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.

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.

Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects.

A high level of polycystin-1 expression is detected in kidneys of all patients with autosomal dominant polycystic kidney disease (ADPKD). Mice that overexpress polycystin-1 also develop renal cysts. Whether overexpression of polycystin-1 is necessary for cyst formation is still unclear. Here, we report the generation of a targeted mouse mutant with a null mutation in Pkd1 and its phenotypic characterization in comparison with the del34 mutants that carry a 'truncation mutation' in Pkd1. We show that null homozygotes develop the same, but more aggressive, renal and pancreatic cystic disease as del34/del34. Moreover, we report that both homozygous mutants develop polyhydramnios, hydrops fetalis, spina bifida occulta and osteochondrodysplasia. Heterozygotes also develop adult-onset pancreatic disease. We show further that del34 homozygotes continue to produce mutant polycystin-1, thereby providing a possible explanation for increased immunoreactive polycystin-1 in ADPKD cyst epithelia in the context of the two-hit model. Our data demonstrate for the first time that loss of polycystin-1 leads to cyst formation and defective skeletogenesis, and indicate that polycystin-1 is critical in both epithelium and chondrocyte development.

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.

Partial hydatidiform mole: clinicopathological features, differential diagnosis, ploidy and molecular studies, and gold standards for diagnosis.

Partial hydatidiform mole is optimally diagnosed histopathologically when four microscopic features coexist: 1) two populations of villi, 2) enlarged villi (> or = 3-4 mm) with central captivation, 3) irregular villi with geographic, scalloped borders with trophoblast inclusions, and 4) trophoblast hyperplasia (usually focal and involving syncytiotrophoblast). Pathologic mimics of partial mole include Beckwith-Wiedemann syndrome, placental angiomatous malformation, twin gestation with complete mole and existing fetus, early complete hydatidiform mole, and hydropic spontaneous abortion. Because partial hydatidiform mole results from diandric triploidy, flow cytometry (or another method to assess ploidy) can be utilized by pathologists for supporting diagnostic classification of problematic specimens, or for educational or quality assurance purposes. Confirmation of the histopathologic diagnosis by ploidy or molecular studies is important for scientific reports of partial hydatidiform mole, especially when unusual or aggressive outcomes (such as choriocarcinoma) are reported.

Placental site trophoblastic tumor: a 17-year experience at the New England Trophoblastic Disease Center.

OBJECTIVE: We reviewed cases of placental site trophoblastic tumors from the New England Trophoblastic Disease Center (NETDC) database from 1982-1999 in an effort to identify prognostic factors for recurrent disease. METHODS: A chart review was performed utilizing patients identified from the NETDC database. Data obtained included patient age at diagnosis, antecedent pregnancy, duration and extent of disease, presenting symptoms, pre- and posttreatment hCG levels, diagnostic and therapeutic procedures, treatment and outcome of patients. Statistical analysis was performed using Student's t test and chi(2) test when appropriate. RESULTS: Thirteen patients were identified. All ultimately underwent hysterectomy although initial treatment of 1 patient was uterine resection. There were 5 recurrences (43%)--3 among the 9 patients who had no metastases on presentation (33%) and 2 of 3 patients who presented with metastases (66%). The 5 patients who recurred were among 8 who had received peri- or postoperative chemotherapy (62.5%). Treatment of recurrences included continued or alternate chemotherapy, radiotherapy, and/or excision of locally recurrent disease. Follow up time averaged 56.2 months (range 12-182 months). One of the 4 patients receiving chemotherapy < or =1 week after hysterectomy recurred, whereas all 4 patients who received chemotherapy 3 weeks or more after hysterectomy recurred. Uterine tumor volume was significantly greater, 154.1 cm(3), in patients with initial metastases versus 42.3 cm(3) in patients without initial metastases (P = 0.04). Mitotic index (P = 0.04) was significantly increased in patients who developed recurrent disease. CONCLUSION: High mitotic index appears to be an adverse prognostic indicator for recurrence. Hysterectomy remains the mainstay of treatment. Chemotherapy is indicated for patients with metastases and may be indicated when the mitotic index is >5 mitoses/10 HPF. Radiation treatment may play a role in recurrent disease but must be evaluated on a case-by-case basis.

Sonographic appearance of first trimester complete hydatidiform moles.

OBJECTIVE: Complete hydatidiform moles are now being diagnosed earlier in gestation, thus the clinical presentation and pathologic findings of complete molar pregnancy have changed. We studied the sonographic appearance of first trimester moles and the ability of ultrasound to detect them. METHODS: We reviewed the sonographic interpretation and sonograms, when available, from all patients with first trimester complete moles diagnosed at our institution from January 1988 to March 1996. RESULTS: Of the 24 patients in our study, the mean gestational age at time of the sonogram was 8.7 +/- 2.0 weeks (mean +/- SD) with a range of 5.7-12.3 weeks. The initial sonographic interpretation was a complete mole in 17 (71%) cases, partial mole versus failed pregnancy in two (8%), and failed pregnancy in five (21%) cases. Of the 22 patients with sonograms available for review, interpretation on review of the images was a complete mole in 18 (82%) cases, partial mole versus failed pregnancy in one (5%), and failed pregnancy in three (14%) cases. The typical sonographic appearance of a first trimester complete mole was a complex, echogenic, intra-uterine mass containing many small cystic spaces. CONCLUSION: The majority of first trimester complete moles demonstrate a typical ultrasound appearance such that the diagnosis can be made with ultrasound in most cases.

Expression of epidermal growth factor receptor-related family products in gestational trophoblastic diseases and normal placenta and its relationship with development of postmolar tumor.

OBJECTIVE: The goal of this work was to study the expression of epidermal growth factor receptor (EGFR) and c-erbB-3 and c-erbB-4 oncogenes in gestational trophoblastic diseases and normal first-trimester placenta. STUDY DESIGN: Paraffin sections of 16 cases of partial mole, 25 cases of complete mole, 10 cases of gestational choriocarcinoma, and 11 cases of therapeutic abortion were studied immunohistochemically for EGFR, c-erbB-3, and c-erbB-4 proteins. The presence of EGFR mRNA was studied using in situ hybridization. RESULTS: Staining for EGFR was detected immunohistochemically in all cell types in gestational trophoblastic diseases and normal placenta. In situ hybridization for EGFR mRNA correlated with immunostaining for EGFR in all tissues studied. All 10 cases of choriocarcinoma exhibited strong immunoreactivity for EGFR. The levels of expression of EGFR in choriocarcinoma and syncytiotrophoblasts and cytotrophoblasts in complete mole were significantly greater than those in syncytiotrophoblasts and cytotrophoblasts in both normal placenta and partial mole (P < 0.01, P < 0.01). Expression of c-erbB-3 did not significantly differ among placental and gestational trophoblastic disease tissues and trophoblastic cell types except for significantly increased expression in choriocarcinoma as compared with cytotrophoblasts of partial mole (P = 0.02). The placenta, complete and partial mole, and choriocarcinoma tissues demonstrated similar immunoreactivity for c-erbB-4. Strong immunostaining for EGFR (P = 0.02) and c-erbB-3 (P < 0.01) in extravillous trophoblasts of complete mole was found to be significantly correlated with the development of persistent postmolar gestational trophoblastic tumor. CONCLUSION: The EGFR-related family of oncogenes may be important in the pathogenesis of gestational trophoblastic diseases. The increased expression of EGFR and c-erbB-3 in complete mole may also influence the development of persistent gestational trophoblastic tumor.

Differential gene expression pattern between normal human trophoblast and choriocarcinoma cell lines: downregulation of heat shock protein-27 in choriocarcinoma in vitro and in vivo.

OBJECTIVE: Our purpose was to identify potential differences in gene expression between normal trophoblast and choriocarcinoma cells. METHODS: The Atlas human cDNA expression array hybridization technique was used to study the gene expression pattern in normal trophoblast and choriocarcinoma cell lines. Furthermore, to confirm heat shock protein-27 (Hsp-27) expression data, reverse transcriptase-PCR (RT-PCR), Western blot, and immunohistochemical analyses were used in vitro with cell lines and in vivo with paraffin sections. RESULTS: The expression of nine genes was strongly different comparing a normal trophoblast cell line with choriocarcinoma cells on the Atlas membranes. Compared to normal trophoblast cells, six genes were upregulated and three were downregulated in choriocarcinoma cells. Furthermore, the downregulation of Hsp-27 in choriocarcinoma cells was confirmed both in vitro with cell lines and in vivo with paraffin sections using RT-PCR, Western blot, and immunohistochemical techniques. CONCLUSION: cDNA expression array is a useful technique for identifying differentially expressed gene patterns in normal trophoblast and choriocarcinoma cells. The strong expression of Hsp-27 in placental villous trophoblast cells may play a role in trophoblast differentiation. The downregulation of Hsp-27 in choriocarcinoma may contribute to the extreme sensitivity of trophoblastic tumors to chemotherapy.

Circumferential abdominal skin defect possibly due to umbilical cord encirclement.

We report on a newborn black male twin with a distinctive circumferential abdominal skin defect who was identified through the Active Malformation Surveillance Program at the Brigham and Women's Hospital. There were no other malformations, and amniotic disruption was not present. Although it cannot be proven, we believe that this skin defect may have been caused by in utero encirclement of the abdomen by an umbilical cord.

Matrix metalloproteinases and their inhibitors in gestational trophoblastic diseases and normal placenta.

OBJECTIVE: Our purpose was to investigate the expression of matrix metalloproteinases (MMPs) in gestational trophoblastic diseases and normal first-trimester placenta. METHODS: Paraffin sections of 16 partial moles, 25 complete moles, 10 gestational choriocarcinomas, and 11 normal first-trimester placentas were studied immunohistochemically for expression of MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, and tissue inhibitor of metalloproteinase-1 (TIMP-1). RESULTS: Nine (90.0%) of the choriocarcinoma cases showed strong intensity of staining for MMP-1. Choriocarcinoma exhibited significantly stronger staining for MMP-1 than syncytiotrophoblast in normal placenta (P < 0.01), partial mole (P < 0.01), and complete mole (P < 0.01). Choriocarcinoma also showed significantly stronger staining for MMP-1 than the extravillous trophoblast in placenta (P < 0.05). MMP-2 was expressed only in syncytio- and extravillous trophoblasts in normal placenta, partial mole, and complete mole. Choriocarcinoma and the extravillous trophoblast in partial mole and complete mole had significantly stronger staining for MMP-2 than the extravillous trophoblast in placenta (P < 0.05, P < 0.01, P < 0.01, respectively). Choriocarcinoma also exhibited significantly stronger staining for MMP-2 than syncytiotrophoblasts in placenta (P < 0.01), partial mole (P = 0.05), and complete mole (P < 0.01). The expression of MMP-3, MMP-9, and MMP-13 was similar in all four tissues with the predominance of syncytiotrophoblast for MMP-3 and MMP-13 and cytotrophoblast for MMP-9. While 8 (73.0%) placentas, 14 (87.5%) partial moles, and 19 (76.0%) complete moles showed strong immunoreactivity for TIMP-1 in syncytiotrophoblasts, no strong staining was found in choriocarcinomas (P < 0.01, P < 0.01, P < 0.01, respectively). CONCLUSION: The extravillous trophoblast of first-trimester placenta has significantly less expression of MMP-1 than choriocarcinoma and significantly less expression of MMP-2 than choriocarcinoma and extravillous trophoblast of partial and complete mole. The expression of TIMP-1 was significantly less in choriocarcinoma than the syncytiotrophoblast of normal placenta, partial mole, and complete mole. MMPs and their inhibitors may play a role in the pathogenesis of gestational trophoblastic diseases.

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.

Human DAZL1 encodes a candidate fertility factor in women that localizes to the prenatal and postnatal germ cells.

The human DAZ (Deleted in AZoospermia) gene family contains a cluster of DAZ genes on the Y chromosome and a single autosomal homologue, DAZL1 (DAZ-Like) that maps to chromosome 3p24. Although the role of the Y chromosome gene family in determining fertility and the expression of the gene family has been well explored in men, little is known of the role of the DAZL1 gene in determining the fertility of women. In mice, loss of function of the homologue of DAZL1 results in the loss of male and female germ cells. In mice, Dazl1 protein is localized to prenatal and postnatal follicles. Here we demonstrate using two antisera that recognize human DAZL1 that the protein is expressed embryonically in germ cells of girls and in mature oocytes. This pattern of expression suggests that the DAZL1 gene is a candidate fertility factor in women and that it would be appropriate to search for mutations in the DAZL1 gene in peripheral blood DNA from women with primary amenorrhoea or premature ovarian failure.

Subclassifying atypical squamous cells in Thin-Prep cervical cytology correlates with detection of high-risk human papillomavirus DNA.

Recent studies have proposed subclassifying ASCUS into "favor reactive" (ASFR), "not otherwise specified" (ASNOS), and "favor squamous intraepithelial lesion (SIL)" (ASFS). This study explored the reproducibility of these diagnoses with Thin-Prep cytology and their association with high-risk human papillomavirus DNA (HRHPV). Three pathologists and 1 cytotechnologist with 2 to 25 years of experience reviewed 144 Thin-Prep (Cytyc, Boxborough, MA) specimens previously diagnosed as normal, ASFR, ASNOS, ASFS, and SIL. Interobserver reproducibility was computed with the kappa statistic. The original laboratory diagnosis was compared with the presence of HRHPV types. Interobserver reproducibility for a normal or SIL diagnosis was very good (kappa = .68 and .63). Reproducibility for ASFR, ASNOS, and ASFS ranged from poor to fair (kappa = .21, .19, and .32). In a weighted analysis, kappa values for ASFR/ASNOS and ASFS/SIL were .36 and .62, respectively. HRHPV-positivity for preparations originally diagnosed as N, ASFR, ASNOS, ASFS, and SIL were 5.7%, 8.8%, 17.4%, 47.8%, and 54.5%, respectively. The difference in index of HRHPV for either N or ASFR and ASFS or SIL was significant (P < .001). Reproducibility for ASCUS is generally poor, but better reproducibility is obtained by combining ASFS with SIL and, to a lesser degree, ASNOS with ASFR. ASFS and SIL confer a similar index of HRHPV and merit similar management. ASFR may be managed with cytologic follow-up; but this may depend upon the individual laboratory. HPV testing, in conjunction with cytologic and biopsy follow-up, appears useful for estimating the significance of ASCUS subgroups in laboratory practice.

Terminal transverse limb defects with tethering and omphalocele in a 17 week fetus following first trimester misoprostol exposure.

We report a fetus from an elective termination at 17 weeks gestation following maternal ingestion of 1200 micrograms of misoprostol at 7 weeks of gestation. The fetus had abscence of the middle and distal phalanges of fingers 1, 3, 4 and 5 with tethering by thin strands of tissue on one hand, a below-knee amputation of one leg and omphalocele. There was absence of amnion on the chorionic surface of the placenta, a pathologic feature of early amnion rupture. The association in this case of the phenotypic features of the amniotic band syndrome suggests that the teratogenicity of misoprostol at 9 to 12 weeks gestation can overlap that of other acute insults at that time, such as chorionic villus sampling, dilatation and curettage and abdominal trauma in the first trimester.

Coexistence of low and high grade squamous intraepithelial lesions of the cervix: morphologic progression or multiple papillomaviruses?

BACKGROUND: The diagnosis of both low (LSIL) and high (HSIL) grade squamous intraepithelial lesions in the same cervical specimen may reflect classification variation, morphologic progression in situ, and, conceivably, different HPV infections. We addressed these possibilities in cervical specimens previously diagnosed as containing both LSIL (condyloma/CIN1) and HSIL (CIN2/3). METHODS: All cases with a histologic diagnosis of LSIL and HSIL from 1994-1996 were reviewed. On review, lesions were scored as (1) no significant variation in lesion grade (classification discrepancies) and showing a (2) one (CIN1-2) or (3) two (CIN1-3) grade shift in the same case. In cases in which a one or two grade shift was confirmed, low (CIN1) and high (CIN2-3) grade foci were microdissected and extracted DNA analyzed for HPV by PCR and RFLP analysis. RESULTS: Of 98 cases available for review, 58 (59%) did not exhibit significant variation in grade (classification discrepancy), and 40 (41%) showed a one (25) or two (15) grade shift. Of the latter group both LSIL and HSIL foci were HPV(+) in 26 (65. 0%). The same HPV was present in both LSIL and HSIL foci in 15/15 lesions with a one grade shift (CIN1-2). In contrast, a significantly higher proportion of lesions with a two grade shift (CIN1-3) contained two different HPV types (4/11 vs 0/15; P = 0.01). Combinations of HPVs in the low/high grade foci, respectively, included HPV 11/16 (1), 11/16 + 18 (1), and HPV39/16 (2). CONCLUSIONS: Lesions containing LSIL and HSIL which span two grades (CIN1 and CIN2) most likely represent morphologic progression in a single infection. Lesions containing CIN1 and CIN 3 may be attributed to both lesion progression and two coincident infections; the latter sometimes present in the same histologic section. The latter phenomenon has implications for both the diagnosis of CIN and interpretation of "morphologic progression" from very low to high grade in the same case.

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.

Qualifying the cytologic diagnosis of "atypical squamous cells of undetermined significance" affects the predictive value of a squamous intraepithelial lesion on subsequent biopsy.

OBJECTIVE: To evaluate whether different qualifications of a cytologic diagnosis of "atypical squamous cells of undetermined significance" predict a greater or lesser likelihood of cervical pathology. DESIGN: Comparison of different cytologic qualifications of atypical squamous cells of undetermined significance with the frequency of significant cervical disease as documented by tissue biopsy. PARTICIPANTS AND SETTING: Four hundred, fifty-two consecutive Papanicolaou smears showing atypical squamous cells of undetermined significance (diagnosed by nine cytopathologists) in women who had undergone cervical biopsy within the previous 90 days at Brigham and Women's Hospital, Boston, Mass (January-June 1995). MAIN OUTCOME MEASURE: The histopathologic diagnosis of squamous intraepithelial lesion of the cervix. RESULTS: The 452 smears were qualified as "favor reactive" (22%), "not otherwise specified" (42%), "favor squamous intraepithelial lesion" (29%), and "favor high-grade squamous intraepithelial lesion" (6%). High-grade squamous intraepithelial lesions and total squamous intraepithelial lesions were pathologically confirmed by cervical biopsy in 3.6% and 6% of the favor reactive smears, in 11% and 21% of the not otherwise specified smears, in 12% and 30% of the favor squamous intraepithelial lesion smears, and in 53% and 59% of the favor high-grade squamous intraepithelial lesion smears. Significant associations were seen between a favor reactive smear and a benign finding on cervical biopsy (94%, P = .04) and between a favor high-grade squamous intraepithelial lesion smear and a biopsy that showed a high-grade squamous intraepithelial lesion (53%, P = .00001). CONCLUSIONS: Qualifying atypical squamous cells of undetermined significance stratifies women into different risk groups for squamous intraepithelial lesion. It is reasonable for physicians to make patient management decisions based, at least in part, on such qualifications.

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.