Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2.

The p57KIP2 protein is a cell cycle inhibitor and tumor suppressor encoded by a strongly paternally imprinted gene. We explored the utility of p57KIP2 as a diagnostic marker in hydatidiform mole, a disease likely the result of abnormal dosage and consequent misexpression of imprinted genes. Using a monoclonal antibody on paraffin-embedded, formalin-fixed tissue sections, the authors evaluated p57KIP2 expression in normal placenta and in 149 gestations including 59 complete hydatidiform moles, 39 PHMs, and 51 spontaneous losses with hydropic changes. p57KIP2 was strongly expressed in cytotrophoblast and villous mesenchyme in normal placenta, all cases of partial hydatidiform moles (39 of 39) and all spontaneous losses with hydropic changes (51 of 51). In contrast, p57KIP2 expression in cytotrophoblast and villous mesenchyme was absent or markedly decreased in 58 of 59 complete hydatidiform moles. In all gestations p57KIP2 was strongly expressed in decidua and in intervillous trophoblast islands, which served as internal positive controls for p57KIP2 immunostaining. p57KIP2 immunohistochemistry can reliably identify most cases of complete hydatidiform mole irrespective of gestational age and is thus a useful diagnostic adjunct, complementary to ploidy analysis, in the diagnosis of hydatidiform mole.

Fetal vasculitis in preterm newborns: interrelationships, modifiers, and antecedents.

Histologic expressions of the fetal inflammatory response predict preterm delivery and neonatal disorders. We examined 1146 placentas in the Developmental Epidemiology Network data set for histologic evidence of membrane inflammation (subchorionitis, chorionitis, and chorioamnionitis) and fetal vasculitis (acute umbilical vasculitis or chorionic vasculitis). Our main findings are that (1) in the presence of membrane inflammation, fetal vasculitis is common, (2) duration of membrane rupture and gestational age appear to modify the risk of fetal vasculitis, (3) this risk modification differs for the different components of fetal vasculitis, i.e. umbilical and chorionic vasculitis, and (4) antecedents can be identified that appear to increase or decrease the risk of fetal vasculitis among births with membrane inflammation. We conclude that fetal vasculitis, the morphologic component of the fetal inflammatory response, might not be a homogeneous entity and deserves further study.

Early complete hydatidiform moles contain inner cell mass derivatives.

In four cases of early complete hydatidiform moles, confirmed to be androgenetic in origin by DNA studies, we have identified nonchorionic inner cell mass derived structures which are not commonly observed in specimens of later gestational age. These structures include nucleated red blood cells, endothelial cells, stromal macrophages, amnion and yolk sac. The latter four structures were confirmed by specific immunocytochemical stains. Recognition that such structures can accompany complete hydatidiform moles has both theoretical and practical significance. From a theoretical perspective, it demonstrates that the maternal genome is not required for the initiation of amniogenesis, development of the yolk sac, vasculogenesis, or hematopoiesis. From a practical perspective it emphasizes that complete hydatidiform moles, with their markedly increased risk of subsequent choriocarcinoma, cannot be excluded based on the finding of "fetal structures."

Absence of normal-appearing proximal tubules in the fetal and neonatal kidney: prevalence and significance.

Rare fetuses and neonates with kidneys lacking normal-appearing proximal tubules have been described. In order to ascertain the prevalence of this histologic finding, and to study its associated clinicopathologic features, 500 consecutive perinatal autopsies (performed from 1981 to 1985) were reviewed. Kidneys lacking normal-appearing proximal tubules were found in six of 500 (1.2%) perinatal autopsies (one liveborn and five stillborn cases). The liveborn infant was one of a sibship with renal tubular dysgenesis. Four of the stillborn fetuses were derived from monochorionic twin gestations; the histologic abnormality was present in only one fetus from each twin pair. Three of the four twin pairs had pathologic features suggestive of twin-to-twin transfusion, with the renal abnormality present in the donor twin; renal hypoplasia existed in two instances. The fourth affected twin was a stillborn acardiac fetus with multiple congenital anomalies and unilateral renal agenesis. The fifth stillborn was a hydropic fetus with trisomy 21 and renal hypoplasia. In this series, lack of recognizable renal proximal tubules most often was not a manifestation of renal tubular dysgenesis. The histologic finding was associated with stillborn, renal hypoplasia, and congenital anomalies, and was strongly associated with monochorionic twinning (P = 0.001). In the stillborn cases in this series, we suggest that this finding may represent renal tubular degeneration resulting from renal hypoperfusion.

Localized endometrial proliferations associated with pregnancy: clinical and histopathologic features of 11 cases.

Eleven cases of an unusual endometrial glandular proliferation associated with early pregnancy are reported. All lesions were incidental discoveries in first-trimester gestational endometria (two elective abortions; five spontaneous abortions; three hydatidiform moles; one tubal ectopic pregnancy). Most patients (nine of 11; 82%) were older than 30 years of age; associated clinical features included oligoovulation (two), hypertension (one), and obesity (one). All lesions were small and localized, and displayed similar histological features of variable severity including glandular expansion with smooth external contours; epithelial stratification (4 to 15 layers); cribriforming (focal to extensive); mitotic activity; bland nuclear cytology; and prominent intraglandular calcifications (eight cases; 72%). Although the natural history of these distinctive pregnancy-associated endometrial lesions was unknown, nine lesions were initially classified as benign, and two were interpreted as atypical endometrial hyperplasia or focal adenocarcinoma. Follow-up for an average of 34 months (range, 18 to 56) in nine patients showed no residual endometrial lesion (seven endometrial curettages and two hysterectomies). Three patients followed by curettage have subsequently completed successful pregnancies. This unusual lesion may represent a localized, endometrial proliferation induced by pregnancy; although some endometrial lesions may display striking architectural complexity, follow-up to date suggests a benign behavior.

Fetoplacental histology as a predictor of karyotype: a controlled study of spontaneous first trimester abortions.

It has been suggested that inferences about fetal karyotype can be made from examination of placental and decidual histology in early, spontaneous abortions (SABs). We assessed the reproducibility and predictive value of histologic features in 75 karyotyped, first trimester SABs; 32% (24 of 75) had normal male karyotypes (46,XY) and 68% (51 of 75) were cytogenetically abnormal (29 trisomy, 12 triploidy, eight monosomy X, and two tetraploidy). Three pathologists independently assessed 17 fetal, placental, and decidual histological findings and made predictions about the karyotype (normal, abnormal, or uncertain). Good to excellent interobserver and intraobserver reproducibility (kappa > 0.58) was achieved for the identification of five histological features: villous cavitation, anucleate fetal erythrocytes, amnion, umbilical cord, and fetal tissue. When histology and karyotype were compared using Fisher's exact test, no histological feature was associated with "any abnormal karyotype," two features (anucleate, fetal erythrocytes and umbilical cord) were associated with a normal karyotype, two features (villous dysmorphism and cisterns) were associated with triploidy, and four features (villous hydrops, no umbilical cord, no fetal tissue, and no anucleate erythrocytes) were associated with trisomy. Despite these significant histological-cytogenetic associations, the positive predictive values of each of these histological features with their corresponding karyotypes were low, ranging from 0.41 to 0.73 (mean, 0.53). Our data suggest that certain histological features in first trimester SABs are associated with the SAB's karyotype and are reproducible; however, such histological features did not perform as well as diagnostic tests for predicting the likelihood of normal versus abnormal karyotype.

Pseudoinvasion of vascular spaces: report of an artifact caused by cervical lidocaine injection prior to loop diathermy.

Cervical loop diathermy is a relatively new procedure performed by gynecologists to diagnose and treat squamous intraepithelial lesions. We report a case of pseudoinvasion of vascular spaces noted in an excisional biopsy of a high-grade squamous intraepithelial lesion of the cervix. The neoplastic epithelium was forced into the cervical stroma by injection of local anesthetic through the lesion prior to loop diathermy. The identification of this pseudovascular space invasion as artifact had important prognostic and therapeutic value. With the increasing use of loop diathermy and local anesthesia this type of artifact may be seen more commonly.

Atypical immature metaplastic-like proliferations of the cervix: diagnostic reproducibility and viral (HPV) correlates.

Although some immature squamous lesions (papillary immature metaplasias) of the cervix have been described and associated with human papillomaviruses (HPV), nonpapillary atypical immature squamous proliferations (AISPs) are a poorly defined entity and range from atypical reactive metaplasias to squamous intraepithelial lesions resembling immature metaplasia. This study examined the diagnostic reproducibility of AISPs and their relationship to HPV nucleic acids. Forty-four diagnostically problematic AISPs were studied. Based on nuclear density (crowding), chromasia, variation (anisokaryosis) in nuclear size, and surface cytoplasmic maturation, cases were independently scored by 2 observers as (1) probably reactive (Rx), (2) not otherwise specified (NOS), and (3) squamous intraepithelial lesion (SIL). Extracted archival DNA was scored for HPV by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Interobserver reproducibility (kappa statistic) and HPV correlates (chi square) were computed. Approximately one third of cases were classified in each category by the observers. Interobserver reproducibility was excellent (0.80), poor (0.23), and fair to good (0.41) for a diagnosis of Rx, NOS, and SIL, respectively. Differences in HPV DNA positivity between Rx and SIL were significant for both observers (5.8% to 6.7% v 38.4% to 50.0%, respectively); however, differences between NOS and SIL (30.7% to 42.8% v 38.4% to 50.0%) were not, even when cases were limited to those in which both observers agreed (28.6% v 37.5%). By light microscopy, AISPs exceeding the threshold for presumed reactive changes (NOS or SIL) are a morphologically heterogeneous group that defy precise classification. Furthermore, their histopathologic appearance, even when there is diagnostic agreement, does not consistently correlate with their HPV status. The laboratory management of AISPs should take into account the uncertainty of this diagnosis.

A binary (Bethesda) system for classifying cervical cancer precursors: criteria, reproducibility, and viral correlates.

This study of cervical squamous precursors addressed the consistency with which pathologists could agree on diagnosis using a Bethesda system and the degree to which the classification system discriminated "high-risk" human papillomavirus (HPV) types. Four pathologists independently assessed biopsies of 75 squamous lesions; all contained HPV DNA amplified from archival fixed tissue with polymerase chain reaction (PCR) and typed by restriction digestion of the PCR product. Lesions were categorized as low or high grade using published criteria. In independently performed histologic evaluations a majority (three or more) of observers agreed on the classification of 63 of the 75 cases (84%) with good to very good interobserver (kappa values, 0.43 to 0.63), and fair to excellent intraobserver (kappa values, 0.32 to 0.83) agreement. A majority of the observers classified as high grade 15 of 17 (88%) HPV 16-positive lesions (P < .002), but only 15 of 21 (71%) lesions associated with other high-risk HPV types 18, 31, 35, and 39 (P = .089). Concurrence among observers also varied with HPV type; majority agreement between three or more observers was present for 100% and 94%, respectively, for lesions associated with HPV 6/11 and HPV 16 versus 82% and 76% for lesions associated with HPV 18/31/35/39 and other HPV types. A binary system for grading cervical precursor lesions was applied with good reproducibility among pathologists, and segregated as high-grade virtually all lesions associated with the prototype high-risk HPV (HPV 16). Conversely, other presumed high-risk HPV types, particularly type HPV 18, were not distinguished by this grading scheme and were segregated frequently with low-grade lesions. This finding suggests that variables other than HPV type alone will influence lesion grade. Resolution of these variables will determine whether lesion grade is a more potent biologic parameter than HPV type.

Twins, placentas, and genetics: acardiac twinning in a dichorionic, diamniotic, monozygotic twin gestation.

We describe a human acardiac twin with associated vascular anastomoses in a dichorionic diamniotic fused twin placenta. A 22-year-old woman delivered a healthy 3,554 g male infant and a fused diamniotic dichorionic twin placenta with a 230 g umbilical cord-attached, skin-covered, ovoid mass, consistent with acardiac amorphus. By gross and histological examination, the placental dividing membranes comprised four leaves, one amnion from each placenta, and two centrally fused chorions, diagnostic of dichorionicity. Placental barium injection of the normal twin's umbilical vein showed an anastomosis with the acardiac twin which traversed the dividing membranes, then supplied major vessels of the acardiac mass via its 5.5 cm umbilical cord. DNA-typing studies of the normal twin's placenta and of the acardiac twin's tissues revealed identical alleles at 11 distinct genetic polymorphic loci, consistent with monozygosity. Our findings demonstrate that vascular anastomoses can occur in dichorionic twin placentas, and that human acardiac twinning is not, as heretofore believed, restricted to monochorionic placentas.

Twin pregnancies with complete hydatidiform mole and coexisting fetus: use of fluorescent in situ hybridization to evaluate placental X- and Y-chromosomal content.

Twin pregnancies with a complete hydatidiform mole (CHM) and a coexisting fetus have an aggressive postevacuation behavior; it is, therefore, important to differentiate these cases from partial hydatidiform moles that rarely require treatment for late sequelae. It has been presumed that twin pregnancies with a CHM and a coexistent fetus are dizygotic gestations, but this has not been confirmed in most cases. The authors investigated the sex chromosomal constitution of paraffin-embedded, formalin-fixed placental tissues in nine pregnancies histopathologically diagnosed as twin gestations with CHM and coexisting fetus, using fluorescent in situ hybridization (FISH) with X- and Y-chromosomal probes. Normal placental tissues showed an even sex distribution--four cases: X signal only, presumably female; four cases: X and Y signals, presumably male. In contrast, all molar tissues of these same pregnancies hybridized with the X-chromosomal probe only. Thus, in four of nine cases, gender differences (ie, different sex chromosome content) in molar villi (X chromosome only, cytogenetic female) versus normal villi (both sex chromosomes, cytogenetic male) confirmed the histopathological diagnosis of dizygotic twinning; a strict relationship between villous morphology (molar vs normal) and chromosomal gender was observed in each instance. This study illustrates that use of FISH on paraffin-embedded tissues can retrospectively establish dizygotic twinning in this unusual type of molar gestation.

Massive chronic intervillositis associated with recurrent abortions.

Massive chronic intervillositis (MCI) is an unusual placental lesion associated with poor fetal growth and adverse pregnancy outcome; it has not previously been associated with spontaneous abortion or recurrent pregnancy loss. This article reports a patient who had 10 spontaneous abortions with repetitious massive chronic intervillositis documented in four of five gestations spanning all three trimesters. Characteristic placental histology induced massive infiltration of the maternal intervillous space by chronic inflammatory cells and fibrin, without associated chronic villitis; the cellular infiltrate was composed predominantly of LCA and CD68 immunoreactive cells with scattered CD45RO positivity, consistent with a monocyte/macrophage population with occasional T lymphocytes. Elevated maternal serum alpha-fetoprotein was documented in two pregnancies. These findings support the concept that this unusual placental lesion may have an immunologic basis, and suggest that MCI may be a histopathologically recognizable cause of recurrent spontaneous abortion.

Diagnosis of congenital syphilis from placental examination: comparison of histopathology, Steiner stain, and polymerase chain reaction for Treponema pallidum DNA.

Congenital syphilis is often a presumptive diagnosis (based on serologies), because confirmation requires identification of Treponema pallidum in fetal/neonatal tissues or in the placenta. Placental histological features associated with congenital syphilis include the triad of enlarged hypercellular villi, proliferative fetal vascular changes, and acute or chronic villitis. The authors blindly evaluated 49 formalin-fixed, paraffin-embedded placentas (38 with positive maternal syphilis serologies; 11 with negative serologies) and compared results of histology, Steiner stain, and polymerase chain reaction (PCR) for T pallidum DNA. Histology was categorized as positive (triad present), suspicious (two thirds of triad present), or negative. Treponemal DNA was detected by amplifying a 189 base pair region of the 47 kd treponemal membrane antigen with 44 cycles of PCR; products were detected by Southern blot. Placentas from the 11 seronegative mothers were all negative by histology, Steiner stain, and PCR. Among the 38 placentas from serologically positive mothers, 4 had positive histology (2 of 4 positive Steiner, 4 of 4 positive PCR); 6 had suggestive histology (0 of 6 positive Steiner; 1 of 6 positive PCR); and, 28 had negative histology (0 of 28 positive Steiner; 1 of 28 positive PCR). PCR identification of treponemal DNA was significantly associated with the triad (P = .0003), proliferative fetal vascular changes (P = .0003), acute villitis (P = .003), chronic villitis (P = .004), and spirochetes on Steiner stain (P = .01). These results (1) confirm a strong association between placental histopathologic features and congenital syphilis; (2) indicate that when such features are present, PCR of placental tissue may confirm the diagnosis of congenital syphilis; and (3) suggest that even when such features are absent, PCR of placental tissue may identify additional cases of histologically unsuspected congenital syphilis.

Bethesda classification of cervicovaginal smears: reproducibility and viral correlates.

Fifty-five cervicovaginal smears from women with squamous intraepithelial lesions (SILs) were independently evaluated on two separate occasions by four cytopathologists using a binary classification system (the Bethesda system). Smears were categorized as low-grade (LSIL) or high-grade (HSIL) using previously published criteria. All women had subsequent cervical biopsies containing human papillomavirus (HPV) DNA amplified with the polymerase chain reaction and typed by restriction fragment polymorphism analysis. Three or more observers agreed on classification in 49 of 55 cases (87%); unanimous diagnoses were rendered in 31 cases (56%). Interobserver and intraobserver reproducibility ranged from fair to near-excellent (kappa values 0.40 to 0.63; 0.63 to 0.74, respectively). HPV types included HPV 16 (27%), 18 (7%), 31 (9%), 35 (4%), 39 (4%), 6 (10%), 11 (2%), novel types (30%), and multiple types (4%). High-risk HPV types (16, 18, 31, 35, and 39) were significantly associated (P = .03) with consensus HSIL diagnoses (agreement of three or more observers). This was primarily because of the strong association of HPV 16 with HSIL (P = .001). After excluding HPV 16, the other high-risk HPV types (18, 31, 35, and 39) were no longer significantly associated with consensus HSIL diagnoses (P > .5). Conversely, LSIL diagnoses were significantly associated with non-high-risk HPV types (all HPV types except 16, 18, 31, 35, and 39; P = .006). Binary cytological classification of cervicovaginal SILs is reproducible among cytopathologists. Such classification correlates well with most low-risk HPV types and with the prototypic high-risk HPV 16 but not with other high-risk HPV types.

Flow-cytometric analysis of nuclear DNA content in endometrial adenocarcinoma. Atypical mitoses are associated with DNA aneuploidy.

Flow-cytometric studies have demonstrated that DNA aneuploidy and proliferative activity are independent prognostic factors in endometrial carcinoma. The authors performed flow-cytometric analysis of the nuclear DNA content of 46 fresh endometrial adenocarcinomas to investigate tumor DNA ploidy and cell-cycle kinetics in relation to histologic features with known prognostic significance, mitotic activity (assessed quantitatively), and clinical features suggestive of hyperestrogenism. Thirty-five tumors (76%) were DNA-diploid, and 11 (24%) were DNA-aneuploid. DNA aneuploidy correlated significantly with two histologic features: high cytologic grade (P < .027) and five or more atypical mitoses per 50 high-power fields (P < .001). The presence of one or more atypical mitosis per 50 high-power fields, evaluated independent of DNA ploidy, was associated with stage III or IV tumors (P < .015). A low proliferative index correlated with tumors with grade 1 architecture (P < .006) and grade 1 or 2 cytology (P < .017); a high proliferative index correlated with vascular invasion by tumor (P < .027). DNA ploidy and proliferative activity did not correlate with any feature indicative of estrogenic status including age, parity, menopausal status, obesity, hypertension, diabetes, exogenous estrogen use, or endometrial hyperplasia. Therefore, in endometrial adenocarcinoma, estrogenic status does not correlate with DNA ploidy or proliferative activity; proliferative activity correlates with tumor grade; and atypical mitoses appear to be highly associated with both DNA aneuploidy and advanced tumor stage, and as such, may identify tumors with a poor prognosis.

Detection of enteroviral infection in paraffin-embedded tissue by the RNA polymerase chain reaction technique.

A method using the RNA polymerase chain reaction technique to diagnose infection retrospectively using single-stranded RNA enteroviruses in paraffin-embedded tissue blocks is reported. This method takes advantage of extreme sequence conservation in the 5' untranslated region of the enteroviral genome and uses two rounds of amplification with nested oligonucleotide primers, thus allowing rapid diagnosis without the use of radioactive reagents. The technique should prove useful in cases in which viral infection is suspected after histopathologic evaluation, when fresh or frozen tissues often are unavailable. The sensitivity of the method is demonstrated by successful amplification of Enterovirus 11 RNA extracted from 4-year-old liver tissue obtained at autopsy examination that was initially fixed and embedded 45 hours after death.

Prevalence and significance of implantation site trophoblastic atypia in hydatidiform moles and spontaneous abortions.

The authors studied the prevalence and significance of implantation site trophoblastic atypia in hydatidiform moles and spontaneous abortions. Three pathologists independently categorized 99 early abortion specimens regarding diagnosis (spontaneous abortion, partial hydatidiform mole, complete hydatidiform mole); qualitative atypia of implantation site trophoblast (absent, mild, moderate-severe); and quantitative atypia of implantation site trophoblast (absent, focal, diffuse). Interobserver agreement was good to excellent regarding diagnosis (kappa 0.66-0.79) and poor to fair regarding qualitative atypia of implantation site trophoblast (kappa 0.20-0.43). By consensus diagnosis, implantation site trophoblastic atypia was mild and focal in 5% of 22 spontaneous abortions; predominantly focal in 40% of 30 partial moles (33% mild atypia; 7% moderate-severe atypia); and, predominantly diffuse in 87% of 47 complete moles (21% mild atypia; 66% moderate-severe atypia). Among hydatidiform moles, the subsequent development of persistent gestational trophoblastic tumor did not relate to the degree of implantation site trophoblastic atypia. The authors conclude that trophoblast of the implantation site exhibits focal, mild atypia in some partial hydatidiform moles,and diffuse marked atypia in most complete hydatidiform moles. Thus, implantation site trophoblastic atypia may be a useful pathologic guideline regarding the diagnosis and classification of hydatidiform moles.

Histology and Ureaplasma urealyticum culture in 63 cases of first trimester abortion.

The association between chorioamnionitis caused by Ureaplasma urealyticum and preterm delivery has been well documented. In contrast, a pathogenic role for Ureaplasma has been postulated in early spontaneous abortions, but definitive evidence for this association has been lacking. In 42 early spontaneous abortions and 21 elective abortions (both first trimester), the chorion was cultured for Ureaplasma. Each case was evaluated histologically for four features of inflammation and one feature of degeneration. For comparison, 32 selected placentas from third trimester preterm deliveries (11 with positive Ureaplasma cultures) were examined histologically for umbilical vasculitis and acute chorioamnionitis. In abortion specimens, Ureaplasma cultures were positive in 11 of 42 early spontaneous abortions (26%) versus 0 of 21 elective abortions (EABs). None of the five histologic features correlated with positive Ureaplasma cultures in early spontaneous abortions. In contrast, in preterm placentas, umbilical vasculitis, and acute chorioamnionitis correlated strongly with positive Ureaplasma cultures. The authors conclude that in premature delivery, U urealyticum chorionic culture positivity is associated with histologic chorioamnionitis; and in abortions, Ureaplasma chorionic culture positivity correlates with early spontaneous abortions (vs elective abortions), but not with histologic inflammation. This suggests that mechanisms of Ureaplasma pathogenesis other than acute inflammation should be considered in future studies of early spontaneous abortions.

Should atypical squamous cells of undetermined significance (ASCUS) be subcategorized? Accuracy analysis of Papanicolaou smears using receiver operating characteristic curves and implications for the ASCUS/squamous intraepithelial lesion ratio.

We correlated all Papanicolaou test diagnoses over a 6-month period with biopsy results and determined accuracy using receiver operating characteristic curves and biopsy as the "gold standard." Accuracies were calculated using all atypical squamous cells of undetermined significance (ASCUS) cases or by eliminating subsets thereof. Retaining the ASCUS category resulted in significantly greater accuracy for the diagnosis of squamous intraepithelial lesion (SIL) on biopsy compared with eliminating it by diagnosing all such cases as negative. Subcategorization significantly improved the accuracy of the test only when all cases were included. The highest accuracy without subcategorization was achieved when ASCUS, favor reactive, cases were diagnosed as negative, but this threshold was significantly less sensitive than including all ASCUS cases. Increasing or decreasing the estimated ASCUS/SIL ratio from 2.4 without subcategorization significantly reduced accuracy. Similar results were obtained when high-grade SIL on biopsy was used as the gold standard. Use of the ASCUS category significantly improves the accuracy of the Papanicolaou test. Eliminating any subset of ASCUS reduces the ASCUS/SIL ratio but also significantly diminishes the sensitivity of the Papanicolaou test.

Adenocarcinoma in situ in cervical smears with a small cell (endometrioid) pattern: distinction from cells directly sampled from the upper endocervical canal or lower segment of the endometrium.

Adenocarcinoma in situ (AIS) with small, endometrioid cells in cervicovaginal smears, is a source of false-negative diagnoses because of the difficulty in distinguishing these cells from endometrial cells of the lower uterine segment or benign cells from the upper endocervical canal. This study was designed to elucidate the most useful criteria for this distinction. Three observers blinded to the actual diagnoses reviewed 29 preselected cases (AIS, 17; benign, 12) that had originally caused diagnostic difficulty. Each observer made a diagnosis and evaluated 15 preselected diagnostic criteria. All 3 observers agreed on the correct diagnosis in 19 (66%) of 29 cases, and at least 2 observers agreed on the correct diagnosis in 27 (93%) of 29 cases. No case was misdiagnosed by all 3 observers. The most useful criteria for the diagnosis of AIS are a predominance of groups with marked crowding, focal feathering, nuclear hyperchromatism with coarsening of chromatin, and occasional mitotic figures. Sheets of cells, endometrial tubules, and endometrial stroma favor a benign diagnosis. Although 12 (14%) of 87 possible diagnoses were erroneous, well-preserved, small, endometrioid AIS cells can be identified correctly on cervical smears and distinguished from epithelium from the lower uterine segment and high endocervical canal in most cases using the aforementioned criteria.