David Genest | Harvard Medical School (original) (raw)

Papers by David Genest

Hum Pathol, 1994

Cervical loop diathermy is a relatively new procedure pe$ormed 4 gynecologists to diagnose and tr... more Cervical loop diathermy is a relatively new procedure pe$ormed 4 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 @ithelium 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 artqact may be seen more commonly. HUMPATHOL 25:208-211.

The Journal of Reproductive Medicine, Feb 1, 1998

To determine the expression of bcl-2, c-myc, c-fms and c-erbB-2 oncoproteins in normal placentas,... more To determine the expression of bcl-2, c-myc, c-fms and c-erbB-2 oncoproteins in normal placentas, partial and complete hydatidiform moles, and choriocarcinomas and to examine the possible presence of mutations in the K-ras gene in complete moles and choriocarcinomas. The expression of the above oncoproteins was determined immunohistochemically by specific antibodies for these proteins on formalin-fixed paraffin sections of 18 normal placentas, 17 partial moles, 25 complete moles and 11 choriocarcinomas. This was followed by polymerase chain reaction analysis (exons 12 and 13) of K-ras gene for possible mutations in complete moles and choriocarcinomas. Expression of c-fms oncoprotein appeared confined to the cytoplasm of syncytiotrophoblastic cells. The c-fms protein staining intensity of the syncytiotrophoblastic layer showed no significant difference among the four gestational tissues. c-erbB-2 antibody expression was confined to the cellular membrane of the extravillous trophoblast. When compared with normal placenta or partial mole, the expression of c-erbB-2 protein was significantly stronger in complete mole (P < .0001 and P < .0001, respectively) and choriocarcinoma (P < .0001 and P < .0001, respectively). Expression of bcl-2 protein was significantly stronger in the syncytiotrophoblast in complete mole and choriocarcinoma as compared to both normal placenta and partial mole (P < .0001 and P < .0001, respectively). Staining of c-myc of the syncytiotrophoblastic layer was significantly stronger in placenta, complete mole and choriocarcinoma than in partial mole (P < .0001, P < .0001 and P < .0001, respectively). Mutation in K-ras gene was not found in any of the 22 complete moles or 11 choriocarcinomas examined. Our data suggest that c-myc, c-erbB-2, c-fms and bcl-2 oncoproteins may be important in the pathogenesis of complete mole and choriocarcinoma. However, while both complete mole and choriocarcinoma were characterized by overexpression of c-myc, c-erbB-2 and bcl-2, partial mole generally did not strongly express these three oncoproteins.

Human Reproduction, Oct 1, 1999

The human DAZ (Deleted in AZoospermia) gene family contains a cluster of DAZ genes on the Y chrom... more 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.

The Journal of Reproductive Medicine, Nov 1, 2006

To develop human chorionic gonadotropin (hCG) criteria that determine a patient&a... more To develop human chorionic gonadotropin (hCG) criteria that determine a patient's risk of developing persistent gestational trophoblastic neoplasia (GTN) or achieving remission after partial mole evacuation. We used a database from the New England Trophoblastic Disease Center to analyze hCG levels from 284 women with partial molar pregnancies diagnosed between 1973 and 2003. An hCG level >199 mIU/mL in the third through eighth week following molar evacuation was associated with at least a 35% risk of GTN. Women with partial mole who have elevated hCG levels within the first few weeks after molar evacuation are at increased risk for developing GTN.

Human Pathology, Nov 1, 1995

Eleven cases of an unusual endometrial glandular proliferation associated with early pregnancy ar... more 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.

International Journal of Gynecological Pathology, Aug 1, 1994

The histologic criteria for reactive/reparative lesions and precursor lesions (squamous intraepit... more The histologic criteria for reactive/reparative lesions and precursor lesions (squamous intraepithelial lesions; SIL) of the cervix are established, but a proportion of cervical biopsies contains squamous epithelial alterations that do not fall into either category (nondiagnostic squamous atypia or atypical squamous epithelium of undetermined significance). This study examined (a) the degree to which this diagnosis could be made consistently between two experienced pathologists and (b) its relationship to papillomavirus nucleic acids. One author selected 37 cervical biopsies with a spectrum of cellular changes occurring in the context of inflammatory or reactive epithelial changes, and each case was reviewed by two pathologists independently and classified as reactive, nondiagnostic atypia, and diagnostic (SIL). Concordance between two observers was highest for a diagnosis of SIL (kappa = 0.68), followed by reparative/reactive (kappa = 0.48). Concordance for a designation as nondiagnostic squamous atypia was fair (kappa = 0.39). Seven of 37 (19%) cases were HPV positive, including 2/7, 5/19, and 0/11 cases designated by at least one observer as SIL, nondiagnostic squamous atypia, or neither (i.e., both reactive), respectively. The findings support a category of nondiagnostic squamous atypia but emphasize the value of a second observer and possibly, HPV DNA testing, in resolving such cases. Similarities in HPV positivity between nondiagnostic atypia and SIL in this study may reflect problems of both criteria selection and consistent application of these criteria in a setting of reactive/reparative changes.

Gynecologic Oncology, Jun 1, 2000

Objective.The goal of this work was to study the expression of epidermal growth factor receptor (... more 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,

The Journal of Reproductive Medicine, Jun 1, 2002

Placental site trophoblastic tumor (PSTT) is the least common form of gestational trophoblastic d... more Placental site trophoblastic tumor (PSTT) is the least common form of gestational trophoblastic disease. The tumor represents a neoplastic transformation of intermediate trophoblastic cells that normally play a critical role in implantation. PSTT can occur after a normal pregnancy, spontaneous abortion, termination of pregnancy, ectopic pregnancy or molar pregnancy. It displays a wide spectrum of behavior, and when metastatic, can be difficult to control even with surgery and chemotherapy. Because of PSTT's rarity, limited information is known about its natural history. Several recent studies have indicated that mitotic index is an important prognostic indicator. Advances in chemotherapeutic regimens have also improved clinical response in metastatic disease.

American Journal of Obstetrics and Gynecology, Jan 3, 2002

This study related morphologic subtype, human papillomavirus status, and a second cytologic exami... more This study related morphologic subtype, human papillomavirus status, and a second cytologic examination to the follow-up biopsy-proven high-grade squamous intraepithelial lesion (HSIL; grade II or III cervical intraepithelial neoplasia) after a cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS). Seven hundred four liquid-based cervical cytology specimens were classified as normal, "ASCUS, favor reactive" (AFR), "ASCUS, not otherwise specified," "ASCUS, favor low-grade squamous intraepithelial lesion," "ASCUS, favor HSIL" (AFHS), low-grade squamous intraepithelial lesion, and HSIL. Human papillomavirus typing used polymerase chain reaction-restriction fragment length polymorphism analysis. A longitudinal review of the cytologic and histologic records of ASCUS cases with > or =1 follow-up test or biopsy ascertained the frequency of a follow-up diagnosis of biopsy-proven HSIL (grade II or III cervical intraepithelial neoplasia). Three hundred eighty-six cases (208 ASCUS, 68 normal, 86 with low-grade squamous intraepithelial lesions, and 24 with HSIL) were evaluated. High-risk human papillomavirus (HRHPV positive) was lowest with normal cytology (13%), highest with HSIL (71%), and was present in 29.8% of ASCUS cases, ranging from 22.2% (AFR) to 75% (AFHS). Most ASCUS tests (64%) were followed by a negative cytologic or histologic examination. Overall, 3.8% and 11% of ASCUS and HRHPV-positive ASCUS had histologic outcomes of HSIL. AFHS had the highest (25%) and AFR had the lowest (1.1%) proportion of HSIL outcomes. Sensitivity, specificity, and positive predictive values of human papillomavirus testing for biopsy-proven HSIL were 87.5%, 72.5%, and 11.3%, respectively. HSIL and AFHS are distinguished by the highest frequency of HRHPV types and higher rates of HSIL outcome. The remaining categories of ASCUS are heterogeneous with respect to human papillomavirus type and HSIL risk, and the value of subclassification of these entities is dependent on the practice. A human papillomavirus detection system based on polymerase chain reaction-restriction fragment length polymorphism identifies a smaller percentage of high-risk human papillomaviruses than mixed probe-based methods, probably because of the more precise exclusion of cross-reacting low-risk human papillomavirus. Negative HRHPV findings by either system show a markedly reduced risk of an HSIL outcome. However,…

Journal of Reproductive Medicine, 2002

To study whether nontriploid partial hydatidiform moles truly exist. We conducted a reevaluation ... more To study whether nontriploid partial hydatidiform moles truly exist. We conducted a reevaluation of pathology and ploidy in 19 putative nontriploid partial hydatidiform moles using standardized histologic diagnostic criteria and repeat flow cytometric testing by the Hedley technique. On review of the 19 moles, 53% (10/19) were diploid nonpartial moles (initially pathologically misclassified), and 37% (7/19) were triploid partial moles (initial ploidy misclassifications). One additional case (5%) was a diploid early complete mole (initially pathologically misclassified). Nontriploid partial moles probably do not exist: careful reevaluation of putative specimens will probably uncover pathologic or ploid errors in almost all cases.

The Journal of Reproductive Medicine, Mar 1, 1994

The estimated incidence of twin pregnancy consisting of hydatidiform mole and a coexisting fetus ... more The estimated incidence of twin pregnancy consisting of hydatidiform mole and a coexisting fetus is 1 per 22,000-100,000 pregnancies. Since 1965, nine patients with this entity have been treated at the New England Trophoblastic Disease Center (NETDC), Boston. One patient had a partial hydatidiform mole coexisting with a normal placenta and fetus. The other eight patients had twin pregnancies with a complete hydatidiform mole (CHM) and coexisting fetus. We compared the clinical outcomes in these 8 patients and 14 additional published case reports of multiple gestations composed of CHM and coexisting fetuses with a group of 71 patients with singleton CHM treated at NETDC. Twelve of the 22 patients (55%) with CHM and coexisting fetuses developed persistent gestational trophoblastic tumor, requiring chemotherapy. Five of these patients developed metastases requiring multiple cycles of chemotherapy to achieve remission. The presenting symptoms of multiple conception with CHM and coexisting fetuses were similar to those in patients with a singleton conception and complete mole. However, as compared to singleton CHM, patients having a multiple conception with CHM and coexisting fetuses were diagnosed at a later gestational age, had higher preevacuation beta-human chorionic gonadotropin levels and had a greater propensity to develop persistent tumor. These data indicate that patients with multiple conceptions consisting of CHM and coexisting fetuses are at high risk of developing persistent gestational trophoblastic tumor.

The Journal of Reproductive Medicine, 1998

To investigate whether changes have occurred in the pathologic and clinical features of complete ... more To investigate whether changes have occurred in the pathologic and clinical features of complete molar gestation in recent years. Twenty-three contemporary complete hydatidiform moles (1994-1997) and 20 historical complete moles (1969-1975) were compared regarding clinical features (gestational age at evacuation, maternal age, preevacuation diagnosis and persistence) and pathologic findings (volume of tissue, presence of gross cisterns, maximal villous size, percent of cavitated villi, percent of villi exhibiting circumferential trophoblast hyperplasia, and presence of necrosis and primitive stromal features). Contemporary complete moles were evacuated at an earlier mean gestational age (8.5 vs. 17.0 weeks, P = .00008). Histologically, contemporary complete moles had less circumferential trophoblastic hyperplasia (39% vs. 75% of villi, P = .03), a smaller mean maximal villous diameter (5.7 vs. 8.2 mm, P = .001), more primitive villous stroma (70% vs. 10% of cases, P = .0003) and less global necrosis (22% vs. 54% of cases, P = .02). These striking morphologic differences indicate that pathologic findings in complete molar gestations have changed significantly over the past several decades due to the current practice of very early uterine evacuation. Contemporary complete moles are often characterized by subtle morphologic alterations that may result in their misclassification as partial moles or nonmolar spontaneous abortions. It is important for pathologists to recognize the distinctive histopathologic features of early complete hydatidiform mole.

Obstetrics and Gynecology, Oct 1, 1991

Although the significance of histologic grading in hydatidiform mole has previously been investig... more Although the significance of histologic grading in hydatidiform mole has previously been investigated, most studies evaluated patients treated before 1975. Since 1975, many advances have been made in the understanding and treatment of hydatidiform mole, including the division of molar pregnancy into complete and partial hydatidiform mole. We retrospectively studied 153 cases of complete hydatidiform mole diagnosed and treated at the Brigham and Women's Hospital between 1980-1990 to determine the current prognostic significance of histologic grading in this disease. The histologic grade (based on the criteria of Hertig and Sheldon) was compared with the subsequent clinical course, including the rates of spontaneous remission, persistent gestational trophoblastic tumor, metastatic disease, "high-risk" metastatic disease, chemotherapy resistance, and survival. The histologic grade of the original complete hydatidiform mole did not correlate significantly with any index of clinical outcome evaluated.

Human pathology, 1992

To identify fetal histologic features characteristic of specific chromosomal anomalies, we review... more To identify fetal histologic features characteristic of specific chromosomal anomalies, we reviewed histologic slides of 415 cases, including therapeutic and spontaneous abortuses, stillbirths, and perinatal deaths. These included 126 cases (30%) with karyotypically confirmed trisomy 21 and 23 cases (5.5%) with trisomy 13. Two histologic abnormalities of the fetal heart were identified that correlated with specific karyotypic abnormalities: (1) a discrete central papillary muscle calcification was present in 14 of 85 (16%) cases with trisomy 21, in seven of 18 (39%) cases with trisomy 13, and in six of 255 (2%) controls (P less than .001); and (2) a focal ventricular epicardial lymphocytic infiltrate was present in 22 of 93 (24%) cases with trisomy 21 versus nine of 284 (3%) controls (P less than .001). When both histologic abnormalities coexisted, trisomy 21 was present in five of six cases (83%). Neither histologic finding was significantly associated with fetal or maternal infect...

The Journal of reproductive medicine, 2006

To identify clinical characteristics associated with developing persistent gestational trophoblas... more To identify clinical characteristics associated with developing persistent gestational trophoblastic neoplasia (GTN) after partial hydatidiform molar pregnancy (PHM). Utilizing the Donald P. Goldstein in patients who developed persistence between 1973 and 1989. Older age at diagnosis and history of prior mole were significantly more common in women who developed persistence after partial molar pregnancy in referral of patients the earlier cohort but not in idefined clinical the recent cohort. In recent years no clinical factor was at increase their risk significantly associated with rsistence. database at the New England Trophoblastic Disease Center, 284 women with partial molar pregnancy diagnosed between 1973 and 2003 were characteristics identified. Clinical charac- for pe teristics, such as gravidity, parity, age, uterine size, gestational age at diagnosis, human chorionic gonadotropin levels at presentation and time to development of persistence (GTN) were analyzed. Data were a...

The Journal of reproductive medicine, 2004

To determine if immunohistochemistry for PHLDA2 (also known as IPL and TSSC3), the product of a p... more To determine if immunohistochemistry for PHLDA2 (also known as IPL and TSSC3), the product of a paternally imprinted, maternally expressed gene, can be used as a tool in the differential diagnosis of molar gestations. Twenty-five cases (15 complete moles, 5 partial moles and five hydropic abortions) were stained by immunohistochemistry for PHLDA2 and scored (without knowledge of the diagnosis) for positivity in the villous cytotrophoblast and then compared to adjacent sections stained by p57KIP2 immunohistochemistry. All partial moles and hydropic abortions were positive for PHLDA2 and p57KIP2. There was strong PHLDA2 staining of the cytoplasm in virtually all cells of the villous cytotrophoblast, while p57KIP2 was localized to the nucleus in a subset of those cells. All complete moles were negative for both markers in the villous cytotrophoblast. Immunohistochemistry for PHLDA2 serves as a practical and reliable diagnostic marker for the discrimination of complete mole from partial...

The Journal of reproductive medicine, 2002

To determine whether the combination of flow cytometry and immunohistochemistry for p57 expressio... more To determine whether the combination of flow cytometry and immunohistochemistry for p57 expression is useful for the pathologic classification of diagnostically challenging hydatidiform moles. Six probable hydatidiform moles that were difficult to classify pathologically were reevaluated by histology, flow cytometry and immunohistochemistry for p57. In all cases, the pathologic diagnoses were easily resolved: two cases were partial moles (triploid, p57 positive), two cases were early complete moles (diploid, p57 negative), and two cases were twin gestations with normal villi (diploid, p57 positive) admixed with villi from a complete hydatidiform mole (diploid, p57 negative). Immunostaining for the paternally imprinted, maternally expressed p57 gene product is a practical and accurate adjunct to flow cytometry in the pathologic classification of hydatidiform moles.

Human pathology, 1999

Although some immature squamous lesions (papillary immature metaplasias) of the cervix have been ... more 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 H...

Human pathology, 1998

We describe a human acardiac twin with associated vascular anastomoses in a dichorionic diamnioti... more 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 oc...

Hum Pathol, 1994

Cervical loop diathermy is a relatively new procedure pe$ormed 4 gynecologists to diagnose and tr... more Cervical loop diathermy is a relatively new procedure pe$ormed 4 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 @ithelium 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 artqact may be seen more commonly. HUMPATHOL 25:208-211.

The Journal of Reproductive Medicine, Feb 1, 1998

To determine the expression of bcl-2, c-myc, c-fms and c-erbB-2 oncoproteins in normal placentas,... more To determine the expression of bcl-2, c-myc, c-fms and c-erbB-2 oncoproteins in normal placentas, partial and complete hydatidiform moles, and choriocarcinomas and to examine the possible presence of mutations in the K-ras gene in complete moles and choriocarcinomas. The expression of the above oncoproteins was determined immunohistochemically by specific antibodies for these proteins on formalin-fixed paraffin sections of 18 normal placentas, 17 partial moles, 25 complete moles and 11 choriocarcinomas. This was followed by polymerase chain reaction analysis (exons 12 and 13) of K-ras gene for possible mutations in complete moles and choriocarcinomas. Expression of c-fms oncoprotein appeared confined to the cytoplasm of syncytiotrophoblastic cells. The c-fms protein staining intensity of the syncytiotrophoblastic layer showed no significant difference among the four gestational tissues. c-erbB-2 antibody expression was confined to the cellular membrane of the extravillous trophoblast. When compared with normal placenta or partial mole, the expression of c-erbB-2 protein was significantly stronger in complete mole (P < .0001 and P < .0001, respectively) and choriocarcinoma (P < .0001 and P < .0001, respectively). Expression of bcl-2 protein was significantly stronger in the syncytiotrophoblast in complete mole and choriocarcinoma as compared to both normal placenta and partial mole (P < .0001 and P < .0001, respectively). Staining of c-myc of the syncytiotrophoblastic layer was significantly stronger in placenta, complete mole and choriocarcinoma than in partial mole (P < .0001, P < .0001 and P < .0001, respectively). Mutation in K-ras gene was not found in any of the 22 complete moles or 11 choriocarcinomas examined. Our data suggest that c-myc, c-erbB-2, c-fms and bcl-2 oncoproteins may be important in the pathogenesis of complete mole and choriocarcinoma. However, while both complete mole and choriocarcinoma were characterized by overexpression of c-myc, c-erbB-2 and bcl-2, partial mole generally did not strongly express these three oncoproteins.

Human Reproduction, Oct 1, 1999

The human DAZ (Deleted in AZoospermia) gene family contains a cluster of DAZ genes on the Y chrom... more 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.

The Journal of Reproductive Medicine, Nov 1, 2006

To develop human chorionic gonadotropin (hCG) criteria that determine a patient&a... more To develop human chorionic gonadotropin (hCG) criteria that determine a patient's risk of developing persistent gestational trophoblastic neoplasia (GTN) or achieving remission after partial mole evacuation. We used a database from the New England Trophoblastic Disease Center to analyze hCG levels from 284 women with partial molar pregnancies diagnosed between 1973 and 2003. An hCG level >199 mIU/mL in the third through eighth week following molar evacuation was associated with at least a 35% risk of GTN. Women with partial mole who have elevated hCG levels within the first few weeks after molar evacuation are at increased risk for developing GTN.

Human Pathology, Nov 1, 1995

Eleven cases of an unusual endometrial glandular proliferation associated with early pregnancy ar... more 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.

International Journal of Gynecological Pathology, Aug 1, 1994

The histologic criteria for reactive/reparative lesions and precursor lesions (squamous intraepit... more The histologic criteria for reactive/reparative lesions and precursor lesions (squamous intraepithelial lesions; SIL) of the cervix are established, but a proportion of cervical biopsies contains squamous epithelial alterations that do not fall into either category (nondiagnostic squamous atypia or atypical squamous epithelium of undetermined significance). This study examined (a) the degree to which this diagnosis could be made consistently between two experienced pathologists and (b) its relationship to papillomavirus nucleic acids. One author selected 37 cervical biopsies with a spectrum of cellular changes occurring in the context of inflammatory or reactive epithelial changes, and each case was reviewed by two pathologists independently and classified as reactive, nondiagnostic atypia, and diagnostic (SIL). Concordance between two observers was highest for a diagnosis of SIL (kappa = 0.68), followed by reparative/reactive (kappa = 0.48). Concordance for a designation as nondiagnostic squamous atypia was fair (kappa = 0.39). Seven of 37 (19%) cases were HPV positive, including 2/7, 5/19, and 0/11 cases designated by at least one observer as SIL, nondiagnostic squamous atypia, or neither (i.e., both reactive), respectively. The findings support a category of nondiagnostic squamous atypia but emphasize the value of a second observer and possibly, HPV DNA testing, in resolving such cases. Similarities in HPV positivity between nondiagnostic atypia and SIL in this study may reflect problems of both criteria selection and consistent application of these criteria in a setting of reactive/reparative changes.

Gynecologic Oncology, Jun 1, 2000

Objective.The goal of this work was to study the expression of epidermal growth factor receptor (... more 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,

The Journal of Reproductive Medicine, Jun 1, 2002

Placental site trophoblastic tumor (PSTT) is the least common form of gestational trophoblastic d... more Placental site trophoblastic tumor (PSTT) is the least common form of gestational trophoblastic disease. The tumor represents a neoplastic transformation of intermediate trophoblastic cells that normally play a critical role in implantation. PSTT can occur after a normal pregnancy, spontaneous abortion, termination of pregnancy, ectopic pregnancy or molar pregnancy. It displays a wide spectrum of behavior, and when metastatic, can be difficult to control even with surgery and chemotherapy. Because of PSTT's rarity, limited information is known about its natural history. Several recent studies have indicated that mitotic index is an important prognostic indicator. Advances in chemotherapeutic regimens have also improved clinical response in metastatic disease.

American Journal of Obstetrics and Gynecology, Jan 3, 2002

This study related morphologic subtype, human papillomavirus status, and a second cytologic exami... more This study related morphologic subtype, human papillomavirus status, and a second cytologic examination to the follow-up biopsy-proven high-grade squamous intraepithelial lesion (HSIL; grade II or III cervical intraepithelial neoplasia) after a cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS). Seven hundred four liquid-based cervical cytology specimens were classified as normal, "ASCUS, favor reactive" (AFR), "ASCUS, not otherwise specified," "ASCUS, favor low-grade squamous intraepithelial lesion," "ASCUS, favor HSIL" (AFHS), low-grade squamous intraepithelial lesion, and HSIL. Human papillomavirus typing used polymerase chain reaction-restriction fragment length polymorphism analysis. A longitudinal review of the cytologic and histologic records of ASCUS cases with > or =1 follow-up test or biopsy ascertained the frequency of a follow-up diagnosis of biopsy-proven HSIL (grade II or III cervical intraepithelial neoplasia). Three hundred eighty-six cases (208 ASCUS, 68 normal, 86 with low-grade squamous intraepithelial lesions, and 24 with HSIL) were evaluated. High-risk human papillomavirus (HRHPV positive) was lowest with normal cytology (13%), highest with HSIL (71%), and was present in 29.8% of ASCUS cases, ranging from 22.2% (AFR) to 75% (AFHS). Most ASCUS tests (64%) were followed by a negative cytologic or histologic examination. Overall, 3.8% and 11% of ASCUS and HRHPV-positive ASCUS had histologic outcomes of HSIL. AFHS had the highest (25%) and AFR had the lowest (1.1%) proportion of HSIL outcomes. Sensitivity, specificity, and positive predictive values of human papillomavirus testing for biopsy-proven HSIL were 87.5%, 72.5%, and 11.3%, respectively. HSIL and AFHS are distinguished by the highest frequency of HRHPV types and higher rates of HSIL outcome. The remaining categories of ASCUS are heterogeneous with respect to human papillomavirus type and HSIL risk, and the value of subclassification of these entities is dependent on the practice. A human papillomavirus detection system based on polymerase chain reaction-restriction fragment length polymorphism identifies a smaller percentage of high-risk human papillomaviruses than mixed probe-based methods, probably because of the more precise exclusion of cross-reacting low-risk human papillomavirus. Negative HRHPV findings by either system show a markedly reduced risk of an HSIL outcome. However,…

Journal of Reproductive Medicine, 2002

To study whether nontriploid partial hydatidiform moles truly exist. We conducted a reevaluation ... more To study whether nontriploid partial hydatidiform moles truly exist. We conducted a reevaluation of pathology and ploidy in 19 putative nontriploid partial hydatidiform moles using standardized histologic diagnostic criteria and repeat flow cytometric testing by the Hedley technique. On review of the 19 moles, 53% (10/19) were diploid nonpartial moles (initially pathologically misclassified), and 37% (7/19) were triploid partial moles (initial ploidy misclassifications). One additional case (5%) was a diploid early complete mole (initially pathologically misclassified). Nontriploid partial moles probably do not exist: careful reevaluation of putative specimens will probably uncover pathologic or ploid errors in almost all cases.

The Journal of Reproductive Medicine, Mar 1, 1994

The estimated incidence of twin pregnancy consisting of hydatidiform mole and a coexisting fetus ... more The estimated incidence of twin pregnancy consisting of hydatidiform mole and a coexisting fetus is 1 per 22,000-100,000 pregnancies. Since 1965, nine patients with this entity have been treated at the New England Trophoblastic Disease Center (NETDC), Boston. One patient had a partial hydatidiform mole coexisting with a normal placenta and fetus. The other eight patients had twin pregnancies with a complete hydatidiform mole (CHM) and coexisting fetus. We compared the clinical outcomes in these 8 patients and 14 additional published case reports of multiple gestations composed of CHM and coexisting fetuses with a group of 71 patients with singleton CHM treated at NETDC. Twelve of the 22 patients (55%) with CHM and coexisting fetuses developed persistent gestational trophoblastic tumor, requiring chemotherapy. Five of these patients developed metastases requiring multiple cycles of chemotherapy to achieve remission. The presenting symptoms of multiple conception with CHM and coexisting fetuses were similar to those in patients with a singleton conception and complete mole. However, as compared to singleton CHM, patients having a multiple conception with CHM and coexisting fetuses were diagnosed at a later gestational age, had higher preevacuation beta-human chorionic gonadotropin levels and had a greater propensity to develop persistent tumor. These data indicate that patients with multiple conceptions consisting of CHM and coexisting fetuses are at high risk of developing persistent gestational trophoblastic tumor.

The Journal of Reproductive Medicine, 1998

To investigate whether changes have occurred in the pathologic and clinical features of complete ... more To investigate whether changes have occurred in the pathologic and clinical features of complete molar gestation in recent years. Twenty-three contemporary complete hydatidiform moles (1994-1997) and 20 historical complete moles (1969-1975) were compared regarding clinical features (gestational age at evacuation, maternal age, preevacuation diagnosis and persistence) and pathologic findings (volume of tissue, presence of gross cisterns, maximal villous size, percent of cavitated villi, percent of villi exhibiting circumferential trophoblast hyperplasia, and presence of necrosis and primitive stromal features). Contemporary complete moles were evacuated at an earlier mean gestational age (8.5 vs. 17.0 weeks, P = .00008). Histologically, contemporary complete moles had less circumferential trophoblastic hyperplasia (39% vs. 75% of villi, P = .03), a smaller mean maximal villous diameter (5.7 vs. 8.2 mm, P = .001), more primitive villous stroma (70% vs. 10% of cases, P = .0003) and less global necrosis (22% vs. 54% of cases, P = .02). These striking morphologic differences indicate that pathologic findings in complete molar gestations have changed significantly over the past several decades due to the current practice of very early uterine evacuation. Contemporary complete moles are often characterized by subtle morphologic alterations that may result in their misclassification as partial moles or nonmolar spontaneous abortions. It is important for pathologists to recognize the distinctive histopathologic features of early complete hydatidiform mole.

Obstetrics and Gynecology, Oct 1, 1991

Although the significance of histologic grading in hydatidiform mole has previously been investig... more Although the significance of histologic grading in hydatidiform mole has previously been investigated, most studies evaluated patients treated before 1975. Since 1975, many advances have been made in the understanding and treatment of hydatidiform mole, including the division of molar pregnancy into complete and partial hydatidiform mole. We retrospectively studied 153 cases of complete hydatidiform mole diagnosed and treated at the Brigham and Women's Hospital between 1980-1990 to determine the current prognostic significance of histologic grading in this disease. The histologic grade (based on the criteria of Hertig and Sheldon) was compared with the subsequent clinical course, including the rates of spontaneous remission, persistent gestational trophoblastic tumor, metastatic disease, "high-risk" metastatic disease, chemotherapy resistance, and survival. The histologic grade of the original complete hydatidiform mole did not correlate significantly with any index of clinical outcome evaluated.

Human pathology, 1992

To identify fetal histologic features characteristic of specific chromosomal anomalies, we review... more To identify fetal histologic features characteristic of specific chromosomal anomalies, we reviewed histologic slides of 415 cases, including therapeutic and spontaneous abortuses, stillbirths, and perinatal deaths. These included 126 cases (30%) with karyotypically confirmed trisomy 21 and 23 cases (5.5%) with trisomy 13. Two histologic abnormalities of the fetal heart were identified that correlated with specific karyotypic abnormalities: (1) a discrete central papillary muscle calcification was present in 14 of 85 (16%) cases with trisomy 21, in seven of 18 (39%) cases with trisomy 13, and in six of 255 (2%) controls (P less than .001); and (2) a focal ventricular epicardial lymphocytic infiltrate was present in 22 of 93 (24%) cases with trisomy 21 versus nine of 284 (3%) controls (P less than .001). When both histologic abnormalities coexisted, trisomy 21 was present in five of six cases (83%). Neither histologic finding was significantly associated with fetal or maternal infect...

The Journal of reproductive medicine, 2006

To identify clinical characteristics associated with developing persistent gestational trophoblas... more To identify clinical characteristics associated with developing persistent gestational trophoblastic neoplasia (GTN) after partial hydatidiform molar pregnancy (PHM). Utilizing the Donald P. Goldstein in patients who developed persistence between 1973 and 1989. Older age at diagnosis and history of prior mole were significantly more common in women who developed persistence after partial molar pregnancy in referral of patients the earlier cohort but not in idefined clinical the recent cohort. In recent years no clinical factor was at increase their risk significantly associated with rsistence. database at the New England Trophoblastic Disease Center, 284 women with partial molar pregnancy diagnosed between 1973 and 2003 were characteristics identified. Clinical charac- for pe teristics, such as gravidity, parity, age, uterine size, gestational age at diagnosis, human chorionic gonadotropin levels at presentation and time to development of persistence (GTN) were analyzed. Data were a...

The Journal of reproductive medicine, 2004

To determine if immunohistochemistry for PHLDA2 (also known as IPL and TSSC3), the product of a p... more To determine if immunohistochemistry for PHLDA2 (also known as IPL and TSSC3), the product of a paternally imprinted, maternally expressed gene, can be used as a tool in the differential diagnosis of molar gestations. Twenty-five cases (15 complete moles, 5 partial moles and five hydropic abortions) were stained by immunohistochemistry for PHLDA2 and scored (without knowledge of the diagnosis) for positivity in the villous cytotrophoblast and then compared to adjacent sections stained by p57KIP2 immunohistochemistry. All partial moles and hydropic abortions were positive for PHLDA2 and p57KIP2. There was strong PHLDA2 staining of the cytoplasm in virtually all cells of the villous cytotrophoblast, while p57KIP2 was localized to the nucleus in a subset of those cells. All complete moles were negative for both markers in the villous cytotrophoblast. Immunohistochemistry for PHLDA2 serves as a practical and reliable diagnostic marker for the discrimination of complete mole from partial...

The Journal of reproductive medicine, 2002

To determine whether the combination of flow cytometry and immunohistochemistry for p57 expressio... more To determine whether the combination of flow cytometry and immunohistochemistry for p57 expression is useful for the pathologic classification of diagnostically challenging hydatidiform moles. Six probable hydatidiform moles that were difficult to classify pathologically were reevaluated by histology, flow cytometry and immunohistochemistry for p57. In all cases, the pathologic diagnoses were easily resolved: two cases were partial moles (triploid, p57 positive), two cases were early complete moles (diploid, p57 negative), and two cases were twin gestations with normal villi (diploid, p57 positive) admixed with villi from a complete hydatidiform mole (diploid, p57 negative). Immunostaining for the paternally imprinted, maternally expressed p57 gene product is a practical and accurate adjunct to flow cytometry in the pathologic classification of hydatidiform moles.

Human pathology, 1999

Although some immature squamous lesions (papillary immature metaplasias) of the cervix have been ... more 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 H...

Human pathology, 1998

We describe a human acardiac twin with associated vascular anastomoses in a dichorionic diamnioti... more 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 oc...