Gastrin-releasing peptide-like immunoreactivity is present in human maternal and fetal placental membranes.

Extracts of human term amnion, placenta, and chorion/decidual tissue (n = 5) contained gastrin-releasing peptide-like immunoreactivity (GRPLI) in amounts of 4.7 +/- 2.9 (pmol/g wet wt; mean +/- SEM), 3.6 +/- 1.1 and 2.9 +/- 1.5, respectively. Using C-terminally directed antisera and gel filtration chromatography and reverse-phase high-performance liquid chromatography (HPLC), each tissue contained molecular forms consistent with the presence of GRP1-27 and GRP18-27 but also contained larger amounts of two GRPLI peaks, which apparently are novel GRP-like peptides. In contrast, tissue extracts of human fetal lung contained only GRP1-27, GRP14-27, and GRP18-27. Using RT-PCR and specific GRP primers and probes, messenger RNA encoding for GRP was readily demonstrable from 6-weeks gestation throughout pregnancy to term in full-thickness membranes, placental villi, and decidua. Positive immunohistochemical staining for GRP occurred in extravillous trophoblasts in decidual septa and fetal membranes, cytotrophoblasts, syncytiotrophoblast, and certain stromal cells in placental villi and amniotic epithelium. GRPLI and GRP messenger RNA were present from the earliest dates examined (6-9 weeks) throughout pregnancy to term. Given the proven trophic nature of GRP and related peptides, these peptides may play important roles in maternal, placental, and fetal development during human pregnancy.

Second genital primary squamous neoplasms in vulvar carcinoma: viral and histopathologic correlates.

OBJECTIVE: To determine whether vulvar squamous cell carcinomas associated with certain morphologic features and/or human papillomavirus (HPV) nucleic acids were more likely to be associated with other genital primary squamous neoplasms. METHODS: We surveyed 169 invasive squamous cell carcinomas of the vulva and correlated associated vulvar intraepithelial neoplasia (VIN), invasive growth patterns resembling VIN (intraepithelial-like or basaloid), and the presence of HPV nucleic acids by in situ hybridization with a history of a second primary squamous neoplasm of the genital tract. RESULTS: Twenty-two patients (13%) had a history of a second primary. An intraepithelial growth pattern or an associated VIN correlated significantly with HPV, at P = .0005 and P = .007, respectively, and with a second primary, at P = .077 and P = .009, respectively. When HPV-positive, the same histologic variables correlated with a second primary at P = .099 and P = .25, respectively. Compared with cases lacking both these histologic features and HPV, they correlated with multifocal disease at P = .01 and P = .003. CONCLUSIONS: The findings of HPV nucleic acids, tumor growth patterns, and associated VIN are interrelated and confer risk of other genital primary neoplasms in women with vulvar carcinoma. This supports the concept that subsets of vulvar carcinoma may be distinguished not only by morphology and HPV DNA, but also by a distinctly different risk of a second genital primary neoplasm.

Pathobiology of human papillomavirus.

Human papillomavirus (HPV) has long been recognized as the etiologic agent of skin and genital warts, and only recently has an oncogenic role been attributed to the virus. This article discusses the classification, genetics, and pathogenesis of HPV. HPV detection, epidemiology of HPV and cervical neoplasia, and HPV infections in the genital tract are also reviewed.

The effectiveness of cytologic evaluation of products of conception.

In therapeutic abortions, the major issue of concern to physicians and patients is the documentation of an intrauterine pregnancy and its successful termination. We describe an inexpensive cytologic approach by which results can be obtained in a few hours and a permanent method of documentation provided. Three hundred cases of therapeutic abortion were evaluated by the cytologic method, and 93.7% of cases were positive, ie, they demonstrated the presence of nucleated red blood cells and/or placental villi. By routine histologic examination, 96.3% of the cases were positive. In only 2% of cases was the cytologic finding negative and the histologic finding positive. If the histologic finding is also negative, we recommend, based on our data, that the patient be reevaluated.

Female adnexal tumor of wolffian origin.

We describe a female adnexal tumor of probable wolffian origin with stage 2B disease. The presence of peritoneal implants suggests a more aggressive clinical course than is usually expected. We present the findings of light microscopic and ultrastructural evaluation as well as those of immunohistochemical and DNA ploidy analysis, which, to our knowledge, have not been previously described for this type of tumor.

Primary small cell carcinoma of the vagina arising in a background of atypical adenosis.

BACKGROUND: Primary small cell carcinoma of the vagina is rare, with only nine cases published to date. The authors report what they believe to be the first case of primary small cell carcinoma of the vagina arising in a setting of atypical adenosis. METHODS: The tumor was studied by light and electron microscopy and immunohistochemistry. RESULTS: Intracytoplasmic electron-dense neurosecretory type granules were seen, and immunohistochemical demonstration of chromogranin A was documented. CONCLUSIONS: These features were found to be similar to small cell carcinomas arising elsewhere in the female genital tract (i.e., cervix, endometrium, ovary, and vulva).

Nondiagnostic squamous atypia of the cervix (atypical squamous epithelium of undetermined significance): histologic and molecular correlates.

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.

The binucleate squamous cell: histologic spectrum and relationship to low-grade squamous intraepithelial lesions.

The consistent histologic distinction of HPV-related precursor lesions from nonspecific epithelial changes is hampered by the fact that the scoring of nuclear atypia is subjective and nuclear alterations or cytoplasmic halos may occur with both HPV and non-HPV-related changes. To determine the potential role of another parameter--bi- or multinucleated cells--in the diagnosis of HPV-related lesions, we analyzed a series of epithelial alterations for anisokaryosis, hyperchromasia, and cytoplasmic halos and correlated their presence with the maximum of binucleate cells per high-power field (hpf) and the detection of HPV DNA. A positive correlation was seen between the presence of both anisokaryosis and hyperchromasia and the number of binucleate cells/hpf (p = 0.011) and the presence of HPV nucleic acids by in situ hybridization (p = 0.005). Only one of 23 (5.3%) known HPV-positive lesions did not exhibit any binucleate cells. These findings indicate that, although binucleation may be associated with a spectrum of both HPV and non-HPV related changes, it is most conspicuous and virtually always present in association with HPV-positive low-grade precursor lesions. Thus, this parameter may be useful to confirm the presence when other parameters suggest the diagnosis of a low-grade squamous intraepithelial lesion.

Mucinous endometrial epithelial proliferations: a morphologic spectrum of changes with diverse clinical significance.

BACKGROUND: Mucinous differentiation of the endometrium can occur in a spectrum of changes ranging from benign (metaplasia) to malignant (adenocarcinomas with mucinous differentiation). Mucinous proliferations with simple architecture are generally considered benign; however, more complex growth patterns have an uncertain biologic behavior, particularly when these changes are focal and/or are encountered in biopsy or curettage material. The disparity between the degree of cytologic atypia and the neoplastic potential makes their interpretation difficult in routine practice. We categorized and prospectively studied a series of these lesions based upon their degree of architectural complexity and correlated them with follow-up curettings and hysterectomies over a period of three years. METHODS: Mucinous proliferations of the endometrium were subdivided into three categories (A, B, or C) based upon increasing degrees of architectural complexity. Type A were mucin-containing epithelial cells, present singly or in small tufts, within architecturally benign glands or involving the endometrial surface. Type B proliferations were more complex, consisting of mucin-containing epithelial cells forming small pseudoglands with rigid, punched out spaces and no supporting stroma Conspicuous cytologic atypia or architectural features such as a filiform growth pattern characterized type C alterations. One hundred two curettings and 36 hysterectomies from 52 patients were reviewed. RESULTS: Patient's ages ranged from 39 to 71 years (median, 55 yr); 41 patients (80%) were over age 50. Twenty patients (40%) were receiving hormone replacement therapy. Nineteen type A, 17 type B, and 16 type C mucinous endometrial proliferations were analyzed. Excluding those cases in which a conventional coexisting precancerous lesion was also present in the initial endometrial sample, the percentages of endometrial carcinoma following a curettage diagnosis of types A to C, respectively, were 0, 64.7%, and 100%. Carcinomas following type B alterations were all well-differentiated and all were confined to the endometrium or inner third of the myometrium. CONCLUSION: Mucinous endometrial proliferations comprise a spectrum subdivisable into biologically meaningful subsets. A high percentage of type B alterations were found to have endometrial adenocarcinoma on follow-up; however, all were well-differentiated and showed either no or minimal invasion. This finding suggests that the absence of cytologic atypia in complex mucinous lesions identifies subsets of lesions at low concurrent risk for deeply invasive cancer. The presentation of type B lesions as predominantly microglandular surface lesions without co-existing atypical hyperplasias suggests that a subset of well-differentiated adenocarcinomas arise via neoplastic alterations in surface epithelium.

Analysis of HPV-positive and -negative vulvar carcinomas for alterations in c-myc, Ha-, Ki-, and N-ras genes.

Mutation or overexpression of certain host genes, including c-myc, Ha-ras, and Ki-ras, have been associated with genital squamous neoplasia, specifically in the cervix, and have been implicated in the natural history of these tumors. The relationship of these host gene alterations to vulvar squamous cell carcinomas has not been previously studied. We analyzed archival material from 13 human papillomavirus-positive and -negative vulvar squamous cell carcinomas for mutations in Ha-, Ki-, and N-ras genes, and a smaller number of fresh samples for c-myc amplification, using PCR-based assays. For comparison, eight cervical squamous cell carcinomas (three fixed and five fresh) were also analyzed. Analysis for ras mutations revealed a previously reported silent allelic variant at nucleotide 1744 in the Ha-ras gene, but no mutations in codons 12, 13, or 61. Similarly, genomic amplification of c-myc beyond a maximum of three haploid copies was not identified in the cases. These findings indicate that alterations in myc or ras sequences are not linked to vulvar squamous cell carcinomas or to the presence or absence of HPV nucleic acids. Moreover, they apparently will not distinguish vulvar from cervical carcinomas, both groups appearing to be unlikely to harbor these sequence alterations.