Proliferations and tumors of intermediate trophoblast of the placental site

The clinical and pathologic features of proliferations and tumors of intermediate trophoblast of the placental site are reviewed. These lesions include the exaggerated placental site reaction, which is a florid form of the process that occurs normally at the placental site; a hitherto undescribed variant of this lesion, which we have designated placental site nodule, and the neoplasm of intermediate trophoblast that has been termed placental site trophoblastic tumor. Problems encountered in distinguishing these lesions from one another and from nontrophoblastic lesions, particularly in endometrial biopsy specimens and curettings, are discussed.     

The binding and processing of monoclonal human IgG1 by cells of a human macrophage-like cell line (U937)

The goal of these experiments was to assess the relationship between the binding and processing of IgG by Fc-receptor-bearing cells. Cells of the U937 human macrophage-like cell line were incubated with 125I- labeled monomers, dimers, oligomers (composed of 2-4 IgG1 subunits), and HP (heavy polymers composed of 5 or more subunits per polymer) of monoclonal human IgG1 in vitro. Binding was assessed by spinning cells through a layer of phthalate oils. Internalization of IgG1 was assessed by quantitating residual binding to cells after surface-bound IgG was removed by a brief treatment with a solution containing 0.25 M acetic acid and 0.5 M sodium chloride. Catabolism was assessed by measuring the release of radioactive fragments of IgG1, which were not precipitated by 10% trichloroacetic acid. Unstimulated U937 bound about 10,000 molecules per cell of IgG1 monomer, with an equilibrium binding constant (Ka) of 5 X 10(8) M-1. After stimulation with a conditioned medium in vitro, binding per cell was increased 3-7--fold, and the Ka was decreased 2-4--fold. Both unstimulated and stimulated cells internalized and catabolized labeled IgG1 HP, but stimulated cells internalized and digested much more IgG1 HP per cell than unstimulated cells. Both monomers and dimers of IgG1 were internalized and degraded very slowly by stimulated cells, even though both preparations readily bound to cells. In contrast, oligomers and (to an even greater extent) IgG1 HP were internalized and degraded much more rapidly. Internalization of IgG1 HP was markedly inhibited by incubation at 4 degrees C, but not by incubation with a variety of metabolic inhibitors. Catabolism was inhibited by chloroquine and monensin (inhibitors of lysosomal acidification) and by cytochalasin (an inhibitor of microfilament polymerization). Binding to the surface of cells was not markedly inhibited by any agent tested. The capacity of cells to bind labeled IgG1 was markedly reduced by prior incubation in the presence of unlabeled IgG1. This reduction was in part due to the steric blockade of receptors caused by the avid, but reversible, binding of IgG1. In addition, IgG1 oligomers or HP (but not IgG1 monomers or dimers) also caused an irreversible reduction in the number of Fc receptors by a process analogous to receptor down-regulation, as observed in other receptor--ligand systems.     

Possibility of selection against mtDNA mutations in tumors

Several studies of tumors have revealed substantial numbers of clonally expanded somatic mutations in mitochondrial DNA (mtDNA), not observed in adjacent intact tissues. These findings were interpreted as indicating the involvement of mtDNA mutations in tumorigenesis. Such comparisons, however, ignore an important confounding factor: the monoclonal origin of tumors as opposed to the highly polyclonal nature of normal tissues. Analysis of recently published data on the incidence of somatic mutations in nontumor monoclonal cells suggests that, contrary to the prevailing view, the process of tumorigenesis may be accompanied by active selection against detrimental mtDNA mutations.     

Cervical adenoid basal tumors comprised of adenoid basal epithelioma associated with various types of invasive carcinoma: clinicopathologic features, human papillomavirus DNA detection, and P16 expression

Adenoid basal tumors are uncommon cervical lesions that some pathologists consider invasive carcinomas but others consider "epitheliomas" due to their low-grade histological appearance and rarely documented malignant behavior. We report the clinicopathologic features of 10 tumors comprised of both typical low-grade adenoid basal tumors (epitheliomas) intimately associated with invasive carcinomas having infiltrative growth, increased cytological atypia and mitotic activity, and various types of differentiation, including adenoid basal/squamous, pure squamous, adenoid cystic, and small cell neuroendocrine. Tumors were evaluated for the presence of human papillomavirus (HPV) DNA and immunohistochemical p16 expression. The patients in the study group ranged in age from 45 to 81 years (mean, 65 years). Most of the patients presented with abnormal cervicovaginal smears. The initial diagnosis was made on specimens obtained by cervical biopsy, laser electrocautery excision procedure (LEEP), or cone biopsy in 8 patients. Two 2 patients were incidentally diagnosed in hysterectomy specimens. All 10 patients had squamous intraepithelial lesions (9 high-grade, 1 low-grade). In all cases diagnosed in LEEP or cone biopsy specimens, the invasive carcinoma component was present in the excisional specimen and extended to the margins. Seven patients diagnosed on excisional or biopsy specimens who underwent hysterectomy had residual tumor in the cervix, ranging from microscopic foci to deeply invasive. No lymph node metastases were identified in 4 patients who were staged. Seven patients with follow-up were alive without evidence of disease after follow-up intervals of 8 to 84 months (mean, 45 months; median, 29 months). One patient with a component of small cell carcinoma died of other causes without evidence of disease at 18 months. HPV 16 DNA was detected in both the adenoid basal epithelioma and invasive carcinoma components in 9 tumors by in situ hybridization, and HPV 33 was detected by polymerase chain reaction in 1 tumor. All tumors expressed p16 diffusely. Adenoid basal tumors are high-risk HPV-related tumors that can be comprised of both a low-grade adenoid basal tumor, which can be designated as epithelioma, and invasive carcinomas of various types. The invasive component is usually evident in the excisional biopsy specimen, allowing for recognition of a tumor that needs further management.     

Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors

Molecular genetic changes that are associated with the initiating stage of tumor development are important in tumorigenesis. Ovarian serous borderline tumors (SBTs), putative precursors of low-grade serous carcinomas, are among the few human neoplasms with a high frequency of activating mutations in BRAF and KRAS genes. However, it remains unclear as to how these mutations contribute to tumor progression. To address this issue, we compared the mutational status of BRAF and KRAS in both SBTs and the adjacent epithelium from cystadenomas, the presumed precursor of SBTs. We found that three of eight SBTs contained mutant BRAF, and four SBTs contained mutant KRAS. All specimens with mutant BRAF harbored wild-type KRAS and vice versa. Thus, seven (88%) of eight SBTs contained either BRAF or KRAS mutations. The same mutations detected in SBTs were also identified in the cystadenoma epithelium adjacent to the SBTs in six (86%) of seven informative cases. As compared to SBTs, the cystadenoma epithelium, like ovarian surface epithelium, lacks cytological atypia. Our findings provide cogent evidence that mutations of BRAF and KRAS occur in the epithelium of cystadenomas adjacent to SBTs and strongly suggest that they are very early events in tumorigenesis, preceding the development of SBT.     

Decreased progesterone receptor expression in the intermediate trophoblastic cells of spontaneous abortions

OBJECTIVE: To determine whether there are differences in the expression of progesterone receptor (PR) in intermediate trophoblastic cells of pregnancies ending in either spontaneous abortion (SAB) or elective abortion. DESIGN: Immunohistochemical identification of PR in intermediate trophoblastic cells. SETTING: Academic medical center. PATIENT(S): Subjects were 86 patients who either underwent first trimester SAB or elective abortion. INTERVENTION(S): All SAB and elective abortion specimens were serially sectioned and immunohistochemically stained for PR and for melanoma cell adhesion molecule. Melanoma cell adhesion molecule immunohistochemical staining was used as a sensitive and specific marker to identify intermediate trophoblastic cells on the adjacent tissue section. MAIN OUTCOME MEASURE(S): The PR staining of intermediate trophoblastic cells by semiquantitative immunostaining score. RESULT(S): The PR expression in intermediate trophoblastic cells was significantly greater in elective abortion specimens than in SAB specimens. When controlling for estimated gestational age, the difference in PR expression was even greater. CONCLUSION(S): The quantity of PR in intermediate trophoblastic cells is significantly less in SAB when compared to elective abortion pregnancies. Although it is unknown whether this is a primary or secondary event, this information may be an important finding in attempting to characterize both the molecular etiology of implantation and the molecular pathophysiology of SAB.