HER-2/neu expression in Paget disease of the vulva and the female breast.

OBJECTIVES: Paget disease of the vulva is a rare lesion that accounts for <1% of vulva neoplasms. A 12% prevalence of invasive Paget carcinoma and a 4% prevalence of associated adenocarcinomas are described. Furthermore, a high recurrence rate of 30% after surgical therapy is observed. This study aims to search for therapeutic strategies for recurrent Paget disease, which are less mutilating and less aggressive than reexcision, x-ray therapy, or chemotherapy. Trastuzumab (Herceptin) is a recombinant monoclonal antibody against HER-2/neu, approved by the U.S. FDA for the treatment of patients with HER-2/neu-positive metastatic breast carcinomas. The results of recent studies indicate that HER-2/neu oncoprotein may play a role in the pathogenesis of extramammary Paget disease. METHODS: Using HercepTest, we analyzed HER-2/neu overexpression in seven noninvasive Paget lesions, two invasive lesions, and one Paget disease of the vulva with underlying adenocarcinoma. In addition, we investigated five mammary Paget diseases. RESULTS: Overexpression of HER-2/neu oncoprotein labeling exclusively the membranes of Paget cells was demonstrated in 8 out of 10 cases. One noninvasive and one with underlying adenocarcinoma stained negatively. Overexpression of HER-2/neu was demonstrated in all five cases of mammary Paget disease. CONCLUSION: Using HercepTest as a standardized detection system, overexpression of HER-2/neu can be demonstrated in a majority of both noninvasive and invasive Paget disease of the vulva. The use of Trastuzumab should be considered for the treatment of patients with recurrent Paget disease of the vulva with overexpression of HER-2/neu.

[Endocrine-active tumors of the ovary]. / Endokrin aktive Tumoren des Ovars.

Most hormonally active ovarian tumors belong to the category of tumors of the gonadal stroma. These account for less than 5% of all ovarian tumors. About two-thirds of tumors of the gonadal stroma produce steroid hormones. The pathologic secretion of estrogenic or androgenic hormones leads to specific effects on the hormone-sensitive target organs. The clinical manifestations depend on both the amount of hormones secreted and the age of the patient. Tumors of the gonadal stroma are potentially malignant, ranging between noninvasive (borderline) tumors and invasive epithelial tumors of the ovary. Besides the specifically steroid hormone-producing tumors, a wide variety of ovarian tumors other than those in the stroma of the ovary and steroid cell tumors may be hormonally active as the result of an increase in and/or stimulation of nonneoplastic ovarian stromal cells within or adjacent to the tumor.

Scintimammography with technetium-99m methoxyisobutylisonitrile: results of a prospective European multicentre trial.

The aim of the trial was to determine the diagnostic accuracy of scintimmammography with technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) in the detection of primary breast cancer and to verify its clinical usefulness. A total of 246 patients with a suspicious breast mass or positive mammogram were included in this prospective European multicentre trial. At 5 min and 60 min (optional) p.i. two lateral prone images were acquired for 10 min each; 30 min p.i. one anterior image was acquired for 10 min. There were 253 lesions (195 palpable and 58 non-palpable), in respect of which histology revealed 165 cancers and 88 benign lesions. Institutional and blinded read results were correlated to core laboratory histopathology results obtained during excisional biopsy. Diagnostic accuracy for the detection of breast cancer was calculated per lesion. The overall sensitivity and specificity of blinded read scintimammography were 71% and 69%, respectively. For palpable lesions, the sensitivity of blinded read and institutional read scintimammography was 83% and 91%, respectively. Sensitivity was not dependent on the density of the breast tissue. Invasive ductal and invasive lobular cancers showed similar sensitivity. The sensitivity and specificity of mammography were 91% and 42%, respectively, and did not depend on the tumour size. In 60% of false-negative mammograms, 99mTc-MIBI was able to diagnose malignancy (true-positive). High-quality imaging with 99mTc-MIBI has a high diagnostic accuracy for the detection of primary breast cancer. Used as a complementary method, scintimammography with 99mTc-MIBI can help to diagnose breast cancer at an earlier stage in patients with dense breasts.

[Uterine stromal tumor with ovarian sex cord differentiation]. / Uteriner Stromatumor mit ovarieller Keimstrangdifferenzierung.

Uterine tumors resembling sex-cord ovarian structures are exceptionally rare. Clement and Scully divided them into two groups. The first group includes cases with less than 50% and the second with more than 50% sex-cord elements. Group one tumors show a higher incidence of recurrences. We report a case of a 54-year-old women with a partly retroperitoneal, cystic tumor 7.6.6 cm. Histologically, sex-cord differentiation of more than 50% was seen with positive immunostaining against vimentin, desmin and focally against myoglobin and cytokeratines. The reaction against EMA, CEA and S 100 was negative. The patient was treated by abdominal hysterectomy with bilateral salpingo-oovorectomy. She shows no evidence of disease 2.3 years after the initial surgery. Based on the light microscopic features and immunohistochemical pattern, the tumor was interpreted as arising from the endometrial stromal cells or multipotential uterine mesenchyme that showed diverse differentiation toward ovarian sex-cord stroma and uterine smooth muscle with interspersed stromal cell clusters.

Gliomatosis peritonei combined with mature ovarian teratoma: immunohistochemical observations.

Gliomatosis peritonei (GP) is the metastatic implantation of glial cells within the peritoneal cavity of patients with ovarian teratomas. The case of a young woman is presented, who initially developed a mature teratoma in the left ovary that was surgically removed. Nine years later a mature teratoma in the right ovary was excised, upon which GP was found in the greater omentum. To identify the cellular composition of the ovarian teratoma and of the omental implants, immunostainings were performed using antibodies against glial and neuronal antigens as well as against determinants of hematopoietic cells. In the teratoma the neuroectodermal part was strongly HNK-1-positive and contained GFAP- and vimentin-positive astrocytes and some NSE-positive neuron-like cells. In addition, neuroectodermal tissue was infiltrated by numerous CD68-positive macrophages/histiocytes and CD20-positive B lymphocytes. The omental nodules consisted of astrocytes, which expressed GFAP, vimentin and desmin. The implants also contained macrophages/histiocytes, which exhibited morphologic features reminiscent of microglial cells. In GP, macrophages might release glia-promoting trophic factors, which could allow the neural component of ovarian teratoma to implant in the peritoneal cavity and survive there for many years. Macrophage-derived factors might induce astroglial differentiation, which could explain why the peritoneal implants are mostly mature even when they originate from immature teratomas.

[Primary lymphoma of the cervix uteri--2 case reports]. / Primäres Lymphom der Cervix uteri--zwei Kasuistiken.

Two cases of primary non-Hodgkin's lymphoma of the uterine cervix are described. Diagnostic pitfalls and therapeutic applications of this rare disease are discussed. The main approach in local therapy is external beam radiation--with or without surgical staging. Prognosis is favourable--depending on the stage of disease.

Polymerase chain reaction-assisted evaluation of low and high grade squamous intraepithelial lesion cytology and reappraisal of the Bethesda System.

Between January 1991 and 1992, 5,652 cervical smears from 4,918 women were classified according to the traditional Papanicolaou/cervical intraepithelial neoplasia (CIN) categories and to the recently developed Bethesda System. Koilocytosis without atypia was identified in 3.7% (183 cases), CIN 1 in 1.8% (87 cases) and high grade squamous intraepithelial lesions (SILs) (CIN 2 and 3) in 1.9% (93 cases) (total, 363/4,918 = 7.4%). Human papillomavirus (HPV)-directed polymerase chain reaction analysis with general primers and subsequent hybridization with HPV 16/18 probe cocktail was carried out in 35% of cases with koilocytosis and dysplasia of any degree (127/363 cases). Seventy-five percent (95 cases) were positive in contrast to a detection rate of 30.8% (53/172 cases) for nonsuspicious smears. While low grade SILs were HPV positive in 67% (koilocytosis only) and 75% (CIN 1), high grade SILs harbored HPV in 87%. The rate of HPV 16/18 infections varied from 71.9% in low grade SILs to 88.9% in high grade SILs. Our results point to the questionable value of koilocytosis as a specific marker of HPV infection and call for confirmatory tests prior to classifying cervical smears suggestive of HPV infection in the low grade SIL category.

Intracellular sex hormone-binding globulin (SHBG) in normal and neoplastic breast tissue--an additional marker for hormone dependency?

Recent studies indicate that in addition to free diffusion, uptake of sex hormones into target cells is mediated by sex hormone-binding globulin (SHBG). The purpose of this study was to investigate localization and distribution of SHBG in normal and neoplastic breast tissue. We examined 31 normal, 21 non-invasive, 52 invasive breast cancer tissues and 33 cases of recurrences and metastases of breast cancer immunohistochemically for SHBG by the ABC-peroxidase method, using a polyclonal, monospecific antiserum derived from rabbit. The proportion of stained cells was evaluated semiquantitatively. In 81 malignant cases the oestrogen receptor (ER) content was evaluated by the ER-ICA method. Positive staining for SHBG was found exclusively in epithelial cell cytoplasm. Benign tissue was focally SHBG-positive and showed more stained cells in proliferating epithelium. Staining of neoplastic tissue was more heterogeneous. Half of the non-invasive carcinomas were SHBG-positive; particularly the highly differentiated. Independent of subtype and differentiation, invasive tumours were SHBG-negative in 32.5% of cases, while 19.3% were SHBG-positive in most cells. In 13 cases of invasive carcinomas, associated intraductal parts showed more staining for SHBG than the invasive tissue. Recurrences and metastases of breast cancer were SHBG-negative in 45.5% of cases, while only 3% were positive in most cells. SHBG-staining was unrelated to ER content. These results suggest that the demonstration of cytoplasmic SHBG represents a physiological feature of breast epithelium and its presence is compatible with a mechanism for cellular uptake of SHBG-bound sex hormones preceding their interaction with nuclear receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Human papillomavirus detection in cervical adenocarcinoma by polymerase chain reaction.

Twenty-five primary cervical adenocarcinomas and five cervical infiltrates from endometrial or rectal adenocarcinomas were analyzed for human papillomavirus (HPV) DNA by polymerase chain reaction with consensus and type-specific primers. Sixty-four percent (16 of 25) of the primary carcinomas and 20% (one of five) of the secondary infiltrates were positive for HPV types 16 and/or 18 DNA. Among the primary tumors HPV DNA was found in 80% of the endocervical cell-type tumors and in 60% of the endometrioid tumors, whereas two undifferentiated scirrhous carcinomas, one clear cell carcinoma, and one serous-papillary tumor were HPV negative. Human papillomavirus-positive patients were younger than HPV-negative patients (mean ages, 49.2 v 64.2 years). Our results indicate that papillomavirus play a major role in the etiology of cervical adenocarcinomas, at least in premenopausal women. However, in contrast to other studies, HPV type 18 was not the predominant type of HPV, HPV types 16 and 18 occurring with similar frequency in our patients.

DNA cytophotometry and prognosis in ovarian tumors of borderline malignancy. A clinicomorphologic study of 80 cases.

Surgical specimens of 80 ovarian tumors of borderline malignancy (OTBM) were investigated by scanning DNA cytophotometry. Diploid or euploid DNA histograms were found for 21 tumors, whereas 59 OTBM showed noneuploid or aneuploid DNA patterns. All patients were followed-up after surgery for at least 3 years (mean observation period, 6.7 years). Follow-up showed 11 cases of recurrent disease and 6 deaths. DNA findings and several other morphologic and clinical details (including patient age, histologic type and stage of disease, and extent of therapy) were correlated to the postoperative course. Statistical analyses disclosed that, of these parameters, only DNA content significantly affected prognosis. Recurrences and deaths resulting from tumor exclusively were observed among patients with noneuploid or aneuploid OTBM, whereas none of the diploid or euploid tumors recurred (P less than 0.05). DNA cytophotometry thus might be regarded as an effective complementary means to assess the prognosis of individual OTBM cases.

DNA-cytophotometry and immunocytochemistry in ovarian tumours of borderline malignancy and related peritoneal lesions.

A total of 34 surgical specimens, obtained from 13 patients with ovarian tumours of borderline malignancy (OTBM), were investigated by conventional histology, immunocytochemistry and DNA cytophotometry. The lesions were obtained by primary ovarian surgery or second-look procedures and altogether comprised 19 (single and bilateral) OTBM, 8 cases of endosalpingiosis, 4 in situ and 2 invasive peritoneal implants and 1 overt adenocarcinoma. The morphological findings were related to follow-up data, which showed neoplasms with clinically malignant behaviour in 2 patients. The histology of the extra-ovarian manifestations was not associated with their immunocytochemical properties or with their DNA content. There were no correlations between the evolution of disease and microscopical features but the clinical course appeared to be linked to the DNA content of the extra-ovarian lesions, which was of greater prognostic importance than DNA ploidy of the ovarian tumours. Recurrence-free survival was noted in all 5 patients with diploid or euploid extra-ovarian proliferations, while the 2 clinically malignant cases fell into the group of 3 patients with noneuploid or aneuploid specimens. DNA estimations may be a methodology which increases the prognostic value of second-look procedures in OTBM patients.

[Results of treatment following breast-saving therapy: analysis of intramammary recurrence]. / Behandlungsergebnisse nach brusterhaltender Therapie: Analyse der intramammären Rezidive.

1,135 patients were subjected to conservation treatment of the breast between 1972 and April 1990. The probability of survival without relapses and metastases is 82.2% (5 years) or 72.1% (10 years), respectively. Local recurrence from relapses is 94.8% (5 years) or 88.9% (10 years), respectively. 31 patients developed an intramammary relapse, whereas 3 presented a renewed ductal in-situ manifestation, that was not considered to be a relapse. An unfavourable prognosis in respect of the rate of local relapses is considered to be dependent upon the size of the tumour. Other unfavourable factors are youthful age, concomitant DCIS formations, lymphangiosis carcinomatosa and "incomplete" resection (i.e. not including healthy tissue surrounding the tumour). These various "risk factors" are discussed on the basis of the literature and the authors' patient material.

[Clinical and histopathologic studies of primary glandular cancer of the uterine cervix. An analysis of 78 cases from 1972 to 1984]. / Klinische und histopathologische Untersuchungen an primären Drüsenkrebsen der Cervix uteri. Eine Analyse von 78 Fällen der Jahre 1972 bis 1984.

In the period between 1972 and 1984 716 cervical carcinomas, of which 78 were glandular cancers, were diagnosed at the University Hospital in Hamburg-Eppendorf. The incidence of invasive adenocarcinomas of the cervix is 10.9%. When compared with a study published in 1949 (19) the incidence of adenocarcinoma has risen from 3% to 10.9%. In the period of observation, i.e., from 1972 to 1984, no trend to an increase in incidence was observed. The average age of the patients, 62.6 years, is relatively high in comparison with other studies. An earlier onset of disease has not been observed. The available data do not provide any evidence of connection between the use of oral contraceptives and later development of an adenocarcinoma. The five-year survival rate for all stages taken together was 40.4%. The five-year survival rate, and thus the prognosis for glandular carcinomas of the cervical glands, depends primarily on the clinical stage of the disease, though also on the histological type and the degree of differentiation of the tumor.

Ultrastructure of preneoplastic lesions of the vulva.

Ultrastructural analysis using electron microscopy was performed on 16 cases of preneoplastic lesions of the vulva. They included specimens from patients with condylomatous dysplasia, carcinoma in situ, melanoma in situ and extramammary Paget's disease. Each showed significant differences from normal in the ultrastructural details.