Rebecca N. Baergen

Phase III Trial of Carboplatin and Paclitaxel Compared With Cisplatin and Paclitaxel in Patients With Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study

PURPOSE In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population. PATIENTS AND METHODS Patients with advanced ovarian cancer and no residual mass greater than 1.0 cm after surgery were randomly assigned to receive cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 (arm I), or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours (arm II). RESULTS Seven hundred ninety-two eligible patients were enrolled onto the study. Prognostic factors were similar in the two treatment groups. Gastrointestinal, renal, and metabolic toxicity, as well as grade 4 leukopenia, were significantly more frequent in arm I. Grade 2 or greater thrombocytopenia was more common in arm II. Neurologic toxicity was similar in both regimens. Median progression-free survival and overall survival were 19.4 and 48.7 months, respectively, for arm I compared with 20.7 and 57.4 months, respectively, for arm II. The relative risk (RR) of progression for the carboplatin plus paclitaxel group was 0.88 (95% confidence interval [CI], 0.75 to 1.03) and the RR of death was 0.84 (95% CI, 0.70 to 1.02). CONCLUSION In patients with advanced ovarian cancer, a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel.

Fetal Vascular Obstructive Lesions: Nosology and Reproducibility of Placental Reaction Patterns

The purpose of this study was to assemble and test the reliability of a complete set of the placental reaction patterns seen with chronic fetal vascular obstruction in the hope that this might provide a standardized diagnostic framework useful for practicing pathologists. Study cases (14 with fetal vascular obstructive lesions, 6 controls) were reviewed blindly by seven pathologists after agreement on a standard set of diagnostic criteria. Majority vote served as the gold standard and 80% of the 180 diagnoses rendered (9 diagnoses each for 20 cases) were agreed upon by at least six of the seven scores. The sensitivity of individual diagnosis relative to the group consensus averaged 83% (range, 69–100%) and specificity averaged 91% (range, 86–100%). Reproducibility was measured by unweighted kappa-values and interpreted as follows: < 0.2, poor; 0.2–0.6, fair/moderate; > 0.6, substantial. Kappa values for lesions of distal villi were generally superior to those for lesions involving large fetal vessels: avascular villi (0.49), villous stromal-vascular karyorrhexis (0.58), and villitis of unknown etiology (VUE) with stem villitis and avascular villi (0.65) versus large vessel thrombi (any vessel, 0.34; chorionic plate vessel, 0.40) and intimal fibrin cushions (recent, 0.47; remote, 0.78). Reproducibility for a global impression of any villous change consistent with chronic fetal vascular obstruction was substantial (0.63), while that for a more severe subgroup was moderate (0.44). Three points are worthy of emphasis. Our system separately recognizes, but later combines, uniformly avascular villi and villous stromal-vascular karyorrhexis as manifestations of the same underlying process. We propose that this combined group of villous lesions be dichotomized with the terms fetal thrombotic vasculopathy or extensive avascular villi (and/or villous stromal-vascular karyorrhexis) being reserved for the group with 15 or more affected terminal villi per section. Scattered foci of avascular villi (and/or villous stromal-vascular karyorrhexis) could be used to describe less severe cases. Finally, we distinguish VUE with stem villitis and avascular villi (obliterative fetal vasculopathy) as a distinct process with substantial perinatal morbidity.

Examination of the Placenta

Most placentas are normal, as are most babies. Therefore, an examination of all placentas may not be warranted, although this has been advocated repeatedly. Practical guidelines, including indications for the examination, have been published by the College of American Pathologists (Langston et al. 1997). This reference describes in tabular form the major abnormalities and their association with clinical features. Booth et al. (1997) inquired what reasons constituted the submission of a placenta for examination and found, regrettably, that it was Cesarean section delivery. This is hardly a good reason, as will be seen. A large number of surgical deliveries are repeat sections and have little impact on perinatal problems for which placental examination might be useful. Altshuler and Hyde (1996), on the other hand, found that 92% of placentas for which an examination was requested by an obstetrician or neonatologist had relevant pathology. Salafia and Vintzileos (1990) made a strong plea for the study of all placentas by pathologists. We concur with this view, as the sporadic examination does not provide sufficient training for young pathologists and it does not allow the “routine” pathologist to obtain sufficient background knowledge as to what constitutes a truly normal placenta. Another reason for the examination of all placentas is today’s litigious climate; it makes study of placentas highly desirable (see Chap. 27). Furthermore, it has been shown repeatedly that a placental examination is needed to understand the causes of perinatal deaths. This was demonstrated, especially for stillbirths, by the study of Las Heras et al. (1994). The most important lesions were found in the umbilical cord (18%), with inflammatory lesions being second. Altshuler (1999) wrote a searching essay on the “placenta-related epidemiology” from his vast experience in these matters. Because placentas differ widely in shape, size, and in appearance, the novice must become familiar with this spectrum of placental shapes. To do so, a large number of placentas must be examined routinely. In hospitals with large numbers of deliveries, however, it may be prudent to select placentas for examination by the pathologist.

h-Caldesmon, a novel smooth muscle-specific antibody, distinguishes between cellular leiomyoma and endometrial stromal sarcoma.

The difficulty in distinguishing between smooth muscle and endometrial stromal-derived neoplasms of the uterine corpus is a notorious and clinically relevant problem in pathology of the female genital tract. Immunohistochemistry offers some aid in resolving this difficulty, because the expression of smooth muscle markers is reputed to indicate smooth muscle derivation. This expression, however, is not entirely specific, and difficult cases may still present in which immunohistochemistry is of little help. To explore this problem, the authors evaluated the expression of traditional muscle markers and high-molecular-weight caldesmon (h-cal), an actin and tropomyosin binding protein that has recently been described as a useful muscle marker, in uterine leiomyosarcoma (LMS), cellular leiomyomata (CL), and endometrial stromal sarcoma (ESS). Formalin-fixed and paraffin-embedded tissue sections from nine LMSs, 11 CLs, and 12 ESSs were evaluated with commercially available monoclonal antibodies against smooth muscle actin (SMA), desmin, and h-cal. Established morphologic criteria were used to classify the neoplasms. We found that there was, as expected, a significant difference in the expression of traditional smooth muscle markers (SMA and desmin) between tumors derived from smooth muscle and those derived from endometrial stroma (p = 0.005 for LMS and 0.013 for CL). We further found that h-cal was most useful in distinguishing between CL and ESS (p = 0.01). A significant difference between h-cal expression in LMS versus ESS was not found. Of note, one ESS expressed both SMA and desmin but lacked h-cal expression. Our findings confirm the most useful immunohistochemical data to date; smooth muscle neoplasms are generally distinguishable from endometrial stromal tumors by the expression of conventional muscle markers. We also report here that h-cal is useful more specifically in the differentiation of CL from ESS.

Morbidity, Mortality, and Placental Pathology in Excessively Long Umbilical Cords: Retrospective Study

The purpose of this study was to compare specific fetal, maternal, and placental factors, including neonatal morbidity and mortality, in infants with umbilical cords (UCs) of normal length to the same factors in infants with excessively long umbilical cords (ELUCs). We performed an 18-year retrospective chart review of the medical records of mothers and infants with ELUCs (926 cases) and normal-length UCs (200 cases) and recorded maternal factors, fetal factors, and neonatal outcomes. Corresponding placental pathologic reports and slides were reviewed. Statistical analysis comparing the two groups included univariate and multivariate analyses.ELUCs were significantly associated with certain maternal factors (systemic diseases, delivery complications, increased maternal age), fetal factors (non-reassuring fetal status, respiratory distress, vertex presentation, cord entanglement, fetal anomalies, male sex, increased birth weight), gross placental features (increased placental weight, right-twisted cords, markedly twisted cords, true knots, congestion), and microscopic placental features (nucleated red blood cells, chorangiosis, vascular thrombi, vascular cushions, meconium, increased syncytial knots, single umbilical artery). Some of these histopathologic features have previously been associated with fetal hypoxia and/or altered blood flow in the placenta. Infants with ELUCs were found to be at a significantly increased risk of brain imaging abnormalities and/or abnormal neurological follow-up. In addition, mothers with a history of an ELUC are at increased risk of a second long cord.

Reclassification of serous ovarian carcinoma by a 2-tier system: a Gynecologic Oncology Group Study.

A study was undertaken to use the 2‐tier system to reclassify the grade of serous ovarian tumors previously classified using the International Federation of Gynecology and Obstetrics (FIGO) 3‐tier system and determine the progression‐free survival (PFS) and overall survival (OS) of patients treated on Gynecologic Oncology Group (GOG) Protocol 158.

Diagnostic Accuracy of Cervical Low-Grade Squamous Intraepithelial Lesions Is Improved With MIB-1 Immunostaining.

There is considerable interobserver variation in the diagnosis of low-grade squamous intraepithelial lesion that involves mature squamous epithelium. Our aim was to evaluate the utility of MIB-1 immunostaining as an adjunct test to increase diagnostic accuracy. Consecutive cervical biopsies originally diagnosed as normal (n = 26) or low-grade squamous intraepithelial lesion (n = 23) were reviewed by three pathologists to obtain a consensus diagnosis. MIB-1 immunostaining was performed, and positive staining was defined as a cluster of at least two stained nuclei in the upper two thirds of the epithelial thickness. Human papillomavirus (HPV) DNA detection was performed using a polymerase chain reaction assay. All cases were subsequently reclassified as low-grade squamous intraepithelial lesion (LSIL) or normal (NL) when two or three of three gold standard criteria were satisfied (LSIL gold standard criteria = consensus diagnosis of LSIL, HPV+, MIB-1+; NL gold standard criteria = consensus diagnosis of NL, HPV−, MIB-1−). Using the gold standard diagnoses, we have identified that 14 normal cases (36%) were originally overdiagnosed as LSIL, and one LSIL case (10%) was originally underdiagnosed as normal. All MIB-1-positive cases were HPV+ and identified as LSIL in the consensus review. All MIB-1-negative cases were NL by gold standard criteria. The sensitivity (1.0) and the specificity (1.0) of MIB-1 staining for identifying LSIL were superior to the sensitivity (0.9) and the specificity (0.8) of HPV testing. In conclusion, MIB-1 is a highly sensitive and specific marker for identifying low-grade squamous intraepithelial lesion and is helpful in verifying the diagnosis of equivocal cases.

Enrichment for DNA mismatch repair-deficient cells during treatment with cisplatin

In addition to playing a role in tumorigenesis, loss of DNA mismatch repair results in low‐level intrinsic resistance to cisplatin and carboplatin. We used a mismatch repair‐deficient (clone B) and ‐proficient (clone B/rev) pair of Chinese hamster ovary sublines to determine the ability of cisplatin to enrich for repair‐deficient cells during growth in vitro and in vivo. Clone B cells were 1.8‐fold resistant to cisplatin as measured by a clonogenic assay. These cells were molecularly engineered to express constitutively the green fluorescent protein, and changes in the fraction of these repair‐deficient cells were monitored by flow cytometric analysis. A single 1‐hr exposure to cisplatin at an IC50 concentration enriched populations initially containing either 5 or 10% clone B cells by 81 and 75%, respectively, when measured at 5 days. Enrichment increased as a function of drug concentration to 158 and 169%, respectively, following an IC90 exposure. When grown as a xenograft, a single LD10 dose of cisplatin enriched the tumors by 48% from 4.6 to 6.8% repair‐deficient cells (p = 0.04). To determine whether similar enrichment occurs during the treatment of human ovarian cancer patients, paired tumor samples were obtained from 38 patients before and after treatment with a minimum of 3 cycles of platinum drug‐based primary chemotherapy and analyzed immunohistochemically for changes in the fraction of tumor cells expressing hMHL1. Following treatment there was a reduction in hMLH1 staining in 66% of the cases (p = 0.0005). Our results demonstrate that, despite the fact that loss of mismatch repair yields only modest levels of cisplatin resistance, even a single exposure to cisplatin produces quite a marked enrichment for repair‐deficient cells in vitro andin vivo. Our results are consistent with the concept that treatment with cisplatin or carboplatin selects for pre‐existing mismatch repair‐deficient cells, and that this contributes to the frequent development of clinical resistance. Int. J. Cancer 77:741–746, 1998.

Early uterine serous carcinoma: clonal origin of extrauterine disease.

Uterine serous carcinoma (USC) is an uncommon but aggressive type of endometrial carcinoma that is frequently associated with extrauterine disease despite minimal or no myometrial invasion. The origin of the extrauterine tumors in this setting remains controversial. The majority of USCs (90%) and endometrial intraepithelial carcinomas (78%), the putative precursor of USC, have p53 mutations, suggesting that p53 alterations occur early in the pathogenesis of USC. To determine if the extrauterine tumors associated with minimally invasive USC and endometrial intraepithelial carcinoma (EIC) represent metastases or multifocal primary tumors, we examined the mutational pattern of the p53 gene in 3 cases of minimally invasive USC and 1 case of EIC and in the corresponding extrauterine tumors associated with each of the cases. In all 4 cases, the primary tumors and the associated extrauterine tumor foci had identical p53 mutations. Our results support the premise that extrauterine serous tumors found in association with EIC or minimally invasive USC represent a unifocal process and thus are early metastases.

Manual of pathology of the human placenta

Evaluation of the First Trimester Products of Conception.- Evaluation of the Second Trimester Products of Conception.- Macroscopic Evaluation of the Second and Third Trimester Placenta.- Microscopic Evaluation of the Second and Third Trimester Placenta.- Early Placental Development.- Chorionic Villi: Histology and Villous Development.- Overview and Microscopic Survey of the Placenta.- Extravillous Trophoblast, Trophoblast Invasion and Fibrinoid.- Multiple Gestation: General Aspects.- Multiple Gestation: Twin Variants and Related Conditions.- Abortion and Chromosomal Anomalies.- Postpartum Hemorrhage, Subinvolution of the Placental Site and Placenta Accreta.- Placental Shape Aberrations.- Pathology of the Fetal Membranes.- Pathology of the Umbilical Cord.- Infectious Diseases.- Maternal Diseases Complicating Pregnancy.- Placental Malperfusion.- Miscellaneous Placental Lesions.- Placental Abnormalities in Fetal Conditions.- Fetal Thrombotic Vasculopathy.- Neoplasms.- Hydatidiform moles.- Choriocarcinoma.- Lesions of ExtravillousTtrophoblast.- Legal Considerations.- New Directions.- index.