Search PubMed⌕ Search

Biomedical subjects

Christopher P Crum

Publications and source records attributed to Christopher P Crum.

At least 37 records · Page 2Linked to original sources
PubMed2004

Prognostic significance of lymph node variables and human papillomavirus DNA in invasive vulvar carcinoma.

OBJECTIVE: The present study investigates the influence of lymph node pathological features and HPV DNA status on the prognosis of vulvar invasive tumors. METHODS: This study includes 184 consecutive cases of primary invasive squamous cell carcinoma of the vulva treated by radical surgery from 1975 to 1992, in São Paulo, Brazil. Clinical follow-up data was collected from patient files and hematoxilin-eosin sections were reviewed. HPV detection and typing was done by polymerase chain reaction (PCR), using specific and generic primers, followed by dot blot hybridization (DBH) with type-specific oligonucleotide probes for 19 HPV types. Age-adjusted Kaplan-Meier survival curves and Cox proportional hazards models were used to analyze the cancer risk associations for all DNA and pathology-related variables. RESULTS: Among 161 cases tested by PCR, 38 (23.6%) were positive for high-risk HPV types. Regional lymph nodes of 43 cases, including all those of HPV-positive tumors and a sample of the ones removed from patients with HPV negative tumors, were evaluated by the same method. HPV DNA was found in the lymph nodes of 10 cases. In every case, at least one lymph node was metastatic and the HPV detected in the lymph nodes were of the same type as those found in the primary tumor in all cases. Multivariate analysis including age, race, pattern of invasion, tumor thickness, inflammatory reaction, surgical margins, number of node metastases, presence of extracapsular growth, depth of invasion, and presence of high-risk HPV DNA was performed. Following automated selections of this model, node variables important for prognosis that remained were number of node metastases and presence of extracapsular growth. CONCLUSIONS: Patients with four or more node metastases associated with extracapsular spread were 5.6 (95%CI: 2.3-13.1) times more likely to die from cancer and 10.0 (95%CI: 4.0-24.9) times more likely to have a recurrence than patients without metastases. The HPV status in the tumor was not important as a prognostic factor.

Aged↗
PubMed2004

Spectroscopic diagnosis and imaging of invisible pre-cancer.

The theme of this paper is the use of optical spectroscopy to diagnose invisible pre-cancer in patients undergoing endoscopy and similar medical procedures. We describe three techniques that provide diagnostic information and two instruments to implement them, the FastEEM for studying small regions of tissue and the LSS (light scattering spectroscopy) imaging system for wide-area surveillance. The FastEEM is an optical fiber clinical device that collects spectra of reflected light and fluorescence at multiple excitation wavelengths from the tissue, all in a fraction of a second. Quantitative information is obtained in real time, without removing the tissue and without the need for staining and fixation. Three types of spectral information are extracted intrinsic fluorescence, diffuse reflectance and elastic light scattering. Each of the three analyses is based on a biophysical model, and each provides complementary quantitative physical and chemical information about cellular/tissue structures. This information is used to make a combined spectral diagnosis, a method we call tri-modal spectroscopy (TMS). Promising clinical studies are being carried out on patients undergoing routine pre-cancer surveillance in the oral cavity, the uterine cervix and the gastrointestinal tract. The LSS imaging system provides wide-area spectroscopic images of the epithelium, typically 2 cm in each dimension, depicting the size distribution and chromatin content of the cell nuclei, which are key parameters in diagnosing pre-cancer. This instrument is in preclinical stages of development, although a laboratory prototype has been used to create diagnostic images in resected colon polyp samples. The combination of the TMS/FastEEM and LSS imaging instrument will constitute a powerful new diagnostic tool, with LSS imaging to provide wide area surveillance and the TMS probe to provide detailed information on suspect tissue sites.

Cervix Uteri↗
PubMed2004

Vulvar acanthosis with altered differentiation: a precursor to verrucous carcinoma?

Verrucous carcinoma (VC) of the vulva is a rare variant of squamous cell carcinoma (SCC) of the vulva that afflicts older women and is characterized by a well-differentiated morphology with minimal nuclear atypia. The pathogenesis of VC is uncertain and a putative role for human papillomavirus (HPV) is doubtful. We analyzed 9 vulvar VCs from 7 patients diagnosed as VC of the vulva over the past 10 years at Brigham and Women's Hospital and Beth Israel Deaconess Medical Center. The patients ranged from 75 to 93 years in age (median, 83 years). One also involved the vagina and another coexisted with a keratinizing SCC. VC was associated with lichen sclerosus in 1 case; 7 others contained lichen simplex chronicus with verrucous architecture. In 7 cases, a distinctive noninvasive squamous epithelial proliferation, exhibiting a triad of marked acanthosis with variable verruciform architecture, loss of the granular cell layer with superficial epithelial cell pallor, and multilayered parakeratosis. We have designated these changes vulvar acanthosis with altered differentiation. In 5 of the 9 lesions, formalin-fixed, paraffin-embedded material was available for polymerase chain reaction analysis of HPV nucleic acids and all scored HPV negative. In conclusion, VC is a rare HPV-negative neoplasm that may be associated with other HPV-negative SCCs or its precursors, shares similar morphologic risk factors (lichen sclerosus and lichen simplex chronicus), and is frequently associated with an unusual intraepithelial lesion that can be distinguished from both classic and differentiated forms of vulvar intraepithelial neoplasia. The possibility that vulvar acanthosis with altered differentiation is a precursor to, or a risk factor for, vulvar carcinoma, merits further study.

Acanthosis Nigricans↗
PubMed2004

Evidence supporting the current management guidelines for high-grade squamous intraepithelial lesion cytology.

OBJECTIVE: The study was undertaken to provide consensus guidelines for the management of women with a cytologic interpretation of high-grade squamous intraepithelial lesion (HSIL) on cytologic examination. This review article presents relevant literature supporting the proposed guidelines. PARTICIPANTS: An independent panel of 121 experts in various aspects of the diagnosis and management of cervical cancer precursors, including representatives from 29 participating professional organizations, federal agencies, national and international health organizations, and others were invited by the American Society for Colposcopy and Cervical Pathology. CONSENSUS PROCESS: Guidelines for the management of women with HSIL cytologic results were developed through a multistep process. Draft management guidelines were developed by the HSIL working group after formal literature reviews and obtained input from the professional community at large by way of an interactive internet-based bulletin board. At the American Society for Colposcopy and Cervical Pathology Consensus Conference, September 6 through 8, 2001, in Bethesda, Maryland, the guidelines were discussed, revised, and adopted by formal vote. CONCLUSIONS: Evidence-based guidelines have been developed for the management of women with HSIL cytologic results.

Journal Article↗
PubMed2004

ZYC101a for treatment of high-grade cervical intraepithelial neoplasia: a randomized controlled trial.

OBJECTIVE: The objective of this study was to assess the safety and efficacy of a novel therapeutic, ZYC101a, for the treatment of women with histologically confirmed cervical intraepithelial neoplasia (CIN) 2/3. ZYC101a contains plasmid-DNA-encoding fragments derived from the E6 and E7 proteins of human papillomavirus (HPV) 16 and 18, and is formulated within small biodegradable microparticles. METHODS: A multicenter, double-blind, randomized, placebo-controlled trial was conducted in a group of women with biopsy-confirmed CIN 2/3. Subjects were randomized to 3 intramuscular doses of either placebo or ZYC101a (100 or 200 microg). Six months after the first injection, subjects underwent cervical conization. The primary endpoint for this study was histologically confirmed resolution of CIN 2/3. A total of 161 subjects were randomized, dosed, and evaluated for safety. After central pathology review, 127 subjects were evaluable for efficacy. RESULTS: The most common adverse events were related to the injection site, were mild to moderate, and did not worsen at later treatments. The proportion of subjects who resolved was higher in the ZYC101a groups compared to placebo (43% versus 27%), but the difference was not statistically significant (P =.12). In a prospectively defined population of women younger than 25 years (n = 43), resolution was significantly higher in the combined ZYC101a groups compared to placebo (70% versus 23%; P =.007). ZYC101a activity was not restricted to HPV-16-or HPV-18-positive lesions. CONCLUSIONS: ZYC101a was shown to be well tolerated in all patients and to promote the resolution of CIN 2/3 in women younger than 25 years. LEVEL OF EVIDENCE: I

Adolescent↗
PubMed2004

Eosinophilic dysplasia of the cervix: a newly recognized variant of cervical squamous intraepithelial neoplasia.

A proportion of cervical squamous intraepithelial lesions encountered in surgical pathology practice contain both metaplastic features and some degree of atypia [so-called eosinophilic dysplasia (ED)] that defy classification according to established criteria. To elucidate the nature of these lesions, we compared 44 cases of ED to 20 classic high-grade squamous intraepithelial lesions (HSILs) and 10 squamous metaplasias using a panel of biomarkers and human papillomavirus (HPV) testing. EDs were defined as 1) lack of normal maturation; 2) relatively abundant eosinophilic cytoplasm and distinct cell borders compared with conventional HSIL; 3) mildly to moderately increased nuclear to cytoplasmic ratio; and 4) focal dysplastic nuclei showing nuclear enlargement, hyperchromasia, variable nuclear membrane irregularities, and appreciable nucleoli. Expression of p16 (p16), MIB-1 (Ki-67) labeling index, and HPV DNA detection and typing were performed on each case. The majority of EDs showed more than three atypical cells in an entire lesion but lack of apparent features of HSIL. It was common to find neighboring cervical squamous metaplasia and/or conventional SILs (either HSIL or low-grade squamous intraepithelial lesion [LSIL]). Among the 44 cases, 18 (45%) ED lesions were found to be associated with HSIL, 15 (34%) with LSIL or condylomatous lesions, and 13 (30%) EDs were seen without any SILs in the entire specimens. Area of benign squamous metaplasia was found in all ED cases. High levels of p16 and MIB-1 expression were seen in 41 (93%) of 44 ED cases with degrees of immunoreactivity closely resembling those seen with HSIL. Of 16 EDs tested, 13 (81%) were positive for HPV DNAs. Among 10 HPV-positive cases subtyped, 9 (90%) cases contained intermediate- and/or high-risk HPVs and 1 case contained a novel HPV. In the follow-up of pure ED cases, the majority showed presence of dysplastic lesions of either HSIL or LSIL on either loop electric excision procedures or Papanicolaou test samples after a 6- to 10-week period. Therefore, ED represents an unrecognized and potentially clinically significant subgroup of cervical intraepithelial lesions. Based on the unique histologic appearance of ED, its association in some cases with HSIL, the overall immunohistochemical findings, frequent association of ED with intermediate- and/or high-risk HPV infection, and limited follow-up data, we believe that ED represents a variant of HSIL (CIN 2). Since ED possesses histologic features of both dysplasia and metaplasia, we speculate that it may arise from metaplastic cervical squamous epithelium that has subsequently become infected with intermediate- or high-risk HPV.

Adolescent↗
PubMed2004

Atypical glandular cells of undetermined significance. Outcome predictions based on human papillomavirus testing.

Cases of atypical glandular cells (AGC) diagnosed on liquid-based preparations were culled from a 3-year period. When available, residual cellular material was analyzed for human papillomavirus (HPV) by polymerase chain reaction and correlated with cytologic and histologic (biopsy) outcome. Of 178,994 cytologic cases, 187 (0.1045%) contained AGC compared with 8,740 (4.8828%) atypical squamous cells (ASC) for an AGC/ASC ratio of 0.021. HPV results and follow-up were available for 108 specimens from 106 patients. Depending on the end-point (histologic/cyto-logic), the sensitivity range of HPV testing for significant cervical disease (high-grade squamous intraepithelial lesion [SIL], adenocarcinoma in situ [ACIS], invasive carcinoma) was 83% with a specificity range of 78% to 82%, a positive predictive value of 57% to 61%, and a negative predictive value of 91% to 95%. Fifteen false-positive results included concurrent ASC or low-grade SIL, ASC on follow-up cytology, and previous ACIS with a negative follow-up cone biopsy result. Noncervical glandular neoplasia (including atypical endometrial hyperplasia) was confirmed in 13 cases (1 recurrent), only 2 of which scored positive for HPV. HPV-positive AGC has a substantially higher positive predictive value for significant disease than ASC (61% vs historic 20%) and merits consideration in the triage of patients with atypical endocervical cells not otherwise specified. However, noncervical or other HPV-negative glandular neoplasia must be considered in all patients with AGC, particularly older patients.

DNA, Viral↗
PubMed2003

Innovations in understanding the biology of cervical cancer.

Revelation of the connection between the human papillomavirus (HPV) and cervical neoplasia and invasive cervical cancer is prompting new investigations to expand that understanding and promote vaccines, gene therapy, and other interventions. At the Second International Conference on Cervical Cancer (Houston, TX, April 11-14, 2002), laboratory and clinical researchers reported advances in new studies meant to increase understanding of the natural history of HPV and cervical intraepithelial neoplasia, to evaluate new cervical cancer screening techniques, and to promote new therapies. Using K14-HPV type 16 transgenic mice, researchers are investigating the effects of estrogen on cervical cancer carcinogenesis, and results are lending support to epidemiological theories showing a difference in HPV infection rates and the development of cervical lesions in women using oral contraceptives. Other work involves investigating genes that are up-regulated by HPV infection and the role of the p53 homologue, p63, in cervical neoplasia evolution. Telomerase also is under investigation as a biomarker in high-risk populations. Gene therapy that replaced p53 in cervical cancer cell lines in vitro and a nude mouse model inhibited cell and tumor growth, confirming previous findings in squamous epithelial carcinomas of the head and neck. Furthermore, research in intracellular targeting of antigens to subcellular locations shows promise for treating cervical cancer preclinically. Identification of molecular changes in cervical cancer and knowledge about the importance of HPV infection in cervical cancer can lead to new therapies to treat existing cervical cancer and, in the long term, prevent the disease.

Animals↗
PubMed2003

The significance of the Papanicolaou smear diagnosis of low-grade squamous intraepithelial lesion cannot exclude high-grade squamous intraepithelial lesion.

BACKGROUND: Cervical cytologic specimens that show a low-grade squamous intraepithelial lesion (LSIL) occasionally contain a few cells that are suspicious for, but not diagnostic of, a high-grade squamous intraepithelial lesion (HSIL). In such cases, a diagnosis of LSIL cannot exclude HSIL is rendered. The objective of the current study was to assess the positive predictive value (PPV) for HSIL in follow-up cervical biopsies for these cases. METHODS: One hundred forty-four women with a Papanicolaou (Pap) diagnosis of LSIL cannot exclude HSIL and their follow-up cervical biopsies were reviewed. Results were compared with a control group of 155 women with a Pap diagnosis of LSIL. A subset of biopsies was tested and typed for human papillomavirus (HPV) DNA by polymerase chain reaction amplification using consensus primers followed by restriction fragment length polymorphism analysis. HPVs were scored as low-risk or high-risk types. RESULTS: Women with LSIL cannot exclude HSIL had a higher incidence of HSIL (PPV = 29%) on follow-up cervical biopsy than the control group (PPV = 15%, P < 0.01). In addition, SIL, indeterminate grade was diagnosed in 10% of cervical biopsies in the study group as compared with 4% in controls. Review of Pap smears from the study group showed that there were 3 types of cells suspicious for a high-grade lesion: atypical squamous metaplastic cells (62%), atypical keratinized cells (20%), and dysplastic cells of borderline nuclear-to-cytoplasm ratio (18%). HPV analysis confirmed the presence of high-risk HPV types in the study cases with high-grade cervical biopsies. CONCLUSIONS: Women with a Pap diagnosis of LSIL cannot exclude HSIL appear to be more likely to harbor a high-grade lesion than those diagnosed with LSIL alone. Its use appears warranted. Women with this diagnosis merit appropriate clinical follow-up to exclude HSIL.

Adult↗
PubMed2003

Cervical cancer screening: from the Papanicolaou smear to the vaccine era.

In the next 20 years, cervical cancer screening will have evolved through four phases. The first was traditional screening, which has been associated with a two-thirds reduction in cancer incidence and death rates in the last 50 years and currently is ending. We are entering a second phase, human papillomavirus (HPV) testing, for managing cytologic abnormalities and possibly for primary screening. A third phase, new in development, proposes the use of host biomarkers (or combinations thereof) as either surrogates of HPV infection or, potentially, indicators to assess cancer risk and concentrate available resources on a subset of women. The fourth and, likely, final phase will be screening in an era of vaccines. If HPV vaccines are successful, the pool of at-risk individuals and the prevalence of papillomaviruses that place them at risk will gradually shrink. In this climate, screening strategies that target HPVs alone (as opposed to cytologic testing) may become more economical. If so, previous strategies may become obsolete as the balance of cervical cancer prevention shifts from traditional screening to primary prevention coupled with HPV testing.

Biomarkers, Tumor↗
PubMed2003

Co-expression of p16(INK4A) and laminin 5 gamma2 by microinvasive and superficial squamous cell carcinomas in vivo and by migrating wound and senescent keratinocytes in culture.

The high frequency of mutation, deletion, and promoter silencing of the gene encoding p16(INK4A) (p16) in premalignant dysplasias and squamous cell carcinomas (SCC) of epidermis and oral epithelium classifies p16 as a tumor suppressor. However, the point during neoplastic progression at which this protein is expressed and presumably impedes formation of an SCC is unknown. Induction of p16 has been found to be responsible for the senescence arrest of normal human keratinocytes in culture, suggesting the possibility that excessive or spatially abnormal cell growth in vivo triggers p16 expression. We examined 73 skin and oral mucosal biopsy specimens immunohistochemically to test this hypothesis. p16 was not detectable in benign hyperplastic lesions, but instead was expressed heterogeneously in some dysplastic and carcinoma in situ lesions and consistently at areas of microinvasion and at superficial margins of advanced SCCs. p16-positive cells in these regions coexpressed the gamma2 chain of laminin 5, identified previously as a marker of invasion in some carcinomas. Normal keratinocytes undergoing senescence arrest in culture proved to coordinately express p16 and gamma2 and this was frequently associated with increased directional motility. Keratinocytes at the edges of wounds made in confluent early passage cultures also coexpressed p16 and gamma2, accompanying migration to fill the wound. These results have identified the point during neoplastic progression in stratified squamous epithelial at which the tumor suppressor p16 is expressed and suggest that normal epithelia may use the same mechanism to generate non-dividing, motile cells for wound repair.

Animals↗
PubMed2003

Immunophenotypic and viral (human papillomavirus) correlates of vulvar seborrheic keratosis.

Human papillomavirus (HPV) infections of the genital mucosa classically present as warts (condylomata) and are traditionally defined by the presence of viral cytopathic effect (koilocytosis). In recent years, HPV has been detected in vulvar epithelial changes lacking koilocytosis, including squamous papillomas and lesions closely resembling seborrheic keratosis (SK). The purpose of this study was to determine the frequency and type of HPV associated with vulvar SK (VSK) and to compare expression of biomarkers (p16, Mib-1, and cyclin E) in these lesions. Sixty-seven biopsy specimens, including 25 VSKs, 10 nondiagnostic vulvar acanthoses, 12 fibroepithelial polyps (FEPs), and 20 nongenital cutaneous SKs (CSKs), were studied. Biopsy specimens were typed for HPV by polymerase chain reaction and immunostained with Mib-1, cyclin E, and p16(INK4) antibodies. Eighteen of 25 VSKs (72%), 0 of 10 nondiagnostic vulvar acanthuses (0%; P = 0.0001), 2 of 12 FEPs (16.7%; P = 0.004), and 3 of 20 CSKs (15%; P = 0.0002) scored HPV positive. Increased Mib-1 staining was significantly more common in VSKs than in other vulvar lesions, but not in CSKs; increased p16 and cyclin E staining was not more common. VSKs are morphologically and immunophenotypically similar to CSKs but distinct by their association with HPV. Unlike the cervix, p16 and cyclin E will not consistently distinguish VSKs from HPV-negative lesions due to underexpression in low-risk HPV infections (p16) and less-restricted expression in vulvar lesions (cyclin E). Whether CSKs are associated with other forms of HPV infection remains to be determined.

Adolescent↗
PubMed2003

Immunotherapy of human cervical high-grade cervical intraepithelial neoplasia with microparticle-delivered human papillomavirus 16 E7 plasmid DNA.

OBJECTIVE: The purpose of this study was to evaluate the safety of the administration of a bacterial expression plasmid encoding a 13 amino acid sequence that is highly homologous with human papillomavirus E7 within poly (lactide-co-glycolide) microparticles (ZYC101) in women with HLA A2+ antigen and persistent cervical intraepithelial neoplasia grade 2/3 and human papillomavirus 16. STUDY DESIGN: Fifteen women entered an institutional review board-approved dose-escalating phase I study with the use of three levels of blood monitoring and urine studies, Papanicolaou tests, and colposcopy. Escalation required no serious adverse events. Immunologic responses were evaluated in peripheral blood with the use of human papillomavirus peptide-stimulated interferon gamma enzyme-linked immunosorbent assay for T-cell reactivity. In cervical secretions, immunoglobulin A anti-human papillomavirus 16 E2 concentrations were measured. Three doses every 3 weeks were followed 4 weeks later by surgical excision. RESULTS: No serious adverse events occurred. Five women had complete histologic responses; 11 women had human papillomavirus-specific T-cell responses. Four of five complete histologic responses developed immunoglobulin A anti-E2-specific antibody. CONCLUSION: ZYC101 warrants further investigation because of a 33% complete histologic responses, a 73% immunologic response, and no serious adverse events.

Adult↗
PubMed2003

Symposium part 1: Should the Bethesda System terminology be used in diagnostic surgical pathology?: Point.

During the past 50 years, the histologic classification of cervical intraepithelial neoplasia (CIN) has evolved to incorporate the entire spectrum of genital papillomavirus infections, segregating those lesions with the higher risk of containing prototypic high-risk human papillomavirus types, and recently has meshed with treatment algorithms that include loop electrical excision procedures and follow-up alone. This review describes a classification system that divides CIN into categories of low-grade (CIN 1) and high-grade (CIN 2 and CIN 3). To successfully apply this system, the practitioner must efficiently exclude nonneoplastic entities and base the distinction of CIN 1 from CIN 2/3 on criteria that recognize the effects of viral oncogenes on replicating cells. This is achieved by basing the diagnosis of CIN 1 on uniform polarized epithelial growth, low mitotic index, low mitotic counts, and minimal parabasal cell anisokaryosis and coarse chromatin and CIN 2 on the presence of these features or abnormal mitoses. Simply put, the definition of CIN 2 (or higher) is the presence of atypical immature cells in the biopsy that if seen in a cytologic smear would merit a diagnosis of high-grade squamous intraepithelial lesion. In essence, a successful two-grade system requires careful application of cytologic criteria in a histologic milieu. This model is illustrated in a set of 25 images that underscore the importance of excluding benign changes (with the appropriate use of biomarkers), segregating unusual variants of low-grade squamous intraepithelial lesions, and identifying the morphologic transition to high-grade squamous intraepithelial lesions (CIN 2 or CIN 3) with an acceptable level of reproducibility.

Female↗
PubMed2003

Biomarkers in diagnostic obstetric and gynecologic pathology: a review.

Until recently, the histologic diagnosis of obstetrical and gynecologic neoplasia was based principally on morphologic criteria. However, interobserver reproducibility for entities such as squamous intraepithelial, endometrial, and trophoblastic disease varies widely between observers. This inherent variability in interpretation between individuals has led to wide ranges in diagnostic precision between practices, and in many cases, between recognized experts. The advent of immunohistochemistry, and the more recent accelerated discovery of new genes and their functions has resulted in the discovery of cellular proteins or nucleic acids that are differentially expressed in tumors. When applied in conjunction with existing histologic criteria, these "biomarkers" have the potential to enhance diagnostic consistency and reproducibility. The gains expected are to practicing diagnostic pathologists (who will enjoy greater diagnostic consistency) and to academics (for whom biomarkers may uncover new pathways unappreciated by histologic diagnosis alone). However, fundamental to the success in both arenas will be critical analysis of the potential pitfalls in immunohistochemistry, strict validation of new markers as they arrive in the field, and a realistic view of their value in the laboratory management of obstetrical and gynecologic diseases.

Biomarkers, Tumor↗
PubMed2003

Hertig and beyond: a systematic and practical approach to the endometrial biopsy.

Evaluation of the endometrial biopsy is a challenge to practicing pathologists, largely due to the wide range of morphologic patterns resulting from both normal and abnormal cyclic changes, exogenous hormones, infections, and intrauterine tumors. Successfully addressing these challenges requires that the practitioner (i) understand the clinical questions being asked, (ii) have a realistic expectation for answering these questions, and (iii) have a systematic approach to resolving these questions in the context of these expectations. The approach outlined begins with the subdividing of women with endometrial alterations into three general categories: (i) women in their fourth decade undergoing evaluation for infertility, (ii) women in their fifth decade who experience abnormal uterine bleeding, and (iii) women in their sixth decade and beyond who experience postmenopausal bleeding. The clinical expectations for each group are unique, as are the morphologic patterns most commonly encountered. Algorithms for the laboratory management of cyclic changes, dysfunctional bleeding, and mixed-pattern endometria are provided, as are pitfalls in interpretation and exclusion of neoplasia.

Adult↗