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Any discussion of multiple pregnancy figures prominently in the consideration of the medicolegal aspects of placental pathology. Multiple gestations are common and becoming more so with assisted reproductive techniques, and multiples are associated with a disproportionate share of complications that may result in disputes over quality of care. Higher rates of intrauterine growth retardation, prematurity, stillbirth, morbidity, mortality, cerebral palsy, anomalous development, and malformation as compared with singletons are well documented in multiple pregnancy and should be anticipated. Monochorionic placentation and complications of vascular anastomosis are important factors contributing to poor outcome. Other factors, although occurring in all gestations, are relevant because they are more common in multiple gestations.

Teratomas are the most common germ cell tumor (GCT) of the ovary and include several types with a range of clinical behavior. As in testicular teratomas, they may be benign, malignant or a component of a mixed GCT. In the testis, data support separate pathogeneses for prepubertal and postpubertal teratomas, with derivation of the former from a nontransformed germ cell and the latter from differentiation of a nonteratomatous, malignant GCT. The absence of cytogenetic abnormalities (including isochromosome 12p (i(12p)) in mature ovarian teratomas suggests that they may be analogous to prepubertal testicular teratomas, but there are no data regarding genetic changes in the teratomatous components of ovarian mixed GCTs. We therefore studied the teratomatous components of six mixed GCTs of the ovary using fluorescence in situ hybridization (FISH) for i(12p). Six mixed GCTs of the ovary occurred in patients 4-33 years of age; all had teratomatous and yolk sac tumor components and three also contained foci of embryonal carcinoma. Using FISH with 12p telomeric and 12 centromeric probes, five of six (83%) cases had detectable i(12p) in their nonteratomatous components, and four of six (66%) in the teratomatous component. One of the two cases without demonstrable i(12p) in the teratomatous portion of the mixed GCT also did not have identifiable 12p abnormalities in other elements of the mixed GCT. By comparison, five pure, mature ovarian teratomas and three pure, immature ovarian teratomas showed no evidence of either i(12p) or other forms of 12p amplification. These findings support that teratoma in mixed ovarian GCTs has a different pathogenesis compared to pure teratoma of the ovary. Furthermore, the findings of i(12p) in both the teratomatous and nonteratomatous components of ovarian mixed GCTs supports that the teratoma derives from other components, similar to the situation in the testis.

We set out to determine the relative timing of loss of DNA mismatch repair and KRAS2 mutation in endometrial tumorigenesis. We studied endometrial carcinoma (CA) and synchronous atypical endometrial hyperplasia (AEH), the premalignant precursor of endometrial cancer. Carcinoma and hyperplasia were investigated for loss of mismatch repair as evidenced by microsatellite instability (MSI) and for KRAS2 mutations. Endometrial cancers previously shown to be MSI-positive were evaluated for KRAS2 codon 12 and 13 mutations. DNA was isolated from foci of AEH concomitant with, but physically remote from, the cancers by use of tissues prepared by laser capture microdissection (LCM). The AEH DNAs were then assessed for MSI and KRAS2 mutations. Of 210 endometrial CAs investigated, 51 (26%) were MSI-positive, and among those, 21 (41%) arose concomitantly with AEH. Of 41 foci of AEH (mean, two foci per patient) investigated, 34 (83%) were MSI-positive. KRAS2 mutations were seen in 5/51 (10%) MSI-positive carcinomas. From the five patients informative for both KRAS2 mutation and MSI, 10 foci of AEH were available for investigation. All 10 AEH specimens (100%) were MSI-positive, and six (60%) had the KRAS2 mutation present in the coexisting CA. The observation that some MSI-positive AEH specimens lack the KRAS2 mutation seen in the coexisting CA supports a model in which loss of DNA mismatch repair precedes KRAS2 mutation. However, in addition to the absence of KRAS2 mutations in AEH, we discovered mutations in LCM hyperplasia and carcinoma specimens that were not present in the portion of the cancers originally investigated. These discordant genotypes suggest genetic heterogeneity in endometrial hyperplasia and concomitant cancer., (Copyright 2001 Wiley-Liss, Inc.)

Objectives: The goal of this work was to test the hypotheses that S-phase fraction (SPF) by DNA labeling index (SPF-LI) would predict the course of the disease for ovarian/peritoneal carcinomas and that SPF-LI would correlate better with pathologic classification and outcome than SPF by DNA flow cytometry (SPF-F)., Methods: Tritiated thymidine (1985-1988) and bromodeoxyuridine (1988-1999) DNA labeling (SPF-LI) was evaluated in vitro on 178 tumors. Cellular DNA and SPF-F were measured flow cytometrically. During this time, 90% of ovarian/peritoneal tumors accessioned in surgical pathology were studied., Results: Tumors of low malignant potential (LMP, "borderline") had low SPF-LI (median = 1.2%). High-grade invasive carcinomas of various types and carcinosarcomas all had high SPF-LI (medians = 11.2-23.4%). Serous low-grade invasive carcinomas (median = 1.05) resembled LMP tumors. SPF-LI of ovarian carcinomas other than LMP tumors increased slightly as FIGO stage increased (P = 0.07). Survival of patients with high-grade ovarian carcinomas was not predicted by SPF-LI or SPF-F, nor was DNA ploidy predictive. SPF-LI produced tighter distributions for various tumor types than did SPF-F. Neither SPF nor DNA ploidy contributed to prediction of outcome when tumor type and stage were included in multivariate models. We calculated the mean cell loss rate of high-grade carcinomas to be 94%., Conclusions: LMP ovarian/peritoneal tumors have low proliferation rates in contrast to high-grade carcinomas. Proliferation correlated with tumor type and stage, but neither it nor DNA ploidy predicted survival independently. Proliferation rate is growth limiting only when low. At higher levels cell loss limits growth. SPF-LI measures proliferation more accurately than SPF-F; SPF-F is not sufficiently reliable for clinical use., (Copyright 2001 Academic Press.)

We have previously demonstrated a strong relationship between loss of heterozygosity (LOH) at chromosome 11q23.3 and the presence of extensive tumor plugs in lymphvascular spaces (LVS) in stage 1B cervical carcinoma, suggesting that genes at this locus may regulate vasculoinvasion. This study examined LOH at 11q23.3 in microdissected tumor plugs within LVS and in metastatic foci in lymph nodes (MFLN), as well as corresponding invasive tumor and adjacent cervical intraepithelial neoplasia (CIN) 3 in stage 1B squamous cell carcinoma. Of 49 invasive carcinomas, 38.8% had LOH at 11q23.3. Of 36 tumor plugs in LVS, 39% had LOH at 11q23.3. Twenty percent of 15 MFLN demonstrated LOH at 11q23.3. Patients with LOH at 11q23.3 are significantly more likely to have disease recurrence than patients without LOH at 11q23.3 (P =.02). Of 10 foci of CIN 3, none showed LOH at 11q23.3. Although unlikely to have an impact early in carcinogenesis, tumor-suppressor genes located in the region of 11q23.3 appear to be important in tumor progression, facilitating lymphvascular space invasion and, by inference, spread to lymph nodes in squamous cell carcinoma of the cervix.

Objective: PTEN, a tumor suppressor gene shown to be frequently mutated in endometrial cancers, has been suggested to be a target of microsatellite instability (MSI)-driven mutagenesis. We set out to investigate the relationship between MSI and PTEN mutation in a large series of primary endometrial carcinomas., Methods: Thirty-nine MSI-positive endometrial cancers were evaluated by single-strand conformational variant analysis and direct sequencing to screen all nine PTEN exons for mutation., Results: Fifteen specimens (38%) demonstrated 16 PTEN mutations. We observed only one alteration in the poly-adenine repeat of exon 8 that is suggested to be a target for mutation in endometrial cancers with MSI. Seven of 16 (44%) mutations in our series were deletions of >/=3 bp, a class of mutation not usually associated with tumors with defective DNA mismatch repair. To determine the significance of this high frequency of deletion, 26 additional endometrial cancers without MSI were matched with the 39 MSI-positive cancers for the prognostic factors of tumor histology, stage, grade, and patient race. The MSI-positive tumors had a significantly higher frequency of deletions involving >/=3 bp when compared with the MSI-negative group (5/11 versus 0/10, P = 0.035)., Conclusions: Repeat tract mutation in PTEN is an uncommon event in MSI-positive cancers. Deletion of >/=3 bp in this gene is more common in MSI-positive cancers when compared with tumors without MSI., (Copyright 2000 Academic Press.)

Although clinically associated with von Hippel-Lindau (VHL) disease, the pathogenesis of papillary tumors of the broad ligament, epididymis, and peritoneum arising in patients with VHL disease is not clear. The "classic" VHL-associated neoplasms, including hemangioblastoma and renal ceil carcinoma, have been found to be associated with the inactivation of both VHL gene copies. It is not known whether a similar inactivation of the VHL gene is also responsible for the development of these uncommon VHL-associated lesions. The authors performed PCR (polymerase chain reaction) and PCR-based SSCP (single-strand conformation polymorphism) analysis on five predominantly papillary tumors in five VHL patients (one papillary cystadenoma of the broad ligament, one endometrioid cystadenoma of the broad ligament, two papillary cystadenomas of the epididymis, one papillary tumor of the retroperitoneum) with four polymorphic markers of VHL gene (D3S1038, D3S1110, D3S2452, 104/105). All five tumors showed allelic loss of VHL gene. The results provide the first genetic evidence for the role of VHL gene in the tumorigenesis of these rare benign neoplasms and confirm these tumors as phenotypic manifestations of VHL disease. Int J Surg Pathol 8(3):207-212, 2000

Defective DNA mismatch repair in human tumors leads to genome-wide instability of microsatellite repeats and a molecular phenotype referred to as microsatellite instability (MSI). MSI has been reported in a variety of cancers and is a consistent feature of tumors from patients with hereditary non-polyposis colorectal cancer. Approximately 20% of cancers of the uterine endometrium, the fifth most common cancer of women world-wide, exhibit MSI. Although the frequency of MSI is higher in endometrial cancers than in any other common malignancy, the genetic basis of MSI in these tumors has remained elusive. We investigated the role that methylation of the MLH1 DNA mismatch repair gene plays in the genesis of MSI in a large series of sporadic endometrial cancers. The MLH1 promoter was methylated in 41 of 53 (77%) MSI-positive cancers investigated. In MSI-negative tumors on the other hand, there was evidence for limited methylation in only one of 11 tumors studied. Immunohistochemical investigation of a subset of the tumors revealed that methylation of the MLH1 promoter in MSI-positive tumors was associated with loss of MLH1 expression. Immunohistochemistry proved that two MSI-positive tumors lacking MLH1 methylation failed to express the MSH2 mismatch repair gene. Both of these cancers came from women who had family and medical histories suggestive of inherited cancer susceptibility. These observations suggest that epigenetic changes in the MLH1 locus account for MSI in most cases of sporadic endometrial cancers and provide additional evidence that the MSH2 gene may contribute substantially to inherited forms of endometrial cancer.

Frequent loss of chromosome 10q sequences in endometrial cancers suggests the involvement of a tumor suppressor gene. Previous loss-of-heterozygosity (LOH)studies have pointed to the 10q25-q26 region as the likely site of a tumor suppressor involved in endometrial tumorigenesis (S. L. Peiffer et al., 1995, Cancer Res. 55: 1922-1926; S. Nagase et al., 1996, Br. J. Cancer 74: 1979-1983; S. Nagase et al.,1997, Cancer Res. 57: 1630-1633). In an attempt to define further the localization of a tumor suppressor gene at 10q25, we screened a panel of 123 endometrioid adenocarcinomas for loss of heterozygosity of 10q25.3 sequences. Forty-three (35%) revealed LOH at one or more loci. The observed patterns of allelic loss define a minimum consensus region of deletion between D10S221 and D10S610. A sequence-ready bacterial clone contig and a long-range restriction map for a 1-Mb interval spanning the deletion region were developed as the first step in experiments directed toward the discovery the 10q25 tumor suppressor., (Copyright 1998 Academic Press.)

Hepatic (hepatocellular) adenoma of the placenta is an extremely rare nontrophoblastic placental lesion of disputed histogenesis, four examples of which were diagnosed over a 10-year period. The lesions, which were incidental findings in women 21 to 30 years of age (mean, 25; median, 24.5), ranged from 0.3 to 1.0 cm in greatest dimension. Two were found within the villous parenchyma and two in subchronic locations. On cross section, two examples were tan to dark red nodules without necrosis or hemorrhagic foci, whereas two were not visible grossly. The lesions were composed of semidistinct lobules of cords and nests of polygonal epithelial cells resembling fetal liver. Extramedullary hematopoiesis was a constant feature. The lesional cells contained glycogen and were immunoreactive for cytokeratin, alpha-fetoprotein, alpha-1-antitrypsin, and carcinoembryonic antigen. Although the histogenesis of these lesions remains uncertain, an origin from displaced yolk sac elements with hepatocytic differentiation is the most likely hypothesis. It is important to distinguish hepatic adenoma of the placenta from placental cell island, heterotopic adrenocortical nodule, chorangioma, and placental metastasis of maternal and fetal malignancies.

Loss of heterozygosity (LOH) has been shown to be an important prognostic factor in a variety of malignant neoplasms. The relationship between LOH and established histopathological prognostic factors in cervical carcinoma has not been examined. We studied LOH in 58 FIGO stage IB cervical cancers treated by radical hysterectomy. In a randomly selected subset of 37 of these cases, LOH was examined using markers for all 41 chromosomal arms. Seventy-six percent of the 58 cases and 95% of the extensively studied cases showed LOH at one or more loci. The three most common sites of LOH were 3p21, 6p24-p23, and 11q23.3. In the extensively studied group, LOH on 11q was associated with extensive lymphvascular space invasion (P = .009) and less deeply invasive tumor (P = .042). There was a trend for tumors with LOH on 11q to recur, but this was not statistically significant. No correlation between the presence of LOH on 3p or 6p and lymphvascular space invasion or tumor depth was present. There was no correlation between the number of sites of LOH or between the presence of LOH on 3p, 6p, and 11q and the presence of metastatic tumor in regional lymph nodes, histologic type (squamous v nonsquamous), tumor differentiation, maximum tumor size, degree of inflammation, pattern of invasion, mitotic rate, or clinical recurrence. In summary, tumors with 11q LOH may behave in a more aggressive fashion. Future studies of LOH in cervical carcinoma should include histopathological prognostic information so that the relationship between LOH and these factors can be determined on larger numbers of patients.

Twelve cervical tumors showing morphologic evidence of neuroendocrine differentiation and lesional cells larger than those of typical small cell carcinoma are reported in women 21 to 62 (mean 34) years of age. The patients presented with an abnormal Papanicolaou smear or vaginal bleeding. Two tumors were stage Ia2, nine were stage Ib, and one was stage IIa. All patients were treated by radical hysterectomy, and most received adjuvant chemotherapy. Seven of 10 patients with > 1 year of follow-up died of tumor 6 to 24 months after hysterectomy. The tumors had insular, trabecular, glandular, and solid growth patterns and contained medium to large cells with moderate to abundant cytoplasm; eosinophilic cytoplasmic granules were present in nine cases. The tumors were mitotically active, and necrosis was present in 10 of them. Nine of 10 tumors were argyrophilic, and all 12 were immunoreactive for chromogranin. Individual cells containing somatostatin, serotonin, or glucagon were identified in four of eight cases. Adenocarcinoma in situ was present adjacent to the tumor in eight cases; invasive adenocarcinoma of non-neuroendocrine type was present in three of these tumors. Using diagnostic criteria established for pulmonary neuroendocrine tumors, the 12 tumors were classified as large cell neuroendocrine carcinomas. Cervical large cell neuroendocrine carcinomas are distinctive cervical carcinomas that are frequently misdiagnosed and have an unfavorable outcome, similar to that of small cell carcinoma.

The molecular genetic events underlying endometrial tumorigenesis are ill-defined at present. We have identified a region on the short arm of chromosome 1 which is frequently deleted in endometrial cancers. The region of deletion has been localized to bands 1p32-33. Deletion of 1p32-33 is seen more frequently in cancers of the highly aggressive papillary serous type than in cancers of the less-aggressive endometrioid type. These data suggest the presence of a tumor suppressor gene on 1p32-33 which is specifically involved in the development of endometrial cancers with poor outcome.

Granulosa cell tumors with bizarre nuclei (GCT-BN) are rare lesions with a prognosis apparently similar to that of conventional granulosa cell tumors (GCT-NOS). The immunohistochemical features of GCT-BN have not been described, and the exact nature of the bizarre nuclei (BN) is unclear. Thirteen GCT-BN were studied with antibodies to cytokeratin, vimentin, epithelial membrane antigen, muscle-specific actin, alpha smooth muscle actin, desmin, and S-100 protein. Six cases were also examined by fluorescence in situ hybridization for trisomy 12, a nonrandom chromosomal aberration found in a proportion of ovarian sex-cord stromal tumors. Histologically, 12 tumors (86%) contained BN areas interspersed with large areas of GCT-NOS. The remaining tumor contained only microscopic foci of GCT-NOS. Immunohistochemically, the tumors stained for vimentin (13 tumors), S-100 protein (11 tumors), muscle-specific actin (10 tumors), cytokeratin (eight tumors), alpha smooth muscle actin (eight tumors), and desmin (one tumor), but none stained for epithelial membrane antigen. Immunostaining results for the BN and GCT-NOS areas were concordant in eight (73%) of the 11 tumors in which both areas could be independently assessed. The remaining three tumors (27%) showed discordant results for only one of the eight markers used. In five patients, trisomy 12 was detected by fluorescence in situ hybridization in areas of BN but not in areas of GCT-NOS present in the same tumor. Trisomy 12 was also present in another BN tumor in which the foci of GCT-NOS were too small to be evaluated. We conclude that within GCT-BN, areas with BN are immunohistochemically similar to areas of GCT-NOS present in the same tumor. The finding of trisomy 12 in areas with BN but not GCT-NOS in the same tumor, however, suggests that cells with BN represent a genetically distinct clone of tumor cells arising within GCT-NOS.

The double circulation of the placenta results in great diversity in the morphologic expression of vascular lesions. Although the etiology and pathogenesis of many of these lesions are not completely understood, it is clear that some have potentially serious implications for fetal well-being. This article focuses on the diagnostic criteria and clinical significance of selected placental vascular lesions.

Thirty-seven endometrial cancers were subjected to an allelotype analysis in an attempt to identify chromosomal regions that are lost in a significant portion of tumors and to identify tumors characterized by replication errors. Thirty-nine highly polymorphic microsatellite markers representing all chromosomal arms, excluding the X and the short arms of the acrocentrics, were examined. An average of 20 informative cases were evaluated for each marker. Genetic alterations were detected in 30 of the 37 tumors. Replication errors were identified in 8 tumor specimens. Loss of heterozygosity was observed for loci on all chromosomes examined with the exception of chromosomes 4 and 20. The two most frequent sites of loss were at the marker loci examined on 10q (40%) and 17p (29%). Six additional simple sequence repeat markers from 10q were genotyped in an effort to refine the region of 10q loss. The chromosome 10 markers used in these studies were physically mapped with the use of a panel of somatic hybrids that retain defined portions of chromosome 10. The observed patterns of loss of sequences on 10q suggest a role for a tumor suppressor gene in the 10q23-26 region in the development or progression of endometrial cancers.

Congenital syphilis had almost become a forgotten disease with the advent of maternal prenatal serology and penicillin therapy for infected mothers. From the 1950s into the mid-1980s, cases of congenital syphilis steadily declined to only 688 cases in the United States in 1988; however, the number of cases increased to 2,841 by 1990. The heralding event occurred between 1981 and 1989 with a 34% increase nationally in the incidence of primary and secondary syphilis. A peak in the number of cases of congenital syphilis was attained in 1992 in the country at large, but in 1993 in the State of Missouri, there were almost three times as many cases as were reported in 1992. Physicians, particularly those who practice in the metropolitan areas of the state, should be alert to the clinical profile of prospective mothers who may have primary or secondary syphilis.

We report nine cases of uterine leiomyomas with an average of more than 10 mast cells per high-power field. The clinical presentation and morphological features of the tumors did not differ from those of conventional leiomyomas. Two cases also showed eosinophilia. The adjacent myometrium did not show an increased number of mast cells. Mast cells are frequently numerous in leiomyomas, but the significance of this finding is unknown.

The Arias-Stella reaction (ASR) is a common and universally recognized feature of gestational endometrium. That identical cytologic changes may, on occasion, occur outside the endometrium or in nonpregnant women is not as well documented. This report describes the clinical and pathologic findings in nine nonpregnant women whose endometria demonstrated ASR. The defining characteristics of ASR, associated pathologic changes, and differential diagnosis are discussed. All of these women were peri- or postmenopausal, and eight of nine had received exogenous hormones, most (n = 7), progestational agents. ASR did not persist in the four patients who underwent subsequent endometrial examination. None of these patients developed adenocarcinoma, although follow-up was short. ASR is an unusual response to hormonal therapy in nonpregnant patients. It is important to recognize the phenomenon in this setting and not overinterpret the characteristic cytologic atypia as adenocarcinoma.

This report describes the clinical, histological, and immunohistochemical features of 38 cases of placental site nodule (PSN), a recently described lesion of intermediate trophoblast (IT). The patients ranged in age from 20 to 47 years (mean, 31.1 years). PSNs were diagnosed in endometrial (30 cases), endocervical (seven cases), and both endometrial and endocervical specimens (one case). The majority of biopsies were prompted by an abnormal Pap smear (13 cases) or complaints of menorrhagia (21 cases). All PSNs were microscopically detected, lobulated nodules composed of acellular, hyalinized material admixed with IT. Mitotic activity was noted in seven cases. Immunohistochemically, the IT expressed human placental lactogen (hPL) in 78% of cases and human chorionic gonadotropin (hCG) in 42% of cases, but their expression was weak and focal in contrast to uniform, strong staining for placental alkaline phosphatase (PLAP) (100%), cytokeratins (96%), and epithelial membrane antigen (EMA) (84%). Type IV collagen outlined the IT and stained the extracellular material in the cellular areas. Vimentin-positive cells within the lesions were fewer in number and in a different distribution than those expressing PLAP, CK, and EMA. Two consecutive PSNs occurred in one patient, but no patient developed gestational trophoblastic disease or a significant gynecologic neoplasm.

Extramedullary hematopoiesis is extremely rare in the absence of any hematologic disorder or systemic disease, and there have been no reports of this condition in the endometrium. The authors describe the cases of four patients who complained of irregular uterine bleeding, lower abdominal pain, or both. Microscopic examination of the curetted endometria showed chronic inflammation in two patients, chronic inflammation and leiomyomas in one patient, and a well-differentiated adenosquamous adenocarcinoma with adenomyosis and leiomyomas in one patient. Light-microscopic examination of curetted sections from all four patients revealed isolated foci of extramedullary hematopoiesis composed of one or more lineages of blood cell precursors. Sufficient tissue was available from two patients to confirm hematopoietic differentiation through immunohistologic analysis, using antibodies to von Willebrand factor, ABH blood group antigens, CD34, and CD15.

Chronic inflammatory infiltrates in the human placenta are much less common than acute inflammation. Most often, chronic inflammation is found in the villi (villitis), but rarely it may involve the fetal membranes. Villitis is associated with many well-documented maternal infections. Reviewed herein are features of the villous inflammatory infiltrate and associated villous changes that may suggest a specific bacterial or protozoal etiology. However, the majority of villitides are of unknown etiology. These may be the result of an unrecognized pathogen or, alternatively, may reflect an abnormal immune reaction. Chronic chorioamnionitis is commonly associated with villitis and has accompanied some well-documented viral, bacterial, and protozoal infections, but a specific infectious etiology is not identified in many cases. Maternal floor infarction is not a true infarct; it is characterized by the deposition of fibrin in the decidua basalis and intervillous space where enveloped villi become avascular and sclerotic. Maternal floor infarction is associated with intrauterine growth retardation and fetal demise. It frequently recurs in successive pregnancies.

Brenner tumor variants--such as metaplastic, proliferating, and low-malignant-potential (three categories recently designated as intermediate Brenner tumors)--and malignant Brenner tumors are unusual tumors presenting problems in classification. DNA ploidy and S-phase reflect the intermediate status of metaplastic, proliferating, and low-malignant-potential Brenner tumors. The category of "transitional cell carcinoma of the ovary" has been proposed for those primary ovarian carcinomas in which definite urothelial features are present, but no benign, metaplastic, and/or proliferating Brenner tumor is identified. Two subtypes have been described, the papillary and the malignant Brenner-like types. These tumors are more aggressive than malignant Brenner tumors, but they appear to respond better to chemotherapy than other types of ovarian epithelial cancer.

Twelve cases of ovarian metastases from cervical carcinomas, most with clinical manifestations of ovarian involvement, are reported. The patients were 23-73 years of age (average, 43 years). The ovarian and cervical tumors were synchronous in eight patients; in three, ovarian tumors were discovered 10 months, 2.5, and 3 years after the detection of a cervical neoplasm. In one patient, the cervical tumor was not discovered until autopsy 7 months after presentation. Four patients had abdominal swelling or distention, three had vaginal bleeding, three had an abnormal Papanicolaou smear, and two had masses discovered during pelvic examination. The ovarian tumors, six of which were bilateral, ranged from 5-17 cm (average, 9.5 cm) in maximal dimension in 11 patients; in the 12th patient, the involved ovary was not enlarged. The cervical tumors were grossly evident in 10 patients. They were usually deeply invasive, often with extracervical extension. Four were squamous cell carcinomas; two, small cell carcinomas; one, a mixed small cell carcinoma and adenocarcinoma; one, a mixed poorly differentiated carcinoid and adenocarcinoma; two, adenosquamous carcinomas; one, a transitional cell carcinoma; and one, an undifferentiated carcinoma. Various features, including bilaterality of the ovarian tumors, the finding that the histologic features of the ovarian tumors typically were unusual for a primary ovarian neoplasm, and the presence of extensive extracervical disease, led to the conclusion that the ovarian tumors were metastatic from the cervix. Although ovarian metastases of cervical carcinoma are uncommon, this series illustrates that, occasionally striking examples with clinical manifestations of ovarian involvement occur.

Three cases of hepatocellular carcinoma with ovarian metastases discovered during the patient's life are reported. A 31-year-old woman presented with back pain, and radiographic studies disclosed massive liver enlargement and bilateral ovarian tumors. The second patient, a 38-year-old woman, had an enlarged liver at the time of laparoscopic tubal ligation, and subsequently underwent right hepatic lobectomy for hepatocellular carcinoma. Three months later a left ovarian tumor was detected and a total abdominal hysterectomy with bilateral salpingo-oophorectomy performed. The third patient, a 68-year-old woman, presented with gastrointestinal symptoms and weight loss, and had bilateral ovarian tumors and widespread tumor at laparotomy. Two patients died of their disease at 18 months and 4 years 7 months; the third patient is alive with residual tumor at 7 months. The ovarian tumors, which were bilateral and multinodular in two cases and focally cystic in one case, ranged from 4 to 11 cm in maximum dimension, and had yellow-green or yellow sectioned surfaces. On microscopic examination, they were composed of cells with moderate to abundant eosinophilic cytoplasm growing diffusely and in nodules, nests, and trabeculae; cysts or glands were conspicuous in two cases. Bile was present in one tumor. The main differential diagnostic considerations were hepatoid yolk sac tumor and hepatoid carcinoma, primary or metastatic in the ovary. A variety of features, including the age of the patient, unilaterality or bilaterality of the ovarian tumors, distribution of disease, and microscopic features of the neoplasm, including the identification of bile, established the diagnosis. Metastatic hepatocellular carcinoma must be included in the differential diagnosis of oxyphil cell tumors of the ovary.

Variability in classification in anatomic pathology does not necessarily indicate that a mistake has been made. It is usually an artifact, created when pathologists choose a single category from among two or more justifiable alternatives. This is most common when standard classifications with uniform terminology are not used. It also can occur when classification systems are not constructed so as to insure mutual exclusivity of categories. It is proposed that a proficiency test in anatomic pathology should not be considered scientifically valid until a professional organization primarily concerned with anatomic pathology has endorsed its proposed classification system as having categories that are close to 100% mutually exclusive in the hands of expert pathologists not involved in developing the system. All possible precautions should be taken to insure that the "right answers" for any proficiency test are generated in a way that excludes the possibility of multiple justifiable alternatives.

The clinicopathologic features of 17 cases of an unusual variant of chorioamnionitis distinguished by a pure or predominantly chronic inflammatory infiltrate in the fetal membranes rather than the usual acute inflammatory reaction are reported. In six cases, there was an equal (one case) or minor (five cases) component of acute inflammation in the fetal membranes as well. Concomitant villitis, found in 11 cases, was almost uniformly lymphohistiocytic and destructive, but it varied greatly in severity. Immunoperoxidase stains for cytomegalovirus, herpes simplex I and II, and Toxoplasma gondii; Warthin-Starry, Gomori methenamine silver, Dieterle, Gram and acid fast stains; placental or amniotic fluid culture; and limited maternal serologic studies failed to identify a specific infectious etiology in any case. Seven women had experienced at least one previous spontaneous abortion, fetal death in utero, or preterm birth. No patient reported a history of fever, rash, or flu-like syndrome during pregnancy. Serious antenatal complications were numerous. Preterm birth occurred in 13 cases. Gestational age ranged from 25 to 42 weeks (mean 32 weeks) and birth weight ranged from 740 to 3,230 g (mean 2,100 g). When expressed as a percentile for gestational age, 47% of infants had a birth weight at or below the 25th percentile, and 76% were at or below the 50th percentile. Two infants were born with gross anomalies, and one infant died in the neonatal period.

Small-cell undifferentiated carcinomas comprise a rare but aggressive subset of uterine cervical neoplasms. Analogous to small-cell anaplastic carcinoma of the lung, these tumors frequently exhibit neuroendocrine differentiation. Although human papillomaviruses (HPV) types 16 and 18 are strongly associated with the development of cervical squamous carcinoma, there is as yet little information describing the relationship of these viruses to small-cell carcinomas. To address this question, we analyzed 20 cases of small-cell carcinoma of the cervix using in situ hybridization to detect HPV gene expression. In addition, immunohistochemistry was used to evaluate three markers of neuroendocrine differentiation. Eighteen of 20 tumors (90%) demonstrated some evidence of neuroendocrine differentiation; 17 of 20 (85%) expressed HPV type 16 or 18 messenger RNA. Of the neuroendocrine-positive cases, 14 of 18 expressed HPV 18 messenger RNA. In contrast, both of the cases with squamous differentiation were HPV 16 positive. These findings broaden the spectrum of HPV-associated cervical neoplasia and strongly suggest that HPV 18 is a viral type specifically associated with cervical small-cell neuroendocrine carcinomas.

The presence of eosinophilic, hyaline globules in association with epithelial hyperplasia was noted in the rete testis of three patients with germ cell tumors. In the more florid examples, this proliferation formed a solid and microcystic pattern that, in association with the hyaline globules, mimicked a yolk sac tumor component. However, the bland cytologic features of the cells and the conformation to the configuration of the rete testis were keys to its reactive nature. A subsequent review of 48 testicular specimens containing well-defined areas of the rete testis showed hyaline globule formation in the rete testis or tubuli recti in 16 of 27 germ cell tumors, one of five other testicular tumors (four stromal tumors and one plasmacytoma), and none of 16 nonneoplastic cases. Many of the cases that had hyaline globules also showed epithelial hyperplasia. Further analysis demonstrated an incidence of rete testis invasion by neoplasm in cases that had hyaline globules, with or without epithelial hyperplasia, that was significantly higher (p less than 0.01) than that seen in neoplastic cases lacking hyaline globules. We concluded that this pseudoneoplastic reaction developed secondary to invasion of the rete testis by tumor. Immunostains supported the nonneoplastic nature of the proliferative lesions and indicated that the globules represented various proteins that had been absorbed from the lumen of the rete testis by the epithelial-lining cells but not successfully secreted.

Three postmenopausal patients with giant cell arteritis involving the female genital tract are presented. None of these patients had a prior history of vasculitis. The giant cell arteritis was confined to the myometrium in one patient, involved the cervix and myometrium in another, and involved all the internal genital organs in the third patient. Based on follow-up of our patients and analysis of similar cases in the literature, we conclude that asymptomatic patients may best be managed by close follow-up and monitoring of erythrocyte sedimentation rate levels, but that treatment may be unnecessary.

Female genital tract involvement by hematologic neoplasms is uncommon and is usually associated with disseminated disease. Lymphoid neoplasms, which involve the cervix and uterus primarily, are usually of either diffuse large cell or small cleaved cell type, and rarely Burkitt's (small non-cleaved) lymphoma or granulocytic sarcoma. In this report the authors describe young woman with acute stem cell leukemia which was terminal deoxyribonucleotidyl transferase positive, and involved the bone marrow and peripheral blood. After induction of remission and a 2-year disease-free interval, she relapsed with involvement localized to the uterus and cervix. At relapse the leukemic cells expressed CD1, CD2, CD5, CD7, and CD4 or CD8, antigens of the common thymocyte compartment. The authors postulate that the T-cell antigens, known extracellular matrix receptors, may have determined the tissue infiltration: an unusual pattern of relapse.

The regional concentrations of pancreatic polypeptide (PP), insulin, and glucagon and the cellular distribution of PP were studied in 13 human and nine canine pancreases by radioimmunoassay, immunoperoxidase localization, and cell quantitation. PP concentration was highest in both the uncinate process and the head of the human pancreas and in the right lobe of the canine pancreas. In contrast, glucagon and insulin levels were higher in the body and tail of both the human and canine pancreases. Human F-cells, which contain PP, were located primarily at the periphery of the islets, although a few F-cells were scattered throughout the ducts and acini. Canine F-cells were located in ducts, acini, and islets; the relative proportion of canine F-cells in the endocrine and exocrine tissues differed according to location. Cellular quantitation of F-cells in both species correlated significantly with the tissue concentration of PP in all regions studied, validating the use of morphometric techniques to quantitate the regional distribution of PP.

The clinical and pathologic features in six cases of spindle cell carcinoma of the breast were reviewed. Histologically this tumor is characterized by sheets of spindle cells often containing squamous epithelial islands and numerous cystic spaces lined by epidermoid carcinoma or benign appearing squamous epithelium. Areas of transition from the squamous epithelium or epidermoid carcinoma to malignant spindle cells were seen in all cases. Features of squamous epithelial differentiation were found in the spindle areas of the one tumor examined by electron microscopy. The prognosis in this neoplasm is similar to that in the more common breast carcinomas. Spindle cell carcinoma therefore should be distinguished from fibrosarcoma, stromal sarcoma, and carcinosarcoma. Moreover, it should be separated from the broader category of "metaplastic carcinoma," since this term includes a heterogeneous group of tumors of uncertain histogenesis and prognosis.

The F cell of the dog pancreas has been identified as the specific cell type containing pancreatic polypeptide. This localization of pnacreatic polypeptide was accomplished by immunocytochemical staining of ultrathin sections and direct electron microscopic identification. Verification of the specificity of the reaction was obtained by blocking experiments on serial sections of the same cell. It is proposed that the name F cell be used for defining in all species the islet cell that contains pancreatic polypeptide.

In order to better define the frequency and patterns of metastasis to the female genital tract, all cases of nonhematopoietic metastases to the adnexa, uterus, vagina, and vulva encountered in patients treated at Barnes Hospital between 1950 and 1981 were reviewed. Three hundred twenty-five metastatic cancers from 269 patients were recovered. One hundred forty-nine cases were from extragenital primaries; the remaining tumors were intragenital metastases. Ovary and vagina were the most frequent metastatic sites for both extragenital and genital primaries. The majority of the extragenital metastases were adenocarcinomas from the gastrointestinal tract, but a variety of other primaries did spread, on occasion, to the genital tract. Twenty-seven percent of the metastases presented as possible primary gynecologic lesions, and 75% of these tumors had an extragenital origin. It is shown that despite certain trends in the distribution of metastases, all sites in the female genital tract are at risk for the occurrence of metastases.

The internal female genital tract is rarely involved in neurofibromatosis. This report details a case of diffuse neurofibroma with prominent Wagner-Meissner body differentiation involving uterine cervix and endocervix, vagina, and vulva. The urinary bladder, urethra, and one ureter were also extensively affected. The anatomic localization of the lesions in this case is consistent with segmental neurofibromatosis restricted to the distribution of the second, third, and fourth sacral nerves. Failure to consider the possibility of genitourinary involvement in neurofibromatosis, the potential for localized manifestations in the absence of other easily recognized stigmata, and the subtle histologic features in small tissue biopsies may cause difficulty in diagnosis.

The clinicopathologic, immunocytochemical, and ultrastructural features of 15 small-cell undifferentiated carcinomas (SCUC) of the uterine cervix are reported. Patients ranged in age from 25 to 87 (median, 42 years) and presented as stages IB (nine patients), IIA (one patient), IIB (two patients), IIIB (two patients), and IV (one patient). A variety of treatment regimens were employed. Ten patients died of disease (3-71 months; median, 11 months), one patient has a suspicious lung nodule 10 months after diagnosis, one patient is comatose with brain metastases 4 months after diagnosis, and three patients are alive and well 5, 11, and 78 months after diagnosis. Histologically and cytologically, the tumors were identical to pulmonary small-cell undifferentiated carcinoma. Six tumors were associated with other forms of carcinoma, in situ or invasive or both, including epidermoid carcinoma in situ (two cases), adenocarcinoma in situ and epidermoid carcinoma in situ (one case), adenocarcinoma (three cases), and epidermoid carcinoma (three cases). All 13 tumors expressed one or more epithelial markers and at least one neuroendocrine marker. Electron microscopy demonstrated dense-core granules in six of seven tumors, dendrite-like processes in seven tumors, filament bundles in four tumors, and intracytoplasmic lumina in one tumor. Small-cell undifferentiated carcinoma of the cervix is an aggressive tumor with a propensity for rapid metastasis and high mortality. These tumors may demonstrate multidirectional differentiation, including the frequent expression of neuroendocrine features.

Two cases of neoplastic angioendotheliomatosis are described. Both patients presented with subacute development of dementia punctuated by focal neurologic signs. Postmortem examination in both cases disclosed a vasculocentric distribution of neoplastic cells in many organs. Two characteristic histologic patterns were seen: (1) distension of vascular spaces by free-floating, intraluminal cells and (2) asymmetric, subendothelial tumor growth. Intravascular tumor and secondary vascular changes were associated with microinfarcts in involved organs. Immunohistochemical localization of factor VIII-related antigen in the neoplastic cells of one case provides evidence for their endothelial origin. The neoplastic cells in both cases exhibited similar but nonspecific ultrastructural features. In addition, dramatic fine structural changes including the acquisition of numerous pinocytotic vesicles and bundles of fine filaments with periodic densities were found in the non-neoplastic endothelial cells.

Magnetic resonance (MR) images of 12 fresh uterine specimens obtained with a high-resolution surface coil were correlated with findings on gross and microscopic pathologic examination. The uterine wall can be differentiated into three distinct zones: a central high-intensity zone, a junctional low-intensity band, and a peripheral medium-intensity area. Whereas the endometrium (basale and functionale) corresponded to the high-intensity zone, the myometrium correlated best with the combined width of the areas of low and medium signal intensity. The signal intensity of a leiomyoma varied, depending on its cellularity. Primary endometrial and cervical carcinomas were clearly shown on MR images, as were other abnormalities such as adenomyosis and Nabothian cysts. The potential usefulness of MR imaging in detecting and staging uterine neoplasms is discussed.

Seven pathologists independently classified 50 slides of ovarian tumors using category I of the World Health Organization classification (WHO I), each case being seen twice under different random code numbers. Intraobserver reproducibility and interobserver reproducibility, based on consistent interpretations, were both suboptimal. However, scrutiny suggested that no pathologist was a source of excessive variability, nor was suboptimal interobserver reproducibility simply due to intraobserver variability. Neither could excessive variability be attributed to skewing of results by a subgroup of unclassifiable cases. However, clearcut sources of variability were identified among the categories of WHO I, namely, mixed epithelial, unclassified epithelial, and undifferentiated carcinoma. There was also considerable variability in distinguishing serous and endometrioid neoplasms, and in identifying tumors of low malignant potential. These findings should not be misconstrued as implying that pathologists in routine practice cannot diagnose common ovarian cancers reproducibly for patient care purposes. Availability of clinical and macroscopic data, extensive sampling, histochemistry, and consultation combine, in an uncontrolled and highly individualistic fashion, to render routine service work very different from this highly controlled formal exercise. Furthermore, at the current state of the therapeutic art, many of the taxonomic problems identified in this study may have little clinical significance. Nonetheless, this study has strengthened the evidence that there may be important problems in classifying common ovarian cancers reproducibly using WHO I, and that WHO I may require greater clarity to enhance reproducibility. Current emphasis on quality assurance dictates reconsideration of the literature on reproducibility of histopathologic taxonomy, which has tended to inculpate pathologists as sources of variability. Virtually all of this literature is subject to some degree of skepticism due to deficiencies in methodology. Consideration of the question of how to measure reproducibility in anatomic pathology leads us to suggest that the community of pathologists should address the need to decrease ambiguity in classification systems as an important step toward optimizing reproducibility.

Magnetic resonance (MR) studies were performed on 20 healthy volunteers and 41 patients with proved cervical and uterine neoplasms. MR imaging demonstrated normal uterine landmarks in all patients. On T2-weighted images, the normal uterine wall could be differentiated into three distinct layers: a central high-intensity zone, a junctional low-intensity band, and a peripheral medium-intensity area. While most of the normal cervices had only two distinct zones (central high-intensity zone and peripheral low-intensity zone), a small percentage had three layers of signal intensity, similar to the uterine body. Primary cervical and uterine neoplasms could be identified on MR images. In 18 of 22 patients with proved carcinoma, a mass with a signal intensity higher than that of normal cervical lips was seen on T2-weighted images. Endometrial carcinoma was most often identified as expansion of the central high-intensity area; discrete tumor nodules were visible in nine of 15 patients. Mixed müllerian sarcoma appeared as a large pelvic mass with complete obliteration of normal uterine landmarks. MR imaging delineates primary cervical and endometrial carcinoma better than computed tomography does.

A case of malignant mixed müllerian tumor of the uterus with neuroectodermal differentiation is reported. The most notable feature of the tumor was its large component of central nervous system tissue containing both glial and neuronal elements. The islands of neural tissue were admixed with more conventional carcinomatous and sarcomatous elements typically found in tumors of this type. The neuroectodermal component was conspicuous in the residual uterine tumor removed after radiotherapy, but not in the initial biopsy specimens. The patient died after developing local recurrence and distant metastases, which were treated with chemotherapy.

Five cases of glassy cell carcinoma of the uterine cervix were examined by light and electron microscopy. Light microscopic features included areas of large cells with ground glass and granular cytoplasm, distinct borders, prominent stromal inflammation, and lack of apparent squamous or glandular differentiation. Two neoplasms were associated with separate foci of squamous cell carcinoma in situ and one with endocervical adenocarcinoma. Electron microscopy showed a predominant cell type with cytoplasmic filaments, dilated rough endoplasmic reticulum, Golgi complexes, and large nuclei with complex nucleoli. In some cells there were tonofibrils and well developed desmosomes. The neoplasm of one patient showed poorly developed intracellular lumina. These observations were interpreted to indicate that glassy cell carcinoma is associated with and demonstrates both glandular and squamous differentiation. It is, therefore, properly classified as a type of poorly differentiated adenosquamous carcinoma, which likely develops from the subcylindric reserve cell. The results of this experience reaffirms its poor prognosis.

The concentration and distribution of pancreatic polypeptide (PP) was studied in hyperglycemic obese (ob/ob) mice and homozygous (+/+) controls. By radioimmunoassay, the concentration of PP in the pancreas of ob/ob mice was greater both in the duodenal lobe (70.7%) and in the body and tail (66.3%) when compared to identical areas of control pancreases. Analysis of immunostained pancreatic tissue indicated that the number of PP cells per islet cross-section was significantly increased (58%) in the ob/ob tissue. The calculated total number of PP cells per average islet was elevated three times in the ob/ob islet. However, the proportion PP cell volume relative to the islet volume in ob/ob was one-half that of control islets. These results clearly demonstrate an elevation in both the number of PP cells per islet and the concentration of PP in the diabetic ob/ob murine pancreas.