine, does not necessarily imply that the tumor in question was derived from an endocrine progenitor cell. To reinforce the concept that the histomorphologic, biochemical, and functional properties of tumor cells reflect ongoing differentiation events rather than a static situation, we have presented examples of tumors in which changes in phenotype have been observed during the course of disease, e.g., small cell carcinomas of the lung and prostate, as well as tumors in which divergent differentiation reflects similar lines of differentiation occurring in normal tissues, e.g., certain neurogenic tumors. Finally we have considered important clinical implications of mixed differentiation and changing phenotype and their impact on the pathologist.