Frequency of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from Trentino, North East Italy.

OBJECTIVE: Triple negative breast carcinomas (TNT) are infiltrating breast carcinomas (BC) with negative oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER-2) expression, and are associated with frequent BRCA1/BRCA2 mutations. The aim of the present study is to analyze the frequency and distribution of TNT in our population where a breast cancer screening program for women aged between 50 and 69 years is effective since 2001 with 85% accrual. METHODS: We investigated the records of 2112 consecutive BC and 153 interval BC (i.e. BC detected in the screened negative women in the interval between screening rounds). Tumours with complete negative expression of ER, PgR and Her2 were considered TNT; tumours with negative ER and PgR status and faint Her2 expression (score 1) were considered as possible TNT (pTNT). RESULTS: We identified 82 (3.8%) TNT and 20 (0.9%) pTNT in the series of 2112 consecutive BC and 7 TNT and 1 pTNT (5.2%) in the series of 153 interval BC. In the consecutive series, TNT/ pTNT were observed in 6.5% patients below 50 years and in 4.3% of patients above 50 years. A high proliferation rate (Ki-67 labelling > 36%) was observed in 87.8% of TNT (median labelling 56.3%) and in 60% of pTNT (median labelling 48.4%). CONCLUSIONS: Since TNT/pTNT occurring in women < 50 years is a criterion for selecting patients whom genetic counselling and BRCA1 testing should be offered, our study is of help in foreseeing the workload of the Unit of Medical Genetics and the Laboratory of Molecular Pathology.

Proliferative activity in human breast cancer: Ki-67 automated evaluation and the influence of different Ki-67 equivalent antibodies.

BACKGROUND: Ki67 labeling index (Ki67 LI), the percentage Ki67 immunoreactive cells, is a measure of tumor proliferation, with important clinical relevance in breast cancer, and it is extremely important to standardize its evaluation. AIM: To test the efficacy of computer assisted image analysis (CAIA) applied to completely digitized slides and to assess its feasibility in routine practice and compare the results obtained using two different Ki67 monoclonal antibodies. MATERIALS AND METHODS: 315 consecutive breast cancer routinely immunostained for Ki-67 (223 with SP6 and 92 with MM1 antibodies previously examined by an experienced pathologist, have been re-evaluated using Aperio Scanscope Xs. RESULTS: Mean human Ki67 LI values were 36%± 14.% and 28% ± 18% respectively for SP6 and MM1 antibodies; mean CAM Ki67 LI values were 31%± 19% and 22% ± 18% respectively for SP6 and MM1. Human and CAIA evaluation are statistically highly correlated (Pearson: 0.859, p<0.0001), although human LI are systematically higher. An interobserver variation study on CAIA performed on 84 cases showed that the correlation between the two evaluations was linear to an excellent degree. DISCUSSION: Our study shows that a) CAIA can be easily adopted in routine practice, b) human and CAIA Ki67 LI are highly correlated, although human LI are systematically higher, c) Ki67 LI using different evaluation methods and different antibodies shows important differences in cut-off values.

Prognostic value of estrogen receptor status can be improved by combined evaluation of p53, Bcl2 and PgR expression: an immunohistochemical study on breast carcinoma with long-term follow-up.

Steroid receptor analysis is the only widely accepted prognostic/predictive marker in breast cancer (BC) treatment. In the present study we evaluated the prognostic role of ER/PgR with p53 and Bcl2, in a series of 277 BC (153 pN1/2, 122 pNO, 2 pNx) with a long-term follow-up (67 months for DFS, 75 months for OS). Our results, besides confirming the usefulness of ER immunohistochemical expression as a prognostic marker, showed that PgR expression alone had a borderline/not significant prognostic value in the whole series (p=0.08 for DFS and p=0.09 for OS), while showed to be prognostic in N+ cases (p=0.02 for DFS and p=0.03 for OS). PgR prognostic value, however, was not independent at the multivariate analysis. By combining ER with PgR, p53 and Bcl2, we showed that ER/p53 and ER/Bcl2 phenotypes had a better discriminant role than ER/PgR phenotype. The ER+/p53+ phenotype was at higher risk of relapse/death as compared with ER+/p53- phenotype. Conversely ER-/p53+ phenotype showed the most unfavourable prognosis. Similar results could be observed concerning ER/Bcl2 phenotypes. Our study showed that the combined evaluation of ER/PgR weakly enhanced the prognostic/predictive power of ER status alone. On the contrary, the combined evaluation of ER/p53 and ER/Bcl2, improved this prognostic/predictive capability and allowed the separation of ER positive and ER negative cases into subgroups with different prognosis.

Differential expression of p57kip2, a maternally imprinted cdk inhibitor, in normal human placenta and gestational trophoblastic disease.

Evidence has recently been provided to support a role for genomic imprinting in the regulation of embryonic implantation and development and placental growth, as well as in the pathogenesis of proliferative trophoblastic diseases. The cyclin-dependent kinase inhibitor p57KIP2 has recently been recognized as a maternally imprinted gene. We investigated p57KIP2 expression in first-trimester normal placentas from interrupted pregnancy, spontaneous abortions, and different types of proliferative trophoblastic diseases using single- and double-marker immunohistochemical techniques. In normal placenta, nuclear p57KIP2 expression was observed at high frequency (up to 100%) in extravillous trophoblast, cytotrophoblast, and implantation-site interstitial trophoblast, but was absent in syncytiotrophoblast. p57KIP2 was also expressed in the stromal cells of maternal decidua, which was one of the few adult tissues retaining p57KIP2 expression (most other adult tissues investigated were negative). p57KIP2 expression was either absent or low in all cases of diploid/tetraploid complete moles (20 cases) and in three cases of gestational choriocarcinoma. On the other hand, all spontaneous abortions (12 cases) and triploid partial moles (19 cases) showed p57KIP2 levels comparable to those observed in normal placenta. These findings are in line with the hypothesis that deregulation of genomic imprinting, particularly the loss of cell-cycle inhibitors such as p57KIP2, is involved in the abnormal development of androgenetic trophoblastic proliferations. In addition, this simple immunohistochemical analysis could provide a useful diagnostic marker in difficult cases.

Bax immunohistochemical expression in breast carcinoma: a study with long term follow-up.

Bax and Bcl2 are functionally antagonistic proteins which control apoptosis, whose expression in human tumours could be of prognostic value. We evaluated Bax and Bcl2 expression in 239 breast carcinomas (99 N0, 140 N1/2) with long term follow-up (median 79 months, range 11-140) in relation to clinico-pathologic parameters, clinical outcome, adjuvant therapy and expression of oestrogen receptor protein and p53. The prognostic value of Bax was investigated in the whole series of patients and in subgroups of homogeneously staged and treated patients (i.e., node-negative, N1/2 CMF-treated, N1/2 tamoxifen-treated). Bax immunostaining was cytoplasmic and heterogeneous. Cases were scored as Bax-positive if there were more than 20% reacting cells. High Bax expression was associated with positive nodal status (p = 0.03) and high Bcl2 expression (p = 0.01) and was more frequent in high-grade tumours. In the node-negative subgroup, Bax expression was associated with small tumour size. No association was seen with other parameters or with clinical outcome in any subgroup of patients. Since the apoptotic rate of a tumour is influenced by the ratio Bcl2/Bax, we investigated the combined effects of Bax and Bcl2 expression in relation to clinical outcome. However, no differences in survival were seen in the Bcl2-negative and Bcl2-positive groups when they were subdivided on the basis of the level of Bax expression and vice versa. In experimental systems, p53 is a direct transcriptional activator of the human bax gene. However, we could not observe any relation between Bax and p53 expression. We investigated whether the combined p53/Bax expression could have any prognostic value since it is predicted that tumours with normal p53 expression and concurrent high levels of Bax should be less aggressive and more susceptible to therapy. However, while p53 itself was of prognostic value, Bax expression was not related to prognosis in p53-negative or in p53-positive groups.

Expression of progesterone receptors in solid-cystic tumour of the pancreas: a clinicopathological and immunohistochemical study of ten cases.

A role for sex hormones in the pathogenesis of solid-cystic tumour (SCT) of the pancreas is suggested by its predilection for young fertile women. Controversial data have been provided for the presence of progesterone receptors (PR) and/or oestrogen receptors (ER) in SCT. We report the immunohistochemical detection of PR in ten cases of SCT. Eight were from young women. The remaining two were from a post-menopausal woman and a young boy. All cases showed PR immunoreactivity in the large majority of neoplastic cells, whereas none exhibited ER positivity. In one tumour two types of cell populations were noted, the more anaplastic invasive-type being PR negative, whereas the more typical was PR positive. PR immunoreactivity in the absence of ER may simply reflect a lower sensitivity of ER antibody failing to reveal the biochemically detectable ER, or that the PR in cells of SCT are constitutively synthesized in an oestrogen-independent way, as in T47D breast carcinoma cell line, meningioma cells and some gastric cancer cells. Our findings support the hypothesis of a possible pathogenetic role of progesterone in SCT, independent of the patient's sex and age.

AgNOR distribution in serous tumours of the ovary.

The present paper investigated the distribution of AgNOR in serous tumours of the ovary, with a particular attention to borderline lesion and carcinomas. AgNOR are classified as large AgNOR (LN) and small AgNOR (SN) and are counted separately in 100 nuclei for each tumor. Total number of AgNOR was also recorded (TN). The study shows that the mean values of LN, SN and TN increase from adenomas to borderline lesions and carcinomas, with highly significant differences (p less than 0.001). LN show the most impressive differences between borderline lesion and carcinomas, without overlap of values. The follow up of the patients is not long enough for any correlation between AgNOR counts and prognosis, but preliminary data suggest that high AgNOR counts in borderline tumors should be interpreted very cautiously, because they do not seem to have any correlation with a more aggressive behaviour.

[Primary angiosarcoma of the thyroid gland. Presentation of a clinical case]. / Angiosarcoma primitivo della tiroide. Presentazione di un caso clinico.

A case of angiosarcoma of the thyroid, the most rare tumor of this gland, is discussed. The existence of this form has been denied by many authors, but recent immunochemical analyses (endothelial Factor VII related antigen) and electron microscopy (Weibel-Palade bodies) confirm definitively its vascular origin.

Inflammatory pseudotumour of the lung. Immunohistochemical analysis on four new cases.

Inflammatory pseudotumour of the lung (I.P.) is a quite rare benign lesion, variously named by different authors. In the present report four new cases of I.P. are presented and immunohistochemically studied with a panel of antibodies. Microscopically, the most prominent histological features were the presence of interlacing bundles of elongated histiocytic-like cells, plasma cell aggregates and lymphoid follicles. Immunohistochemistry showed that plasma cells are polyclonal. The spindle cells were negative for desmin, cytokeratins, lysozyme and S-100 and immunoreactive for alpha-1-antichymotrypsin, vimentin and for smooth-muscle alpha-actin. Actin and desmin, were clearly evident in the vessels' smooth muscle layers, highlighting the angioinvasive behaviour of the lesions. Our data are in keeping with literature suggesting that I.P. is due to a mixed histiocytic-myofibroblastic-reactive proliferation and support the inflammatory nature of IP.

[Diagnosis and prognosis of malignant mesothelioma. A description of 8 clinical cases]. / Diagnosi e prognosi del mesotelioma maligno. Descrizione di 8 casi clinici.

A retrospective study of patients at the Trento S. Chiara Hospital in the period 1982-86 showed up 8 cases of malignant mesothelioma (7 pleural and 1 peritoneal). The histology was re-examined for each case and clinical records was also looked at so as to identify onset symptomatology, diagnostic procedures and treatment. A standard questionnaire given to patients or close relations revealed previous exposure to asbestos in 2 of 3 males and in none of the 5 females. There was also a significant delay in formulation of correct diagnosis, attributable on the hand to the nonspecificity of the symptomatology of onset and on the other to the inadequacy of currently available clinical and radiological procedures. Only histology with the aid of immunocytochemical procedures was able to pinpoint correct diagnosis, in life. The ineffectiveness of conventional therapies and the poor overall prognosis for these patients is confirmed.

Duodenal gangliocytic paraganglioma. Report of a case and review of the literature.

A case of gangliocytic paraganglioma (GP) of the ampulla of Vater is reported and the literature reviewed, with special attention to immunohistochemical studies. The present case, which occurred in a 56-year-old woman, shows the typical histological admixture of epithelioid, ganglion and spindle cells. Immunohistochemistry reveals strong reactivity for synaptophysin, Leu-7, somatostatin, S-100 protein and vimentin. A few ganglion cells are reactive for neurofilaments. Chromogranin A, myelin basic protein, desmin and cytokeratin are absent. Immunohistochemical data from literature regarding the cytoskeletal composition of GPs are not unequivocal: cytokeratin and neurofilament positivity is reported by some authors and denied by others. More uniformity is reported concerning the peptides produced by GPs: somatostatin and pancreatic polypeptide are the most frequently found antigens, followed by serotonin. General neuroendocrine markers like neuron specific enolase and protein gene product 9.5 are always positive, whereas chromogranins are rarely found. S-100 protein is always positive in the spindle cell component. Our data are in keeping with those previously reported and add the diffuse positivity for the Leu-7 antigen and the positivity of ganglion cells for synaptophysin. The nature of the tumour is still a matter of debate and it is difficult to agree with either of the proposed hypotheses--hamartoma/choristoma versus true neoplasm. However the recent reports of the occasional malignant evolution of GPs may support their true neoplastic nature.

Primary adenoid cystic carcinoma of the Bartholin's gland: a clinical, histological and immunocytochemical study of a case.

Adenoid cystic carcinoma of the Bartholin's gland is a rare tumor. Only 41 cases, to our knowledge, have been described in literature. It is impossible, at present, to determine the best management of this disease. Local recurrence and distant metastases (mainly of the lung) frequently occur. A case of adenoid cystic carcinoma of the Bartholin's gland is looked into with respect to clinical and immunohistochemical characteristics. Radiation therapy is suggested as effective together with surgery. The efficacy of routine lymphadenectomy has not been demonstrated. The case reported is the first described with nodal metastasis as single mode of recurrences presentation.

[Mediastinal thymoma (presentation of 2 cases)]. / Il timoma mediastinico (presentazione di due casi).

The Authors report on two cases of mediastinal thymoma. Clinical and anatomicopathological aspects are discussed.

Centronuclear myopathy with unusual clinical picture.

The authors describe two cases of familial muscle disease, a mother and her daughter, characterized by centrally placed nuclei and a predominance of hypotrophic type 1 fibers. Clinically the patients exhibited a muscular weakness and atrophy localized mainly distally. Both showed hypertrophy of their calves. The nosological classification of the cases is uncertain; however, both are considered as examples of centronuclear myopathy with unusual clinical features.

Squamous cell carcinoma with sarcoma-like stroma of the nose and paranasal sinuses: report of two cases.

Two cases of squamous cell carcinoma with sarcoma-like stroma of the nose and paranasal sinuses are described. To the best of our knowledge, this is the first report of such a localization for this tumour type. Keratin was localized by immunocytochemistry in the epithelial cells, as well as in occasional stromal-like elements. The importance of distinguishing these tumours from morphologically similar neoplasms is emphasized in view of their different therapeutic approach.

Case of bilateral ovarian metastasis from regressed melanoma.

The Authors report an exceedingly unusual case of bilateral ovarian metastasis from regressed melanoma (spontaneous regression of skin malignant melanoma) in a patient who had undergone removal of a pigmented nevus from left forearm. The diagnosis was established histologically following on the bilateral adnexectomy with total hysterectomy the patient underwent for suspect ovarian tumour. Given the rareness of the clinical from and the diagnostic problems involved the Authors examine the literature dealing with this subject and look for the most adequate diagnostic means.