Invasive breast cancer: a significant correlation between histological types and molecular subgroups.

INTRODUCTION: The special types of breast cancer seem to have not only distinct morphological features but also distinct biological features. MATERIALS AND METHODS: Women diagnosed with a first primary invasive breast cancer in the 2004-2005 period were identified through Tuscan Cancer Registry. Information on age, tumor size, lymph node status, histological type and grade, hormonal receptors, HER2 immunohistochemical expression were collected. Five subtypes were defined: luminal A, luminal B HER2+, luminal B HER2-, triple negative, and HER2 positive. The association between the histological type and molecular subgroups was assessed by a Fisher's exact test, and a multinomial logistic regression model was used. RESULTS: Out of 1,487 patients, 34 % were luminal A subtype, 25 % luminal B HER2-, 11 % luminal B HER2+, 19 % triple negative, and 10.2 % HER2+; 58.5 % of cancers were ductal NOS types. With luminal A as reference, histological types distribution was significantly different between the subgroups. Mucinous, tubular, and cribriform histotypes were found among luminal A cancers more than in other subgroups; all medullary carcinomas were triple negative cancers. Pathological stage at diagnosis was more advanced, and histological grade was lower among subgroups other than luminal A. CONCLUSIONS: Significant association between breast cancer histotypes and molecular subgroups was found.

Biological characteristics of interval cancers: a role for biomarkers in the breast cancer screening.

INTRODUCTION: In a population-based screening program, a percentage of tumors remain undetected; these tumors comprise a heterogeneous group, and they are more likely to have adverse prognostic features. The aim of this study was to identify differences in biological characteristics of screen-detected versus interval breast cancers in a population-based screening program according to molecular subtypes. MATERIALS AND METHODS: We analyzed the population-based data from a long-running screening program in the area of Florence. Data on screening history and on age, T and N status, grade, histotype, hormonal status and Ki-67 and HER2 expression were retrieved. Subtypes of breast cancer were defined on the expression of ER, PR, Ki-67 and HER2: luminal A if ER/PR+, HER2- and Ki67 <14 %, luminal B (HER2 negative) if ER/PR+, HER2- and Ki67 ≥14 %, luminal B (HER2 positive) if ER/PR+ and HER2+, triple negative if ER/PR-and HER2-, HER2 positive if ER/PR- and HER2+. Association between molecular subtypes and mode of detection will be evaluated by a logistic regression model adjusted for the potential confounding variables. RESULTS: Information about biomarkers was known for 277 cases, 211 screening-detected and 66 interval cancers. Among interval cases, the triple-negative cancers were more represented than luminal A (OR = 3.52; CI, 1.112-11.13; p = 0.0319), while the proportion of HER2+ was quite similar (OR = 1.57; p = 0.4709). CONCLUSION: Although made on a small number of cases, our results suggest a difference in distribution of molecular subtypes according to mode detection, confirming the results of earlier studies.

CDX-2, cytokeratin 7 and cytokeratin 20 immunohistochemical expression in the differential diagnosis of primary adenocarcinomas of the sinonasal tract.

Because the histopathological features of some primary adenocarcinomas of the sinonasal tract may show considerable overlap, we assessed the diagnostic value of a panel of immunohistochemical markers in the distinction between these malignancies. Paraffin-embedded tumour tissue sections from a series of 39 primary adenocarcinomas of the sinonasal tract, including 25 cases of intestinal-type adenocarcinoma (ITAC), 10 cases of salivary gland-type carcinoma and 4 cases of tubulopapillary low-grade adenocarcinoma were immunostained for CDX-2, cytokeratin 7 and cytokeratin 20. Diffuse nuclear staining for CDX-2 was identified in 80% of ITACs, while all non-ITACs were negative. Staining for cytokeratin 20 was positive in 84% of ITACs, including all cases negative for CDX-2, but negative in all other adenocarcinomas. Cytokeratin 7 was consistently positive in 88% of ITACs and in 100% of non-ITACs. Normal sinonasal epithelia expressed cytokeratin 7, but not CDX-2 and cytokeratin 20. Staining for CDX-2 and cytokeratin 20 has potential use in separating ITACs from other primary malignant glandular neoplasms of the nasal cavities and paranasal sinuses.

First-line intra-arterial chemotherapy (IAC) with epirubicin and mitoxantrone in locally advanced breast cancer.

BACKGROUND: Approximately 20% of patients with breast cancer present with locally advanced disease without distant metastases. This phase II double-center trial aimed at investigating the activity of epirubicin (Farmorubicin)--mitoxantrone (Onkotrone/Novantrone) combination as first-line intra-arterial chemotherapy (IAC) in locally advanced breast cancer patients. PATIENTS AND METHODS: Thirty-six patients with locally advanced disease and no prior exposure to anthracyclines received the following regimen: epirubicin (Farmorubicin) 30 mg/mq and mitoxantrone (Onkotrone/Novantrone) 10 mg/mq by IAC short infusion on day 1, every 3 weeks for up to six cycles. Prior to IAC an arteriogram of subclavian, internal mammary and lateral thoracic arteries was obtained in all patients, followed by infusion of a blue dye solution into the arteries to determine the most appropriate vessel that supplies the tumor area. RESULTS: Objective responses, confirmed at least 4 weeks after the first documentation, were observed in 25 patients (70%; 95%CI, 62% to 80%): 3 CR, 22 PR. Although three of the patients showed complete tumor regression, operative removal or toilet mastectomy became feasible in 25 patients since tumor shrinkage ranged over 75%. A total of 25 mastectomies were carried out for 36 patients. Four patients had bulky tumors (> 13 cm tumor diameter), while 8 patients had ulcerated tumors, two of which presented with complete infiltration of normal breast tissue. The median time to progression and median overall survival were 11 and 27 months, respectively. The time to local response was 3 weeks and time to mastectomy was 9 weeks. Transient neurological disorders developed in six patients and skin chemical burns with painful inflammatory reactions were encountered in ten patients. No systemic toxicity was observed in terms of bone marrow depression and hair loss. No cardiotoxicity was observed. In all specimens necrosis was reported (complete 3 cases, partial 16 and minimal 6). CONCLUSION: A combination of epirubicin (Farmorubicin) and mitoxantrone (Onkotrone/Novantrone) as IAC appears to be a safe and well tolerated treatment for locally advanced breast cancer without clinical evidence of distant metastases. When combined with surgery it offers interesting results in terms of local control and allows a high rate of mastectomies in otherwise inoperable cases.

Tyrosine kinase inhibitor imatinib mesylate as anticancer agent for advanced ocular melanoma expressing immunoistochemical C-KIT (CD 117): preliminary results of a compassionate use clinical trial.

Imatinib mesylate (IM), is a selective and competitive inhibitor of tyrosine kinases, including BCR-ABL, ABL, KIT, and the platelet-derived growth factor receptors (PDGF-R). It binds to the ATP-binding site of the target kinase and prevents the transfer of phosphate from ATP to the tyrosine residues of various substrates. At oral doses of 200-600 mg, the majority of patients with chronic myeloid leukaemia, Philadelphia chromosome-positive acute lymphoblastic leukemia expressing the BCR-ABL fusion protein and gastrointestinal stromal tumours (GIST) achieve a bio-molecular and clinical response, frequently complete, associated with limited toxicity. Several other human cancers, as small-cell lung carcinoma, melanoma, seminoma, some sarcomas, and adenoid cystic carcinomas may over-express KIT or PDGF-R, and clinical trials to evaluate the role of IM in the treatment of such cancers are currently ongoing. We determined c-KIT with Dako CD 117 antibody in 5 cases of advanced ocular melanoma (OM) and we found positive immuno-reactivity for CD 117 in three patients. We treated all patients with palliative-use IM at the oral dose of 400 mgr daily. We obtained in expressing positive immuno-reactivity for CD 117 patients: a reduction of malignant ascites in one, a partial remission in the neck nodes in another, and progression of liver metastases in the third. Evidences of progression has been reported in the other two patients expressing negative immuno-reactivity for CD 117. We conclude that the effect of IM should be assessed only in OM with positive immuno-histochemical c-kit (CD 117) expression. IM might be a potential therapeutic strategy for these patients.

The availability of histologic grading among 5,923 Italian cancer patients and its relationship with survival: a population-based study.

AIM: The specific goal of the study was to evaluate the availability of the histologic grading of cancer and its effect on survival in an Italian population-based cancer series. METHODS: Data were drawn from the Tuscany Cancer Registry, active in central Italy since 1985. Among the cases incident during the period 1985 to 1989, bladder, prostate, colon, corpus uteri, rectum and stomach cancers, for which the proportion of graded cases exceeded 50%, were analyzed. Overall, 5,923 cancer cases were included. Ten-year relative survival rates by grade were computed. RESULTS: Overall, data on histologic grading was available only for 38% of cases. The sites most frequently graded were urinary bladder (80%), prostate (73%), colon (71%), corpus uteri (69%), rectum (65%) and stomach (56%). For all the cancer sites analyzed, the 10-year relative survival rates increased as the histologic grading improved. The grade distribution resulted related also to the disease extension, more limited the extension higher the proportion of well differentiated cases. CONCLUSIONS: Due to the evidenced importance of histologic grading as a valuable prognostic factor, it should be requested by clinicians and reported by pathologists more frequently than has been done in the area.

Clear-cell smooth muscle tumor of the skin.

We report a case of a previously undescribed benign neoplasm characterized by a poorly circumscribed proliferation of clear cells, arranged both singly and in elongated fascicles oriented in haphazard fashion within the middle and lower reticular dermis. The fascicles consisted of spindle-shaped cells that were periodic acid-Schiff positive and diastase labile. These cells were characterized by oval, hyperchromatic, cigar-shaped nuclei and clear cytoplasm. Immunohistochemically, neoplastic cells were diffusely positive for smooth muscle actin (1A4), common muscle actin (HHF-35), and vimentin. Immunoreactivity for fibronectin was also focally noted. The neoplasm, which we designated clear-cell smooth muscle tumor of the skin, should be distinguished from smooth muscle hamartoma and other smooth muscle proliferations at cutaneous level. We highlight in this case report the histopathologic differential diagnosis among other tumors with myofibroblastic, melanocytic, and neural differentiation.

Characterization of asbestos fibers in pleural tissue from 21 cases of mesothelioma.

Pleural biopsies from 21 patients with pleural mesothelioma and different asbestos exposure were analyzed by means of analytical electron microscopy with the aim of investigating the presence, quantity, types and sizes of asbestos fibers in pleural tissue. The majority of fibers found consisted of ultrathin (< 0.3 micron) and short (< 5 microns) fibers regardless of asbestos types and subject exposure. Concentrations appeared to be poorly related to the estimated exposure level. Fiber dimensions appeared to be the most important characteristic which determined their translocation in the pleural region.

Pleural malignant mesothelioma in Tuscany, Italy (1970-1988): I. Anatomo-pathologic aspects.

Our investigation did not confirm the general experience that significant numbers of cases initially considered malignant mesothelioma or metastatic carcinoma are actually found to be metastatic carcinoma or malignant mesothelioma, respectively, upon deeper investigation using ancillary techniques (e.g., histochemistry, immunohistochemistry, electron microscopy). Well-trained pathologists, expert in thoraco-pulmonary pathology, have a high inter- and intra-rater agreement and significantly better results than standard hospital pathologists in correctly differentiating malignant mesothelioma from metastatic carcinoma. Therefore, epidemiologic investigations which exclude an accurate and rigorous reevaluation of the histologic slides have to be considered unreliable, unless the data come from a specialized medical center experienced in this type of pathology.

Multicystic peritoneal mesothelioma. A fine structure study with special reference to the spectrum of phenotypic differentiation exhibited by mesothelial cells.

Multicystic peritoneal mesothelioma evidenced a complete spectrum of morphodifferentiation extending from classic epithelial-like surface mesothelial cells to myoid-fibroblastoid mesenchymal-like subsurface mesothelial cells. The contemporaneous presence of both epithelial- and mesenchymal-type submicroscopic features in individual cells strongly supported the concept of a holistic histogenetic/differentiative nature of surface and subsurface mesothelial cells on the one hand, and of a single origin for all serosal neoplasms, apart from their actual cytodifferentiation features, on the other. In addition, a profusion of smooth-membrane-bound intracellular collagen was found in myoid-fibroblastoid cells; this finding was interpreted to be, at least in part, due to tangential sectioning of convoluted cell surfaces enfolding extracellular collagen fibrils or to cell processes wrapping around them. A certain finalism might be seen in this event, especially considering the shorter-than-normal period length we found in collagen fibrils; the myoid-fibroblastoid cells might be hypothesized to play a contractile role in shortening collagen fibrils in a process of stroma contraction similar to wound repair or hypertrophic scarring.

Giant-cell arteritis causing severe aortic regurgitation secondary to aneurysm of the ascending aorta--a case report.

This report describes a case of aneurysm of the ascending aorta with secondary, severe, aortic valve incompetence following temporal arteritis in a sixty-five-year-old woman.