Immunohistochemical study of matrix metalloproteinase 9 and tissue inhibitor of matrix metalloproteinase 1 in benign and malignant breast tissue--strong expression in intraductal carcinomas of the breast.

OBJECTIVE: Matrix metalloproteinases (MMPs) are involved in carcinogenesis due to their tissue remodeling capability, and there is convincing evidence linking gelatinase B (MMP-9) with malignant cell invasion. Tissue inhibitor 1 of MMP (TIMP-1) is a strong inhibitor of MMP-9 but has also tumor-enhancing effects. Only few data exist on MMP-9 or TIMP-1 expression in tissue samples of different breast histology. METHODS: MMP-9 and TIMP-1 immunoreactivity was examined in a wide range of breast tissue samples differing in histology from usual ductal hyperplasia (UDH) to fully developed ductal breast carcinoma. Immunohistochemical expression of MMP-9 was studied in 178 samples: 31 UDH samples, 29 atypical ductal hyperplasia (ADH) samples, 28 ductal carcinoma in situ (DCIS) samples and 90 ductal invasive carcinoma samples (30 samples of malignancy grades I, II and III, respectively). TIMP-1 expression was also analyzed in 178 breast tissue samples: 41 UDH, 21 ADH and 34 DCIS lesions, and 82 invasive ductal breast carcinomas (25 in grade I, 30 in grade II and 27 in grade III). RESULTS: A significantly distinctive pattern of MMP-9 protein expression was shown in DCIS samples, where 85.7% of the cases showed moderate or strong positivity and negative staining was rare (p = 0.021). Negative or weakly positive MMP-9 staining was the most prominent finding in UDH (71%), ADH (69%) as well as in invasive carcinoma samples (64.4%). Various degrees of TIMP-1 expression were seen in 86.5% of all cases. DCIS and invasive carcinoma samples revealed similar immunostaining: at least some positivity was seen in 91.1% of the DCIS samples and 91.5% of infiltrative carcinomas. Thus, TIMP-1 negativity (22.2%) was significantly associated with hyperplastic lesions (p = 0.026). CONCLUSIONS: These results suggest that MMP-9 and TIMP-1 overexpression are early markers of breast carcinogenesis preceding tumor invasion. Apparently, DCIS carries the risk to evolve into a malignant phenotype according to these markers. The clinical importance of these findings is discussed.

Ultrasonography-guided core needle biopsy in differential diagnosis of papillary breast tumors.

BACKGROUND: Papillary lesions of the breast are considered diagnostically challenging for various reasons. A relatively high malignancy rate in final pathological analysis has in many cases necessitated excision of these lesions, regardless of core needle biopsy (CNB). PURPOSE: To assess mammographic, sonographic, and CNB findings of papillary lesions, and to correlate them with final histology obtained by surgical excision. MATERIAL AND METHODS: From 2000-2006, 29 benign and 19 malignant papillary tumors examined with CNB were surgically removed. Mammographic, sonographic, and CNB results were analyzed and correlated with final histology. RESULTS: On ultrasonography (US), 69% (20/29) of the benign lesions were solid and 31% (9/29) were cystic, and 47% of the malignant lesions (9/19) were solid and 53% (10/19) were cystic. The mammographic findings were nonspecific, although most of the malignant tumors (67%, 12/18) were categorized as BI-RADS 4 lesions. The sensitivity, specificity, and positive predictive value of the core needle biopsy histology was 32% (6/19), 100% (29/29), and 100% (6/6), respectively, for papillary carcinoma. A negative predictive value of 91% (21/23) for malignancy and 48% (11/23) for either atypia or malignancy was shown. Of the lesions with CNB diagnosis of benign papillary lesion with atypia, 58% (11/19) turned out to be malignant and 11% (2/19) were benign on surgery. CONCLUSION: The probability of malignancy is low when the CNB result shows a benign papillary lesion with no atypia. However, the only way to reliably diagnose atypical papillary lesions is to surgically remove all papillary tumors, irrespective of the CNB result. Differentiation between benign and malignant lesions or malignant noninvasive and invasive tumors is not possible based on sonographic or mammographic appearance.

Ultrasonography and core needle biopsy in the differential diagnosis of fibroadenoma and tumor phyllodes.

BACKGROUND: The diagnosis of phyllodes tumors of the breast is challenging due to many similarities with common fibroadenomas. PURPOSE: To determine the diagnostic accuracy of core needle biopsy in diagnosing phyllodes tumors and to analyze the ultrasonographic (US) features of phyllodes tumors and fibroadenomas. MATERIAL AND METHODS: From 1999 to 2003, 1010 breast lesions underwent imaging-guided core needle biopsy. Of these, 57 fibroadenomas and 12 phyllodes tumors were removed surgically. The US and needle biopsy results of a total of 64 lesions (52 fibroadenomas and 12 phyllodes tumors) were further analyzed, compared, and correlated with surgical histological results. RESULTS: The median sonographic sizes of the phyllodes tumors and the fibroadenomas were 3.2 cm and 1.6 cm, respectively. At US, 58% of the phyllodes tumors (7/12) were classified as equivocal or suspicious of malignancy and 42% (5/12) as probably benign, while 54% of the fibroadenomas (28/52) were classified as probably benign and 46% (24/52) as equivocal. The sensitivity, specificity, and positive and negative predictive values of core needle biopsy histology regarding tumor phyllodes were 83%, 92%, 71%, and 96%, respectively. CONCLUSION: Imaging-guided core needle biopsy was accurate in differentiating between fibroadenomas and phyllodes tumors. US classification was unreliable due to considerable overlap in the findings. Combined use of US feature analysis and needle biopsy may help to avoid the misinterpretation of phyllodes as fibroadenoma.

Lymphoma of the cervix. Imaging and transcatheter arterial embolization.

A case of uterine cervix lymphoma with selective embolization after angiography is described. Chemotherapy and radiotherapy were carried out and surgery was avoided.

Ultrasound-guided percutaneous thoracoabdominal biopsy.

This review will discuss the benefits and disadvantages of ultrasound-guided percutaneous fine-needle aspiration and cutting needle biopsies. Clinical efficacy, cost-effectiveness, some controversies and safety will be reviewed.

Gelatinase A-immunoreactive protein in ovarian lesions- prognostic value in epithelial ovarian cancer.

OBJECTIVE: Gelatinase A (MMP-2) is a member of the matrix metalloproteinase family and it degrades the major component of the basement membrane, type IV collagen. MMP-2 has been linked to invasion in different types of cancer. METHOD: We have studied the localization of MMP-2 in 18 benign, 3 borderline, and 33 malignant ovarian lesions by immunohistochemical stainings using a monoclonal antibody against MMP-2. RESULTS: MMP-2-immunoreactive protein was localized in epithelial cells and in fibroblasts. Two types of cytoplasmic staining were observed, a diffuse and a granular pattern. The diffuse staining model was found more often. In 19% of the cases, both staining patterns were present in epithelial cells. Granular staining was found in epithelial cells in cystadenomas and in ovarian cancer cells. The pattern of MMP-2 positivity in fibroblasts was diffuse. MMP-2 positivity in cancer cells was associated with recurrent disease (P < 0.05) in ovarian cancers. MMP-2 negativity in fibroblasts correlated to Grade 3 (P < 0.01), Stage III-IV (P < 0.001), recurrency (P < 0.05), and refractory disease (P < 0.05) in ovarian cancer. The relative survival rate was 32% in patients with an MMP-2-positive ovarian cancer, 57% in patients with an MMP-2-negative ovarian cancer, and 19% in patients with MMP-2 positivity in cancer cells and concomitant negativity in stromal fibroblasts. The disease-free 5-year survival rates were 25, 57, and 12.5%, respectively. CONCLUSIONS: These data suggest that MMP-2 may contribute to poor prognosis of ovarian cancer.

Multiple endocrine neoplastic-associated thymic carcinoid tumour in close relatives: octreotide scan as a new diagnostic and follow-up modality. Two case reports.

Thymic carcinoid tumours constitute less than 1% of all carcinoids, and differ markedly from true thymomas in natural history, morphology, prognosis and therapeutic options. New clinical and diagnostic modalities are described in two brothers with thymic carcinoid associated with multiple endocrine neoplasia syndrome. Octreotide scintigraphy proved useful for diagnosis and follow-up, and somatostatin receptor positivity may provide new prospects for treatment of non-resectable or recurrent tumour.

Matrix metalloproteinase 2 immunoreactive protein appears early in cervical epithelial dedifferentiation.

OBJECTIVE: Expression of the immunoreactive protein of matrix metalloproteinase 2 (MMP-2) was studied in cervical tumors representing various stages of cell atypia and differentiation. In this study, we evaluated whether the expression of MMP-2 is an early or late event in the process of dedifferentiation and cancer progression. METHODS: Paraffin tissue sections from 60 cervical neoplasias including 38 cervical intraepithelial neoplasias (CINs) and 22 early-stage (stage IB and IIA) squamous cervical carcinomas were studied with respect to the expression of MMP-2 protein by using immunoperoxidase staining. RESULTS: The staining pattern of MMP-2 in the CIN lesions usually differed from that in squamous carcinoma. Latent MMP-2 protein localized, in most of the cases, to the periphery of the CIN cells, but was diffuse in the cytoplasm of the carcinoma cells. No correlation was found between overexpression of MMP-2 protein and degree of dysplasia, nor was there any association between MMP-2 and human papillomavirus (HPV). High scores for MMP-2 were observed only in histologically higher-grade early-stage cervical carcinomas. The lymph node metastases derived from high-MMP-2-score primary tumors were also positive for MMP-2. No correlation between MMP-2 staining and clinical course or prognosis was found. CONCLUSIONS: MMP-2 expression is an early event during dedifferentiation and malignant transformation in cervical neoplasias. The pattern of staining is different in CIN than in squamous carcinoma cells, in which overexpression may correlate with the degree of anaplasia.

Ultrasonography of invasive lobular breast carcinoma.

PURPOSE: To review the US findings in invasive lobular breast carcinoma which is often difficult to diagnose clinically and mammographically. MATERIAL AND METHODS: The mammographic and US findings in 63 cases of pure invasive lobular carcinoma diagnosed at our institution in 1990-1996 were reviewed retrospectively. The US findings were classified as positive, negative or indeterminate for malignancy. RESULTS: Forty-nine of the 63 lobular carcinomas (78%, 95% CI 65.5-87.3%) were US-positive, and 51 (81%, CI 95% 69.1-89.8%) were mammography-positive. The US visibility of the carcinomas was affected by their palpability and mammographic appearance, and the radiographic density of the breasts. Indeterminate US findings (architectural distortion with acoustic shadowing) were visualized in 4 of the 10 cases that had asymmetric densities at mammography. CONCLUSION: The sensitivity of US for lobular carcinoma was not statistically different from that of mammography. The methods were complementary, especially with regard to evaluating dense breasts and lesions which were difficult to assess clinically and mammographically.

Ultrasound-guided fine needle aspiration biopsy in the diagnosis of breast cancer recurrence after mastectomy.

PURPOSE: To define the accuracy and clinical impact of fine needle aspiration biopsy (FNAB) in diagnosing recurrent breast cancer after mastectomy. MATERIAL AND METHODS: The results of ultrasonography (US) and US-guided FNAB of 175 lesions located at the mastectomy site or in the ipsilateral axilla were reviewed. The final diagnosis was recurrent cancer in 77 cases and benign lesion in 98 cases, as verified by histological examination (n = 77) or follow-up (n = 98). RESULTS: FNAB yielded a representative aspirate in 92.6% of cases. The sensitivity, specificity and overall accuracy of FNAB cytology were 96.1%, 89.8% and 92.6% respectively. US and FNAB cytology were complementary methods in recurrent cancer diagnosis. The cytologic examination increased the specificity of US. The only recurrent tumor which appeared benign both sonographically and cytologically was removed because of a suspicious finding at palpation. FNAB cytologic diagnosis was found to have a clinical impact in 92.2% of the recurrent cases. CONCLUSION: US-guided FNAB provided an accurate adjunct to clinical examination and mammography for diagnosing and excluding breast cancer recurrence after mastectomy.

Comparison between the effects of tamoxifen and toremifene on the uterus in postmenopausal breast cancer patients.

Antiestrogens have been widely used in the treatment of breast cancer patients. We wanted to compare the uteral and vaginal effects of tamoxifen to those of toremifene. Thirty-one gynecologically asymptomatic postmenopausal breast cancer patients with an intact uterus were randomized to receive 20 mg of tamoxifen (N = 16) or 60 mg of toremifene (N = 15) as an adjuvant treatment. Gynecological examination with vaginal ultrasonography, Pap smear, endometrial biopsy, hysteroscopy, and curettage was performed before the treatment, and at 6 and 12 months of treatment. Endometrial thickness was found to increase significantly during the treatment to the same extent in both groups. Proliferation or other estrogenic effects in the endometrium were observed in 8 of 14 patients in the tamoxifen group and in 3 of 10 patients in the toremifene group. Three polyps occurred and previously present uterine fibroids increased in size in 3 of 10 patients during the study. Estrogenic changes in Pap smear were observed in all patients. There was no significant difference between tamoxifen and toremifene in any of the parameters investigated. Our results suggest that tamoxifen and toremifene produce comparable estrogenic effects in the uterus and vagina.

Mammography and ultrasound in the diagnosis of contralateral breast cancer.

Forty-nine (5%) of 956 women referred for follow-up imaging after breast cancer treatment had a malignancy in both breasts. The mammograms and ultrasonograms or US reports, and histologic slides or pathologic reports of 31 of these patients were reviewed. Mammography was more sensitive than clinical examination or US in detecting contralateral breast cancer, the sensitivity of mammography being 81%. Thirty-nine percent of the contralateral cancers were nonpalpable, and all were first detected at mammography. No cancers were depicted by US alone. US provided complementary information about palpable masses in 50% of the cases in which the mammographic finding was difficult to interpret. The mammographic appearance and the difficulties in detecting a contralateral cancer were similar to those known to be characteristic for first primaries. Distinguishing a new primary from a metastasis from the first breast cancer was not always possible by means of mammography or US.

Transdermal estrogen with a levonorgestrel-releasing intrauterine device for climacteric complaints: clinical and endometrial responses.

OBJECTIVE: Our purpose was to study the effects of intrauterine release of a daily dose of 20 micrograms levonorgestrel by an intrauterine device on climacteric symptoms, bleeding pattern, and endometrial histologic features in postmenopausal women receiving transdermal estrogen replacement therapy. STUDY DESIGN: Forty parous postmenopausal women were randomly allocated into two groups for 1 year: 20 women receiving a continuous transdermal daily dose of 50 micrograms of estradiol had a levonorgestrel-releasing intrauterine contraceptive device inserted, and the control group of 20 women received a continuous oral dose of 2 mg of estradiol valerate and 1 mg of norethisterone acetate daily. The climacteric symptoms, bleeding patterns, endometrial thickness, and endometrial changes in biopsy samples were analyzed. Serum levels of estradiol in both groups and levonorgestrel levels in the intrauterine device group were also determined. RESULTS: Both treatment regimens effectively relieved climacteric symptoms. Spotting was more common in the intrauterine contraceptive device group than in the oral therapy group for the first 3 months. After that, the proportion of women without any bleeding was similar in both groups. Two patients in each group dropped out because of bleeding. CONCLUSION: These preliminary findings suggest that the levonorgestrel-releasing intrauterine contraceptive device is a useful alternative mode of progestin administration for certain selected women receiving estrogen replacement therapy.

PIP: The purpose was to study the effects of intrauterine release of a daily dose of 20 mcg levonorgestrel by an IUD on climacteric symptoms, bleeding pattern, and endometrial histologic features in postmenopausal women receiving transdermal estrogen replacement therapy. 40 parous postmenopausal women were randomly allocated into 2 groups for 1 year. They were required to be parous, to have an intact uterus, and to have had amenorrhea for at least 6 months but less than 5 years. 20 women received a combination of 50 mcg of estradiol per 24 hours delivered transdermally from a patch, and received estrogen pretreatment for 1 month to make insertion of a levonorgestrel-releasing IUD (Levonova), which was installed a month later, easier. This combination was continued for 1 year. The control group of 20 women received an established form of continuous oral estrogen and progestin with a daily dose of 2 mg of estradiol, and 1 mg of norethindrone acetate also administered for 1 year. Checkup visits were scheduled at 3, 6, and 12 months. The climacteric symptoms, bleeding patterns, endometrial thickness, and endometrial changes in biopsy samples were analyzed. The increase in estradiol concentration was similar in both groups, and the mean concentrations of levonorgestrel in the IUD group were 216 +or- 25 pg/ml at 3 months, 209 +or- 11 pg/ml at 6 months, and 212 + 10.5 pg/ml at 12 months. Both treatment regimens effectively relieved climacteric symptoms. The IUD group experienced more days of bleeding, primarily spotting, during the first 3 months than did the oral therapy group but the differences between the groups had disappeared by 6 months. Both treatments resulted in an atrophic endometrium developing from a proliferative one. Two patients in each group dropped out because of bleeding. The levonorgestrel-releasing IUD is a useful alternative mode of progestin administration for certain selected women receiving estrogen replacement therapy.

Diffuse renal disease. Diagnosis by ultrasound-guided cutting needle biopsy.

The results of ultrasound (US)-guided renal parenchymal cutting needle biopsies in 101 consecutive patients were reviewed. The biopsies were done with the automated Biopty device mounted with a 2.0-mm needle. One or 2 needle passes yielded sufficient material for histologic analysis in 94% (95/101). Three or more passes were required in 6% (6/101) to obtain an adequate specimen. Mesangioproliferative glomerulonephritis, IgA-nephropathy, nephrosclerosis, diabetic nephropathy, secondary amyloidosis, lupus nephritis, minimal change glomerulonephritis and interstitial nephritis accounted for 79% of the final histologic diagnoses. The high quality and quantity of the tissue specimens yielded a definitive histologic diagnosis in renal parenchymal diseases of unknown etiology. Four major complications occurred, but no deaths or loss of kidney function were recorded. US proved useful as a guide to suitable biopsy site and in the detection of clinically significant complications. Prebiopsy screening of coagulation variables did not seem to prevent complications. Special attention should be paid to post-biopsy clinical observation.

Thoracic lesions: diagnosis by ultrasound-guided biopsy.

We reviewed the results of US-guided fine-needle biopsies of peripheral pulmonary, pleural, mediastinal and chest wall lesions in 200 patients. Sufficient material for cytological analysis was obtained in 95%, 92%, 96% and 100%, respectively. Sensitivity was 88%, 94%, 96%, 100% and specificity 89%, 100% and 100%, respectively. The ratio of false-negative results was 7%. A cutting needle biopsy was additionally performed in 24 patients. All but two of the histological samples (92%) were adequate for diagnostic purposes and a correct diagnosis was established in 86% (19/22) of these. 8 patients (4%) with pleural or pulmonary targets had minor complications (5 pneumothorax, 3 haemoptysis), which did not require treatment. Cutting needle biopsies and biopsy of mediastinal lesions proved safe. Due to the many advantages US may be considered for guidance in peripheral larger-sized pulmonary lesions, particularly those abutting the pleura, and also in pleural, thoracic wall and mediastinal masses.

Parathyroid adenomas: pre-operative localization with ultrasound combined with fine-needle biopsy.

Sixteen patients with biochemically proven primary hyperparathyroidism (PHPT) underwent ultrasonography (US), fine-needle aspiration (FNA) for cytologic sampling (n = 9), or intact parathormone assay (n = 3) before operation (n = 15) in order to determine the accuracy of the methods. Pre-operative US was found sensitive (100 per cent), but two thyroid lesions were initially diagnosed as parathyroid tumours by US (i.e. false positives). Parathyroid cells were detected in six cytologic specimens, one sample was insufficient and another inconclusive, while one was diagnosed as thyroid tissue. Parathormone assay revealed a high hormone content in all three patients who underwent the procedure. We conclude that US is sufficiently sensitive to detect enlarged parathyroid tumours. Specificity can be improved by US-guided FNA for cytology or parathormone assay prior to neck exploration.

Endometrial changes in postmenopausal breast cancer patients receiving tamoxifen.

OBJECTIVE: To assess the estrogenic effect of tamoxifen and associated pathologic changes of the endometrium in postmenopausal breast cancer patients. METHODS: The endometrium of 103 gynecologically asymptomatic postmenopausal breast cancer patients was examined. Fifty-one had been treated with tamoxifen and 52 had not received any hormonal treatment. The two groups were similar in age, parity, age at menopause, and body mass index. RESULTS: Compared with the control subjects, the tamoxifen patients had a thicker endometrium (mean +/- standard deviation 10.4 +/- 5.0 versus 4.2 +/- 2.7 mm; P = .0001) and larger uterine volume (45 +/- 27 versus 25 +/- 11 cm3; P = .001), as determined by transvaginal sonography. Hysteroscopy showed an atrophic endometrium in 28% of the patients in the tamoxifen group, as compared with 87% of the control patients (P = .0001). Endometrial polyps were more frequent in the tamoxifen group (36 versus 10%; P = .004), which included one patient with atypical hyperplasia, one with adenomatous hyperplasia, and one with endometrial adenocarcinoma; two controls had endometrial adenocarcinoma. CONCLUSION: The results provide evidence for an estrogenic effect of long-term tamoxifen treatment on the postmenopausal uterus and show it to be associated with an increased occurrence of polyps.