Aneuploidy of human granulosa cells in follicular fluids from in vitro fertilization patients.

OBJECTIVES: To study the proliferative behavior of granulosa cells found in follicular fluids from patients after hormone stimulation in the framework of in vitro fertilization (IVF) with gonadotropins. STUDY DESIGN: The deoxyribonucleic acid ploidy and the proliferation indices of granulosa cells in fresh and unfixed follicles (n = 119) from gonadotropin-stimulated patients (n = 32) were analyzed by flow cytometry. RESULTS: Aneuploid cells were found in a large number of follicles (65/119) as well as patients (25/32). A small number of follicles (8/119) and patients (7/32) contained multiploid cells. There was no correlation between proliferation indices and ploidy. Granulosa cells were the predominant cells in follicular fluids. No malignant cells were found in any case. CONCLUSION: This is the first report concerning the high incidence rate of aneuploidy in ovarian granulosa cells in IVF patients. The clinical relevance of the phenomenon is not clear. There should be further study to determine whether there is any link to a previously discussed possible relation between gonadotropin stimulation in women attempting to become pregnant and the occurrence of ovarian cancer or granulosa cell tumors. Of further interest might be a possible relation between ploidy and proliferation indices of stimulated granulosa cells as well as side effects of gonadotropin therapy and biologic parameters, like maturity, fertilizability of oocytes and rates of pregnancy.

[Modified endocervical vaginal smear for diagnosis of endocervical microinvasive cervix carcinoma]. / Geeignete endozervikale Abstrichentnahme zur Diagnostik eines endozervikalen mikroinvasiven Zervixkarzinoms.

We report about a case of a highly intracervical located microcarcinoma of the cervix uteri, which could solely be diagnosed by a sufficient sampling technique using cyto-brush. The same case could not be diagnosed without the presence of endocervical cells in the endocervical smear either.

[CIN in pregnancy: incidence, diagnosis and therapy]. / CIN in der Schwangerschaft: Häufigkeit, Diagnostik und Therapie.

Over a period of 5 1/2 years, 71 cases of CIN in pregnancy were analysed. In this report, biological tumour behaviour, diagnostic procedures and therapy are discussed. In our study, there was a higher rate of remissions of light to moderate cervical intra-epithelial neoplasia (CIN I-II) in pregnancy than observed in non-pregnant women. In these cases, a conservative management was chosen. If diagnosis of CIN III or Cis (carcinoma in situ) in pregnancy occurred, the management was individualised, depending on gestational age, location of the lesion and extent of the lesion. Colposcopy, cytology and portio biopsy were used for diagnosis. Conisation was only performed in the 2nd. trimenon of pregnancy, if the lesion was large in size or mainly localised in the endocervix. No severe complications were seen. In any case of CIN III or Cis, conisation was performed 6 weeks after pregnancy.

[Clinical aspects and morphology of extra-ovarian serous cancer of the pelvis]. / Klinik und Morphologie des extraovariellen serösen Karzinoms des kleinen Beckens.

An extraovarian peritoneal serous carcinoma is characterised macroscopically by ovaries without pathology, histologically, however, by a serous carcinomatous structure in the pelvis, in an advanced tumour stage of usually marked peritoneal carcinomatosis. Extraovarian pelvic serous carcinomas are rarely described in literature. In our study on five patients with such carcinomas, laparotomy findings revealed peritoneal carcinomatosis as in advanced ovarian carcinomas, but without ovarian involvement. Histogenesis does not reveal any difference between the extraovarian mesothel, which is of Mullerian origin and the serous ovarian carcinoma. Therapy of extraovarian peritoneal carcinoma is similar to that of ovarian cancer with maximal tumour reduction and cisplatinum or carboplatinum containing chemotherapy. The prognosis is extremely unfavourable with little expectation of lengthy remission and survival rates are short. Extraovarian serous carcinomas deserve better recognition because they are underreported. They must be differentiated from malignant mesotheliomas, which are not of Mullerian origin.

[Extent of psammoma carcinomas of the ovary--a clinical, DNA flow cytophotometric and morphometric image analysis study]. / Zur Dignität von Psammomkarzinomen des Ovars--eine klinische, DNA-durchflusszytophotometrische und morphometrisch-bildanalytische Studie.

There is no agreement in literature on the biological behavior of psammoma carcinomas of the ovary. The majority of authors consider psammoma bodies to be the result of tumour regression, associating the occurrence of psammoma bodies with longer survival. On the other hand, several studies reveal a poor prognosis for psammoma carcinomas, similar to that of other epithelial malignant tumours. In our study, the psammoma body content in 174 serous carcinomas stage III/IV was morphometrically quantified by image analysis and the results correlated to survival time and progression time. In 20 carcinomas the psammoma body content was extremely high. In such cases, DNA flow cytometry revealed these tumours to be slowly-growing. The DNA index was 1.0 (DNA-diploid) and the number of S phases was low (max. 5.9%). The five year estimate survival was 50%, as opposed to 10% for other tumours. If no methods are available for cell kinetic analysis and for objectification and quantification of psammoma body content in serous carcinomas it is sufficient to make a semiquantitative assessment of the psammoma body content to differentiate tumours with longer survival from carcinomas of poor prognosis.

[Prognostic significance of cell kinetic parameters of endometrial cancer]. / Prognostische Bedeutung zellkinetischer Parameter beim Endometriumkarzinom.

In 120 patients suffering from carcinoma of the endometrium of a wide variety of histological types, conventional clinical and morphological criteria of prognosis were compared with the DNA index (DI) and the S-phase fraction. The cellular kinetics parameters were obtained via flow cytophotometry. Adenocarcinomas (n = 101) were more frequently DNA diploid and had a lower S-phase share (less than 5%) than adenoacanthomas, clear-cell carcinomas and malignant Müller's mixed tumors. There are close correlations between the conventional prognostic factors such as FIGO stage, relative tumor invasion depth, grading and oestrogen or progesteron receptor content and the DNA content or S-phase fraction. Carcinomas with a DI less than or equal to 1.1 (n = 83) and the S-phase fraction less than 5% (n = 77), have a significantly longer survival time and recurrence-free interval than DNA-aneuploid tumors with a high S-phase fraction. The studies underline the need to use flow cytophotometry in the prognostic assessment of the carcinoma of the endometrium. The method is superior to histological grading, since the results obtained can be objectively assessed.

DNA flow cytometry, clinical and morphological parameters as prognostic factors for advanced malignant and borderline ovarian tumors.

Patients with malignant ovarian (n = 111) and borderline (n = 8) tumors (FIGO stage III/IV) underwent surgery and chemotherapy and were analyzed clinically (age, residual tumor after surgery) and morphologically (type, grade, psammoma body content), and by means of flow cytometry (DNA ploidy, S-phase fraction). Follow-up was 12-72 months for investigation of survival. Patients under 60 years of age (n = 18) with malignant tumors showed longer survival than patients over 60 (n = 93) (P = 0.078). Residual tumor was relevant for prognosis in malignant tumors only if macroscopically there was no residual disease (n = 13). There were no significant differences between residual tumors less than or equal to 2 cm (n = 61) and greater than 2 cm (n = 37). WHO typing was of little importance for survival analysis. Compared to borderline tumors (n = 8), serous (n = 65), endometrioid (n = 13), nonclassifiable (n = 12), mucinous carcinomas (n = 8), and nonepithelial tumors (n = 12) had a poor prognosis. Psammoma bodies were found in 25 patients with serous carcinomas, 7 of them had a high content. The prognosis for these 7 patients was much better than that for patients with a moderate or low psammoma body content (P = 0.006). Twenty-three epithelial tumors were graded G1, 28 were G2, and 47 were G3. However, grading was considered only as a prognostic factor in serous carcinomas (n = 65) (P = 0.028). A total of 199 DNA histograms from 119 patients were analyzed by flow cytometry (FCM). There were no correlations between tumor type and DNA ploidy or S-phase fraction. Seven of eight borderline tumor and all serous carcinomas with a high content of psammoma bodies were diploid combined with a low (less than or equal to 4%) S-phase fraction. DNA ploidy and S-phase fraction were excellent prognosticators. Of 99 epithelial malignant tumors, 35 were diploid and 64 were aneuploid. An S-phase fraction less than or equal to 4% was found in 39 patients, 4.1-10% in 73 patients, and greater than 10% in 23 patients. Diploid tumors and tumors with a low S-phase fraction showed the best survival (P = 0.007, resp. 0.0001). Our study emphasizes the importance of an accurate histology, including information on psammoma body content, and the importance of DNA flow cytometry. The advantage of FCM is that the results are simple, reproducible, and objective.

[Primary malignant non-Hodgkin lymphoma of the uterus]. / Das primäre maligne Non-Hodgkin-Lymphom des Uterus.

Primary extranodal malignant lymphomas of the uterus are rare. Of this type lymphoma of the cervix are the most frequent. This is a case report on a patient with a primary malignant lymphoma of the corpus uteri, who became symptomatic by a meningiosis blastomatosa. By preoperative screening, a large tumor of the uterus was found. Final diagnosis was based on the histology of the curettage material, as well as on laparoscopy and on cytology of the peritoneal fluid. In the initially preterminal patient, chemotherapy led to a complete remission.

[Giant cell sarcoma: a rare breast tumor]. / Das Riesenzellsarkom: ein seltener Mammatumor.

This is a case report on a giant cell sarcoma or malignant osteoclastoma of the mammarian gland. Clinical diagnosis of this very rare tumor was of an exulcerating breast carcinoma. Histologically, this tumor shows epulis-like giant cells. Pathogenetically, a metaplasia of stromal cells, and of the glandular epithelium, is discussed. A simple mastectomy with extirpation of the axillary lymph nodes was performed. No metastases were found.

[Cytologic diagnosis of Paget's disease of the vulva]. / Die zytologische Diagnose des Morbus Paget der Vulva.

Unlike exfoliative cytology for detection of cervical neoplasia and its precursors, the cytologic detection of invasive and intraepithelial neoplasia of the vulva still presents some problems. In cases of Paget's disease of the vulva--a special form of intraepithelial neoplasia with typical histological features--primary cytologic diagnosis is possible. The cytologic criteria that led to preoperative detection are demonstrated on two cases of Paget's disease of the vulva. However, a Paget carcinoma has still to be excluded histologically.

[Preoperative immunocytochemical estrogen receptor determination in fine needle aspirates in breast cancer using monoclonal antibodies]. / Zur präoperativen immunzytochemischen Ostrogenrezeptorbestimmung an Feinnadelpunktaten beim Mammakarzinom mittels monoklonaler Antikörper.

The biochemical detection of ER in breast cancer is of high value for the prognosis and planning of treatment. The conventional biochemical assays of ER are expensive, time-consuming and give little information on the topography and heterogeneity of receptor-protein in the tissue. Observations of different study groups showed a good correlation between the results of the biochemical assay and the monoclonal method in frozen sections. This ER-detection method was used on 34 fine needle aspirates from patients with breast cancer. 30 samples (88.2%) contained sufficient cells for analysis. The value of this method was proven and the results correlated to the measurement resulting from the biochemical assay. In 24 of the 30 fine needle aspirates we found good semi-quantitative correlation between the biochemical assay and the monoclonal method. Cytology, including ER-detection, permits definition not only of the receptor state, but also of the definition of the tumor. The employment of ER-detection in fine needle aspirates is useful in the following cases: Small tumors, which do not supply enough tissue to practice all in vitro tumor tests, as well as in metastasising tumors, in which surgical intervention or histological confirmation is not always necessary. The preoperative knowledge of ER may soon permit a different surgical therapy.

[Preoperative diagnosis, pathologic anatomy and clinical significance of mucoceles of the appendix from the gynecologic viewpoint]. / Präoperative Diagnostik, pathologische Anatomie und klinische Bedeutung der Mukozelen der Appendix aus gynäkologischer Sicht.

Owing to their proximity to the true pelvis and their topography, mucoceles of the appendix frequently cause clinical symptoms which call a gynecologic condition to mind. Sonographically, the structures of mucoceles are often similar to those of ovarian tumors. Within 12 months four patients with mucoceles underwent surgery at Heidelberg University Gynecological Clinic following diagnosis of a gynecologic disease (two tentative diagnoses of ovarian carcinoma, one of advanced ovarian carcinoma, one chance finding during Wertheim's operation). The problems of this rare condition are discussed with reference to the clinical findings, the intraoperative site, and the different morphology and maturity. Pathoanatomically and biologically, however, the clinical picture is not uniform. In mucoceles there is an accumulation of mucus with cystic dilatation of the lumen of the appendix. This is usually due to a tumor, which may be anything from a simple mucous membrane hyperplasia with extreme mucous formation, or an adenoma, to a mucilaginous adenocarcinoma. The rupture of a mucocele or metastasization of a carcinoma often lead to peritoneal mucous spread or peritoneal metastasization: in their patterns of distribution these are similar to a pseudomyxoma peritonei or a metastasizing ovarian carcinoma.

[Diagnosis of occult fallopian tube cancers by intraoperative peritoneal cytology]. / Zur Diagnostik okkulter Tubenkarzinome durch intraoperative Peritoneal-Zytologie.

Clinical and ultrasonographic examination are the usual methods of diagnosis for carcinomas of the fallopian tubes and ovarian carcinomas. It is only in rare cases that the diagnosis is based on the cytology of the cervical smear. The use of cytology--more exactly, the cytological examination of secretion in Douglas' space in cases of vaginal hysterectomies--for the detection of ovarian and tubal carcinomas that cannot be diagnosed by clinical and paraclinical procedures, is a rather unusual and rarely described method. However, it is quite justified, as demonstrated by the detection of two carcinomas of the fallopian tubes within a short time.

Psammomabody content and DNA-flow cytometric results as prognostic factors in advanced ovarian carcinoma.

138 advanced ovarian serous carcinoma--all FIGO stages III/IV--were investigated by prognostic morphological factors like tumour grading and rate of psammomabody content--subdivided in to serous carcinoma with a high, a moderate and a low rate of psammomabodies and a group of serous carcinoma without psammomabodies. Additionally 91 of these tumours were examined by DNA-flow-cytometry--respectively DNA-ploidy and s-phase-fraction. All prognostic factors were correlated to the overall survival time. The psammomabody content factor is only important if histologically a high or moderate rate of psammomabodies is found in the tumour tissue. Tumours with a low rate of psammomabodies do not differ from serous tumours without psammomabodies. DNA-flow-cytometry is a qualified method to demonstrate a slow tumour growth tendency. The majority of carcinomas with a high rate of psammomabodies is DNA-diploid and has a low -phase-fraction. The overall survival rate for these tumours is much better. Tumour grading--a more subjective method--is also of high value, but there is a certain difficulty in reproducing the results in individual cases. By the combination of the two morphological methods--semiquantitative assessment of psammomabodies and DNA-flow-cytometry--we were able to discover a small group of patients with advanced ovarian cancers who have a favourable prognosis.

[Development of cancer (vulvar cancer) in the Netherton syndrome (ichthyosis, hair anomalies, atopic diathesis)]. / Zur Karzinomentstehung (Vulvakarzinom) beim Netherton-Syndrom (Ichthyosis, Haaranomalien, atopische Diathese).

So far there has been only one incidence of a malignant tumour associated with Netherton's syndrome, a rare skin disease consisting of congenital ichthyosiform erythroderma, atopic dermatitis and trichorrhexis nodosa (bamboo hair). The aetiology and clinical consequences are discussed on the occasion of a carcinoma of the vulva occurring in a case of a patient with Netherton's syndrome, both phenomena being interlinked.

[Clinical course of ovarian cancer in relation to morphologic prognostic factors and cell kinetic parameters]. / Klinischer Verlauf des Ovarialkarzinoms in Abhängigkeit von morphologischen Prognosefaktoren und zellkinetischen parametern.

Apart from the stage of the tumour and the method of surgical approach, factors of special importance in prognosis are the histological type of tumour and the histological and cytological grading of malignant ovarian tumours. To supplement the prognostic factors, DNA flow cytometry has recently been introduced to determine parameters of cell kinetics such as ploidy (the status of the chromosome set in the karyotype) and the number of DNA-synthesized cells. In the present study 81 patients with a malignant tumour of the ovary--most of them classified according to FIGO stage III/IV--were followed up for 12 to 56 months (FIGO = Fédération Internationale de Gynécologie et d'Obstétrique). The survival times are correlated with clinical, morphological and cell kinetics data. The FIGO stage is the most important prognostic factor. None of the patients in stage I/II (FIGO) died during the study period, whereas of 63 women in stage III/IV (FIGO) 41 have already died. The histological tumour type is not so significant for prognosis. The survival curves show that of all the examined prognostic factors in stage III/IV (FIGO) the S-phase proportion (i.e. the proportion of DNA-synthesized cells) is the most important one. Statistically significant differences are also seen in ploidy and in grading. However, in histological grading of tumours the differences are noticeable only in grading G 1 and in grading G 3. G 2 carcinomas--which, by the way, account for one-third of all carcinomas-are a kind of collecting "pool" of tumours whose prognosis cannot be assessed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Morphologic criteria of prognosis and clinical course in ovarian tumors of the borderline type]. / Morphologische Prognosekriterien und klinischer Verlauf bei Ovarialtumoren vom "Borderline-Typ".

Borderline tumors of the ovary are morphologically characterized by histologic and cellular criteria and by lack of evidence of invasion. During an observation period of 12 years at Heidelberg University Gynecological Clinic, 49 patients with borderline tumors underwent surgery and the clinical course was followed up. In 15 cases the tumor was at an advanced stage (FIGO III/IV); chemotherapy was instituted after surgery in 12 of these women. None of the patients with early-stage tumors (FIGO I/II) were lost due to the tumor during the period of observation; the death rate among patients with stage III/IV tumors (FIGO) was 40%. However, the death of three of these women was also due to their advanced age and high internal risks. As in the case of ovarian carcinomas, the survival rates improve if the postoperative residual tumor mass is smaller than 2 cm. Subsequent histologic work-up of archived, formalin-fixed tumor tissue and metastases thereof showed that two forms of the metastasizing borderline tumor exist: one with a favorable prognosis, a "pure" form with borderline changes in the ovary and metastases, and one with a less favorable prognosis, with borderline changes in the ovary and destructive-invasive portions of tumor in the metastazation areas. Impulse cytophotometric studies (ICP) showed that all primary tumors had the same degree of ploidy i.e., diploid. However, detection of an aneuploid distribution pattern in a metastasis correlated with subsequent histological confirmation of tumor invasion and rapid tumor death. The S-phase fraction was low, at 2.02% +/- 1.3.(ABSTRACT TRUNCATED AT 250 WORDS)

[Potential malignancy of cystosarcoma phyllodes of the breast. A contribution to the histogenesis of fibrosarcoma]. / Zur potentiellen Malignität des Cystosarcoma phylloides der Mamma. Ein Beitrag zur Histogenese des Fibrosarkoms.

The present case report, which describes the transformation of a cystosarcoma phylloides into a "borderline case" and subsequently a fibrosarcoma, makes it clear that fibrosarcoma of the breast cannot always be regarded as a tumor which has developed primarily from mesenchymal breast tissue. Just as a benign cystosarcoma can turn malignant if therapy is inadequate, it can also turn into a purely sarcomatous tumor. The clinical consequences of this are that a cystosarcoma should not only be shelled out, but excised generously, with a wide border of healthy tissue. The "borderline" type of cystosarcoma phylloides, or respectively the fibrosarcoma, requires far more aggressive therapy, i.e., mastectomy. In fibrosarcoma cases additional selective lymphadenectomy may be considered, although the metastasization pattern is predominantly hematogenic. Overall, however, the prognosis for fibrosarcoma cases is better than for those with breast cancer.