A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif.

Here we describe a protein product of the human septin H5/PNUTL2/CDCrel2b gene, which we call ARTS (for apoptosis-related protein in the TGF-beta signalling pathway). ARTS is expressed in many cells and acts to enhance cell death induced by TGF-beta or, to a lesser extent, by other apoptotic agents. Unlike related septin gene products, ARTS is localized to mitochondria and translocates to the nucleus when apoptosis occurs. Mutation of the P-loop of ARTS abrogates its competence to activate caspase 3 and to induce apoptosis. Taken together, these observations expand the functional attributes of septins previously described as having roles in cytokinesis and cellular morphogenesis.

Pathological work-up of sentinel lymph nodes in breast cancer. Review of current data to be considered for the formulation of guidelines.

Controversies and inconsistencies regarding the pathological work-up of sentinel lymph nodes (SNs) led the European Working Group for Breast Screening Pathology (EWGBSP) to review published data and current evidence that can promote the formulation of European guidelines for the pathological work-up of SNs. After an evaluation of the accuracy of SN biopsy as a staging procedure, the yields of different sectioning methods and the immunohistochemical detection of metastatic cells are reviewed. Currently published data do not allow the significance of micrometastases or isolated tumour cells to be established, but it is suggested that approximately 18% of the cases may be associated with further nodal (non-SN) metastases, i.e. approximately 2% of all patients initially staged by SN biopsy. The methods for the intraoperative and molecular assessment of SNs are also surveyed.

Primary malignant melanoma of the anterior mediastinum in a child.

Primary malignant melanoma of the mediastinum is extremely rare. We report a case not previously reported of primary malignant melanoma located in the mediastinum in a 11-year-old boy. The tumor could not be completely resected as a result of extensive invasion of the large blood vessels. Histologically, the tumor was heavily pigmented and composed of vague fascicles of spindle cells intermingled with epithelioid cells. Immunohistochemical analysis showed vimentin, S-100 protein, Melan-A, and HMB-45 immunoreactivity in most of the tumor cells. Nearly 50% of the tumor cells were also positive for p53. It is suggested that primary malignant melanoma of the anterior mediastinum may have a histogenetic relationship to the recently described aggregates of nevus cells in the thymus or mediastinal lymph nodes.

Calcified concretions in the anterior pituitary gland of the fetus and the newborn: a light and electron microscopic study.

Calcified concretions including typical laminated psammoma bodies can be detected on routine hematoxylin-eosin (H&E) examination of fetal and neonatal anterior pituitary glands. This finding has seldom been reported in the literature and, to the authors' knowledge, no ultrastructural examinations of fetal or neonatal pituitary calcifications have been reported to date. In this study, histological sections of anterior pituitary glands from 200 fetuses and infants ranging in age from 15 weeks of gestation to 1 year of life revealed calcified concretions in all the cases up to 1 month of life. They decreased in incidence postnatally and were not found after 6 months of age. Most were round to ovoid, basophilic or eosinophilic, often laminated, and measured between 5 and 30 microm in diameter. Immunohistochemical stains showed that the calcifications followed no particular pattern of distribution among the most prevalent pituitary cell types. Ultrastructural examination revealed small single or multiple intracellular calcified deposits, and larger, sometimes laminated, extracellular calcifications, suggesting an intracellular origin for the concretions with cell death occurring concomitant with their formation. This phenomenon, which to some extent resembles the formation of psammoma bodies in certain tumors, seems to represent a distinctive morphological type of developmental cell death. Apoptosis, a more common form of developmental cell death, was also found in some of the sections. Pathologists should be aware of the fact that calcified concretions represent a normal finding in the anterior pituitary gland of fetuses and young infants. Their mere presence in cases of fetal or perinatal demise with no other pertinent findings should not be attributed to intrauterine viral infections or ischemic-anoxic events.

Morphometric differentiation between responsive tumor cells and mesothelial hyperplasia in second-look operations for ovarian cancer.

We developed a procedure based on computerized image analysis to establish objective criteria for the differential diagnosis between mesothelial hyperplasia and cancer in peritoneal tissue samples obtained at second-look operations for ovarian cancer. The tumor tissue after chemotherapy was classified as "nonresponsive" if it was found by histologic criteria to be roughly similar to the tumor before chemotherapy and as "responsive" if it was found to be different (small clusters of bland-looking cells with no mitotic activity). Eighty-five samples of tissue had been classified previously by a pathologist into one of the four following groups: ovarian tumor prior to chemotherapy, "responsive" tumor, "nonresponsive" tumor, or mesothelial hyperplasia. Cell profiles of the tissue samples were studied by computerized image analysis using 21 morphometric descriptors derived from the manual tracings of tumor nuclei, including nuclear perimeter, nuclear area, maximal chord, circularity factor, and standard deviations of these descriptors. Size distribution curves of nuclear areas and maximal chords were included in the analysis. A multivariate discriminant analysis confirmed the separation into the four diagnostic groups, accomplished with consideration of the physical descriptors alone, except for some overlapping between groups 1 and 3. The separation between carcinoma and mesothelial hyperplasia was clear in all cases.

Localized Wegener's granulomatosis relapsing as diffuse massive intra-alveolar hemorrhage.

In a 75-year-old patient presenting with a solitary pulmonary mass, a localized form of Wegener's granulomatosis was diagnosed after lobectomy. In the absence of extrapulmonary manifestations and after a benign postoperative course, the patients was discharged without medical treatment. Three months later, diffuse alveolar hemorrhage developed abruptly, necessitating mechanical ventilation, and was followed by cardiac complications and a fatal outcome. This case and another previously reported strongly suggest the need for medical treatment in patients with a localized form of pulmonary Wegener's granulomatosis, even when complete remission after surgical resection of the lung lesion seems to have been achieved.

Tissue-specific p53 expression in the nervous system.

P53 is a transcription factor that has been found to be expressed in association with cell proliferation and apoptosis. Previously, bacterial chloramphenicol acetyl transferase (CAT) enzymatic expression was predominantly found in the testes of p53 promoter driven-CAT transgenic mice. In the current study, we extended this study to survey p53 expression across both the central and peripheral nervous systems of the same strain of transgenic mice as well as their parental strain. High levels of p53 promoter driven-CAT activity was observed in the cerebellum, hippocampus, hypothalamus, pons, thalamus and upper cerebral spine. Furthermore, we consistently found unexpectedly high levels of p53 promoter-driven CAT expression in the eyes. These observations were reinforced by p53 protein analysis using a p53 pan ELISA assay. Immunohistochemical studies confirmed and further defined p53 expression in several regions of the nervous system. Significantly, p53 promoter-driven CAT expression was visualized in the Ammon horn of the hippocampus, in the Purkinje cells of the cerebellum and in the cornea as well as in the retina of the eye. Furthermore, strong p53 protein expression was found in the cornea of the parental mouse strain. p53 ELISA demonstrated a profile of p53 protein concentration, which correlate well with the high p53 promoter-driven CAT activities observed in the cerebellum, hindbrain, hypothalamus, thalamus, hippocampus, whole eyes as well as with the low CAT activities observed in the cortex and spinal cord. In both of these assays considerable p53 promoter activity and p53 protein levels were found in post-mitotic non-dividing cells.

Angiosarcoma of the colon developing in a capsule of a foreign body. Report of a case with associated hemorrhagic diathesis.

A case of angiosarcoma of the colon is reported. The tumor developed in the fibrous capsule of a retained sponge that was lost 25 years earlier during a gynecologic surgical procedure. The postoperative course was dominated by a fatal consumptive thrombohemorrhagic disorder. Angiosarcoma associated with a retained foreign body and development of hemorrhagic diathesis in angiosarcoma are discussed.

Granuloma formation in patients after injection of methanol extraction residue (MER-GCG).

Nine patients with advanced cancer who were receiving the methanol extraction residue of BCG (MER-BCG) intradermally or intratumorally underwent biopsies from the injected sites or from locally enlarged lymph nodes. Most preparations showed a chronic granulomatous reaction consisting of lymphocytes, histiocytes, and epithelioid cells as well as either Langhans's or foreignbody type giant cells, or both. The degree of granuloma formation and giant cell infiltration varied. In only one case did the reactions consist merely of chronic lymphocytic and histiocytic inflammation with no granuloma formation. Examination of melanoma nodules injected with MER showed, in addition to granulomas, large numbers of giant cells penetrating the tumour.

Myotonia dystrophica with heart involvement: an electron microscopic study of skeletal, cardiac, and smooth muscle.

The electron microscopic features of the striated skeletal muscle, the striated cardiac muscle, and the smooth muscle from a woman who had been suffering for many years from myotonia dystrophica with cardiac involvement are described. The skeletal muscle was studied at two different stages of the disease. In the first material the main changes consisted of centrally situated nuclei, disorganisation of the sarcomeres, and focal disruption of the Z-line. The satellite cells were well represented. Three years later atrophy and degenerative, necrotic changes of the skeletal muscle were evident. The satellite cells were absent. Few changes were seen in the striated cardiac muscle. These consisted of slight interstitial fibrosis and large accumulations of mitochondria with intramitochondrial dense granules. The smooth muscle cells of the oesophagus showed disorientated filaments and mild degenerative changes. It is concluded that the skeletal muscle was more severely affected than the other types of muscle.

Evaluation of muscle capillary basement membrane in inflammatory myopathy. A morphometric ultrastructural study.

The capillary basement membranes from 16 skeletal muscle biopsies from patients with a clinical and histological diagnosis of inflammatory myopathy and from six controls were analysed ultrastructurally and morphometrically. Resin sections from 244 endomysial capillaries were examined by light microscope, and the results were correlated with findings seen in electron micrographs of these capillaries. The ultrastructural morphometric measurements and the statistical analysis showed that the capillary basement membrane was thick and multilaminated in 87% specimens affected by inflammatory myopathy. No thick or multilaminated basement membrane was observed in controls. In inflammatory myopathy the endomysial space next to the capillaries contained an increased amount of collagen fibrils and showed signs of a chronic reparative process. It is suggested that the thick multilaminated basement membrane in inflammatory myopathy represents an advanced stage of vascular regeneration.

Discrepancies in current practice of pathological evaluation of sentinel lymph nodes in breast cancer. Results of a questionnaire based survey by the European Working Group for Breast Screening Pathology.

AIMS: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. METHODS: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. RESULTS: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. CONCLUSIONS: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.

Consistency of staining and reporting of oestrogen receptor immunocytochemistry within the European Union--an inter-laboratory study.

To assess the variability of oestrogen receptor (ER) testing using immunocytochemistry, centrally stained and unstained slides from breast cancers were circulated to the members of the European Working Group for Breast Screening Pathology, who were asked to report on both slides. The results showed that there was almost complete concordance among readers (kappa=0.95) in ER-negative tumours on the stained slide and excellent concordance among readers (kappa=0.82) on the slides stained in each individual laboratory. Tumours showing strong positivity were reasonably well assessed (kappa=0.57 and 0.4, respectively), but there was less concordance in tumours with moderate and low levels of ER, especially when these were heterogeneous in their staining. Because of the variation, the Working Group recommends that laboratories performing these stains should take part in a external quality assurance scheme for immunocytochemistry, should include a tumour with low ER levels as a weak positive control and should audit the percentage positive tumours in their laboratory against the accepted norms annually. The Quick score method of receptor assessment may also have too many categories for good concordance, and grouping of these into fewer categories may remove some of the variation among laboratories.

Müllerian adenosarcoma presenting as cervical polyps: a report of seven cases and review of the literature.

OBJECTIVE: To emphasize the importance of early diagnosis in cases of müllerian adenosarcoma that appeared as benign-looking cervical polyps. METHODS: We examined seven cases of müllerian adenosarcoma of the uterus in patients 14-63 years of age (median 39 years). Tissue protruding from the external os and an initial diagnosis of a cervical polyp were common findings for all patients. On repeated examination, all lesions were interpreted as müllerian adenosarcomas. RESULTS: Histologic examination demonstrated benign glands with a sarcomatous stroma, which typically formed periglandular cuffs of increased cellularity. The sarcomatous stroma was homologous in four cases and contained heterologous elements such as striated muscle, lipoblast, and cartilage in three cases; one patient had a sarcomatous overgrowth of stromal elements. The question of a müllerian adenofibroma versus adenosarcoma was raised in three cases with the general appearance of slit-like glands surrounded by a stroma with fibrosis and a low mitotic rate. Using the criteria of stromal cellularity--marked stromal atypia and a mitotic index of two figures per ten high-power fields--the cases were classified as adenosarcomas. The sarcomatous overgrowth, the presence of heterologous elements, and a high mitotic rate seem to be important prognostically. CONCLUSION: Gynecologists and pathologists should be aware of the difficulties and delay in the diagnosis of müllerian adenosarcoma when the tumor presents as a benign-looking cervical polyp.

Extrauterine müllerian adenosarcoma of the peritoneal mesothelium: a clinicopathologic and electron microscopic study.

An unusual case of a müllerian adenosarcoma of the peritoneal mesothelium in a 32-year-old pregnant woman is described. On emergency laparotomy, a tumor was found in the pelvis connected with the right broad ligament only, and was removed. Light and electron microscopic examination showed a rare example of an extrauterine müllerian adenosarcoma composed of a stromal sarcoma, muscle tissue resembling primitive myoblasts, and sex-cord-like tubular lumens. The patient was followed, and after 22 months the primary surgery was reexplored. On laparotomy, no evidence of disease was found, and the ovaries were tumor-free. Histologic examination of the pelvic peritoneum demonstrated small areas of adenosarcoma resembling elements of the previous tumor. Müllerian adenosarcoma is a rare tumor of müllerian origin, and its less aggressive behavior as compared with mixed müllerian sarcoma is warranted. The better prognostic outlook of müllerian adenosarcoma is probably related to the histologic structure, but depends in addition on the size of the tumor and the site of origin. No case of peritoneal origin of müllerian adenosarcoma has been previously reported; we discuss this unusual location.

Concomitant endometrial adenoacanthoma and bilateral (inguinal) lymph node endometriotic adenoacanthomas or nodal metastases of the endometrial adenoacanthoma? A case report with a literature survey of the histogenetic aspects of endometriotic foci in pelvic lymph nodes.

This case report depicts an interesting association of well-differentiated adenocarcinoma of the endometrium with benign squamous metaplastic foci confined to the fundus uteri, superficially invading the myometrium and with concomitant bilateral pelvic lymph node endometriotic adenoacanthomas. Right inguinal lymphadenopathy was detected during the first hospitalization. A lymph node biopsy from the right groin, carried out at Nahariyya, revealed apparent metastatic adenoacanthoma regarded most probably as endometrial in origin. Fractionated curettage later showed a stage Ia G1 adenocarcinoma of the endometrium with benign squamous metaplastic elements (adenoacanthoma). At Rambam Hospital, Haifa, left groin node enlargement was noted as well. The Gynecologic Oncology Unit confirmed the previous histologic findings. At exploratory laparotomy total abdominal hysterectomy and bilateral salpingo-oophorectomy, paraaortic, and bilateral pelvic lymph node sampling as well as appendectomy were performed. Bilateral groin node dissection was then carried out. Out of 37 nodes examined tumor was found in only one node, namely that of the left groin. The paper includes an extensive survey of the literature on the subject of the histopathogenesis of endometriotic foci in pelvic lymph nodes and the discussion is designed to elucidate the diagnostic problem involved in this case report.

Effect of inorganic mercury on in vitro placental nutrient transfer and oxygen consumption.

The effect of mercury (HgCl2) on placental amino acid and glucose transfer as determined by the use of their nonmetabolizable radioactive analogues, aminoisobutyric acid (AIB) and 3-o-methyl glucose (3MG), respectively, was studied in an in vitro perfusion model of a term human placenta. Hg2+ was found to decrease the transfer and accumulation of AIB without affecting 3MG transfer. It was also found to decrease the placental oxygen consumption rate. Placental circulation and tissue morphology remained intact, as demonstrated by the antipyrine transfer rate, and by electron microscopy, respectively. The mechanism by which Hg2+ may interfere with placental amino acid transfer and accumulation is discussed. Although much higher concentrations than those found in the ordinary polluted environment were used, this is the first report showing that Hg2+ interferes with an essential human placental function in a system employing a whole human placental cotyledon. This finding may indicate the possible involvement of Hg2+ in impaired organogenesis in early pregnancy or deranged fetal growth during the last trimester.

An immunohistochemical study of estrogen and progesterone receptors in adenocarcinoma of the endometrium and in the adjacent mucosa.

The immunoperoxidase stain for estrogen and progesterone receptor content in endometrial adenocarcinoma was correlated with the grade and stage, level of myometrial invasion, age and survival of the patients. Anti-estrogen and anti-progesteone receptor monoclonal antibodies were applied to paraffin-embedded tissue from hysterectomy specimens of 100 patients with adenocarcinoma of the endometrium. In 34 of the cases the receptors were studied in the endometrium adjacent to the tumor and compared to the nuclear receptor content in the carcinoma. There was a high inverse correlation between the estrogen receptor status and the grade of tumor (R = - 0.45, P = 0.006). The estrogen receptor measured in the endometrium near the tumor showed a negative correlation with the grade of the tumor (R = -0.42, P = 0.013). The estrogen, but not the progesterone, receptor content, was positively related to the age of the patient (P < 0.05). No significant correlation of the receptor status with the depth of myometrial invasion was found, despite the obvious interdependence between the grade and myometrial invasion. The progesterone receptor staining index appeared to be a distinct independent prognostic factor in endometrial cancer. The immunohistochemical analysis of the steroid hormone status in endometrial cancer therefore offers an alternative to the quantitative ligand-binding assay.

Bilateral adnexal agenesis with an ectopic ovary--case report and review of the literature.

Bilateral adnexal agenesis (both ovaries and tubes) is not a common finding. Ectopic ovaries are also very rare. A report of the combination of the two, as far as we know, has never been published. Such a case is presented here with its endocrinological evaluation. The literature concerning these entities is reviewed.

Ovarian surface papillomatosis of borderline malignancy.

Bilateral ovarian surface papillomatosis of borderline malignancy is a rare condition. In our case it was associated with benign serous cystadenofibroma. The histologic diagnosis and the clinical aspects are discussed.

PIP: A rare case of bilateral ovarian surface papillomatosis of borderline malignancy is reported. A 50-year-old gravida 1, para 0 woman was referred in July 1976 for evaluation of a pelvic mass manifested by vaginal bleeding of short duration 2 months before. Pelvic examination revealed a solid uterus, the size of a 10-week pregnancy, with irregular contour. At laparatomy, the uterus appeared 12 cm long and exhibited several intramural leiomyomata. A bilateral hydrosalpinx was also found. A 20 by 15 cm left ovarian cyst filled the pelvis and was adherent to the uterus. The right ovary was 3 by 2 cm long. On both surfaces of the ovaries multiple small grey solid papillomas were observed. Histologic examination of hysterectomized tissue revealed benign serious cystadenofibroma of the left ovary without inner papillary formations. On the outer surface of both ovaries there were serous papillomatosis; in most of them the epithelium showed proliferation, atypism, and clusters of free atypical cells. In the uterus there were benign leiomyoma and normal proliferative endometrium. The omentum was normal. In addition to surgical treatment, the patient received postoperative radiation to the pelvis and lower abdomen because of bilateral, low-potential malignant tumor on the outer surface of both ovaries. The need for postoperative radiation in cases of ovarian surface papillomatosis is emphasized.