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Aims and Background: The aim of this retrospective multicenter study was to evaluate the impact of progesterone receptor (PgR) loss on locoregional recurrence in patients with estrogen receptor (ER)-positive primary breast cancer and ER-positive locoregional recurrence., Patients and Methods: Eight Italian oncology centers collected data from consecutive patients with ER-positive breast cancer and a subsequent ER-positive locoregional recurrence., Results: Data were available for 265 patients diagnosed with breast cancer between 1990 and 2009. Median metastasis-free survival was 111 months in patients with PgR-positive primary tumors and locoregional recurrence (PgRpos), 38 months in patients with PgR-negative primary tumors and locoregional recurrence (PgRneg), and 63 months in patients with PgR-positive primary tumors and PgR-negative locoregional recurrence (PgRloss). In multivariate analysis, PgR status was independently associated with metastasis-free survival, with a hazard ratio of 2.84 (95% CI 1.34-6.00) for PgRneg compared with PgRpos, and 2.93 (95% CI: 1.51-5.70) for PgRloss compared with PgRpos., Conclusions: PgR absence was found to be a negative prognostic factor in breast cancer patients with ER-positive locoregional recurrence. Thus, PgR status could be a biological marker in ER-positive recurrent breast cancer.

Aims and Background: HER-3 signaling might contribute to resistance to trastuzumab. To clarify the role of HER-3 in HER-2-positive breast cancer, it is important to evaluate the level of HER-3 and its correlations with clinical outcome in metastatic breast cancer patients treated with trastuzumab., Methods: HER-3 status by immunohistochemistry was evaluated in HER-2-positive metastatic breast cancer patients treated with trastuzumab-based therapy at our institution. Two scorings were utilized for interpreting staining for HER-3, and the correlation between HER-3 status and clinical outcome was evaluated., Results: We evaluated HER-3 status in 61 of 76 HER-2-positive metastatic breast cancers treated with trastuzumab-based therapy at our institution from 4/1999 to 3/2006. We observed 55.2% objective responses; median time to progression and overall survival from start of trastuzumab therapy were 9.6 months (0.921-78.87) and 29.1 months (1.4-129.5+), respectively. With a cutoff of 50% staining tumor cells, we found 30 HER-3-negative and 31 HER-3-positive tumors. HER-3 status was not significantly associated with clinical outcome, but a shorter time to progression and overall survival were observed in patients with HER-3-positive tumors., Conclusions: HER-3 status by immunohistochemistry was not significantly associated with clinical outcome in HER-2-positive metastatic breast cancer patients. Further studies are necessary to evaluate the prognostic and predictive role of HER-3.

Aims and Background: Primitive thyroid lymphoma, although rare, is becoming more frequent. Its incidence is increasing, from 0.5% in the sixties to 1-5% of all thyroid neoplasms today. The diagnosis of such neoplasms is not always straightforward. In fact, it is often the result of pathologic findings on a gland resected for an apparently benign disease. Surgical dissection may prove more complicated than in standard cases of thyroidectomy for the possible tight adhesions existing between the gland's capsule and the surrounding structures. In cases of capsular infiltration, postoperative external local radiotherapy is indicated., Methods: A retrospective observational analysis was performed to establish whether patients with incidental thyroid lymphomas who underwent total thyroidectomy for another pathology had major surgical complications and worse prognostic results than patients with an accurate preoperative diagnosis., Results: Six cases of thyroid lymphoma were retrospectively reviewed: 4 diffuse large B-cell lymphomas and 2 MALT lymphomas. Of these, 2 were correctly preoperatively identified by fine-needle aspiration biopsy and 4 were an unexpected finding at histology: 3 cases of total thyroidectomy carried out for huge hypothyroid goiter in patients affected by Hashimoto's thyroiditis and in 1 case of total thyroidectomy carried out for anaplastic carcinoma in a patient affected by Hashimoto's thyroiditis., Conclusions: In our experience, a correct preoperative diagnosis was extremely difficult (33%). In patients who underwent fine-needle aspiration, a correct diagnosis was made in 66% of cases. All patients with stage IE lymphoma who underwent total thyroidectomy had equivalent surgical complications and prognosis.

Aims and Background: The aim of this study was to evaluate the relationship between a panel of biological markers (p53, Bcl-2, HER-2, Ki67, DNA ploidy and S-phase fraction) and clinical-pathological parameters and its impact on outcome in non-small cell lung cancer (NSCLC)., Methods and Study Design: Tumor tissue specimens obtained after surgical resection were collected from consecutive patients with NSCLC. We used an immunocytochemical technique for p53, Bcl-2, HER-2 and Ki67 analysis in fine-needle aspirates obtained from surgical samples that were also evaluated by flow cytometric DNA analysis using a FACScan flow cytometer., Results: From April 2000 to December 2005, 136 patients with radically resected NSCLC were recruited. Median age was 66 years (range, 31-84 years), male/female ratio 117/19, ECOG performance status 0/1 127/4, stage I/II/III 76/25/35, squamous/adenocarcinoma/large-cell/mixed histology 62/49/17/8, smokers yes/no 121/11. Positivity of p53, Bcl-2, HER-2 and Ki67 was detected in 51.4%, 27.9%, 25.0% and 55.8% of the samples, respectively; 82.9% of the cases revealed aneuploid DNA histograms and 56.7% presented an S-phase fraction of more than 12%. Statistically significant associations between high Ki67 and poorly differentiated tumors (P = 0.016) and a smoking history (P = 0.053); p53 positivity and high Ki67 (P = 0.002); HER-2 positivity and adenocarcinoma subtype (P = 0.015) and presence of lymph node involvement (P = 0.006); and Bcl-2 positivity and squamous cell carcinoma subtype (P = 0.058) were observed. At univariate analysis, high Ki67 proved to be the only marker associated with disease-free survival (P = 0.047). After adjusting for stage, none of the examined immunocytochemical markers emerged as an independent factor for disease-free and overall survival; only pathological stage was identified as an independent prognostic factor for disease-free survival (P = 0.0001) and overall survival (P = 0.0001). In the group of 76 patients classified as TNM stage I, high Ki67 was the only marker associated with recurrence of disease (P = 0.05)., Conclusions: Our data do not support a relevant prognostic role of immunocytochemical markers in NSCLC, even if the Ki67 index might have particular relevance to identify patients with more aggressive tumors who are at high risk for disease relapse.

Schwannoma arising within breast parenchyma is very rare. This report describes such a case in a 58-year-old woman. The tumor, which measured 4.4 x 3.5 x 2.1 cm, was painless, mobile and elastic-soft. Mammography showed a well-circumscribed, oval-shaped nodule without microcalcifications. At ultrasonography it appeared as a hypoechoic solid mass. Fine-needle cytology revealed several clusters of spindle cells indicative of a neoplasm of mesenchymal origin. Histological examination evidenced the characteristic morphological appearance of a schwannoma with Antoni A and Antoni B areas. A review of the 23 proven cases of breast schwannoma is included. The main differential diagnostic findings are also discussed.

Aims and Background: The availability of new drugs offers the opportunity to improve the outcome of locally advanced rectal cancer. Raltitrexed and oxaliplatin are effective in advanced colorectal cancer with acceptable toxicity and can act as radiation enhancers as shown in phase I-II studies. The aim of the study was thus to determine the recommended dose of oxaliplatin concomitantly administered with raltitrexed and concurrent preoperative radiotherapy in patients with stage II-III extraperitoneal rectal cancer., Methods: From September 2001 to September 2002, 18 consecutive patients with T3/T4 rectal cancer were treated at our Institution with preoperative chemoradiation followed by surgery after 6-8 weeks. Pelvic radiotherapy was delivered at a dose of 45 Gy in 25 fractions in 5 weeks followed by a 5.4 Gy boost at 1.8 Gy daily. Concomitant chemotherapy consisted of 3 mg/m2/i.v. of raltitrexed on days 1, 19, 38 of radiotherapy treatment with incremental doses of oxaliplatin according to dose finding rules (4 dose levels: 65, 85, 110, 130 mg/m2). Dose-limiting toxicity for oxaliplatin was defined as either grade 3-4 hematological or grade 3-4 gastrointestinal or neurological toxicity. We studied a minimum of 3 patients at each dose level., Results: Three patients were treated at 65, 85, and 110 mg/m2/i.v., respectively, while 9 patients were recruited at the last dose level. Neither grade 3-4 gastrointestinal nor neurological toxicity were documented. Dose-limiting toxicity was documented in 2/9 subjects at the 130 mg/m2 level consisting of grade 3 transient asymptomatic leukopenia. Thirteen patients developed transient increase of one or more liver enzymes (grade 3-4) and 2 patients developed grade 3 perineal dermatitis. All patients received the programmed dose of radiotherapy. The chemotherapy regimen was not completed in 4 cases due to grade 2 protracted leukopenia., Conclusions: The maximum tolerated dose of oxaliplatin was not reached at the maximum dose level (i.v.); 130 mg/m2 can therefore be defined as the recommended dose. The combination of oxaliplatin with raltitrexed and radiotherapy can be considered feasible and well tolerated.

Aims and Background: Amplification/overexpression of HER-2/neu and inactivation of p53 may be reliable parameters for the prognostic assessment of breast carcinomas. Several studies have addressed the prognostic significance of simultaneous expression of these gene abnormalities with controversial results., Methods: In this study we analyzed the biopathological profile of 45 breast cancers with both HER-2/neu and p53 overexpression and compared their features with those of 45 randomly selected cases negative for these gene products., Results: Tumors with HER-2/neu and p53 coexpression were found in younger patients, were more often multifocal and/or multicentric, were poorly differentiated in 55% of cases and lymph node-positive in 57%, showing a statistically significant difference compared to tumors with neither alteration (11% and 28%, respectively). Moreover, they were prevalently negative for estrogen (71% vs 22%) and progesterone receptors (78% vs 40%) and showed a higher proliferative activity., Conclusions: Our data demonstrate that the coexpression of p53 and HER-2/neu is an additive effect in terms of genetic instability reflected by both morphological and biological adverse features; patients with such coexpression should be assigned to specific therapeutic and follow-up protocols.

Inflammatory myofibroblastic tumor is an uncommon lesion which mainly develops in the lung and is extremely rare in the larynx. It may be easily misinterpreted as a malignant epithelial or mesenchymal spindle cell neoplasm. Histological and clinical knowledge of this lesion is important to exclude misdiagnosis and inappropriate treatment. We report a case of inflammatory myofibroblastic tumor arising on the right vocal cord of a 23-year-old man. The tumor was composed of a mixture of spindle cells and inflammatory elements. Immunohistochemical investigation revealed that the neoplastic cells expressed anaplastic lymphoma kinase (ALK) protein.

Anthracycline-based adjuvant chemotherapy is very effective in early breast cancer, but there are limited data on the use of epirubicin in patients with chronic renal failure undergoing hemodialytic treatment. We report the case of a patient with early breast cancer and chronic renal failure who was treated with adjuvant weekly epirubicin. Treatment was well tolerated. The patient is still alive and relapse free 58 months after surgery. If the patient will be disease free after 5 years, she will be reconsidered for renal transplantation. In conclusion, weekly epirubicin appears to be a safe adjuvant chemotherapy option for early breast cancer patients with chronic renal failure undergoing hemodialytic treatment.

Aims and Background: Adjuvant 5-FU chemotherapy plus radiotherapy represents the standard treatment for radically resected rectal cancer at high risk of relapse according to the NIH Consensus Conference. The therapeutic gain was obtained with a high rate of severe treatment-related toxicity and a suboptimal patient compliance with this regimen. Raltitrexed is a specific thymidylate synthase inhibitor with a convenient administration schedule, acceptable toxicity and radiosensitizing properties, as the published phase I trials in combination with radiotherapy have shown. The aim of this prospective multicenter phase II study was to evaluate the feasibility, gastrointestinal and hematological acute toxicity of raltitrexed in combination with radiotherapy in rectal cancer patients., Methods: From September 2000 to June 2004, 50 patients with radically resected stage II-III rectal adenocarcinoma were treated. All patients were evaluable for compliance and acute toxicity. Within 45-60 days of surgery, each patient underwent concomitant adjuvant radiochemotherapy. Radiotherapy was administered to the pelvis (plus perineum after abdominoperineal resection) with photon beam energy exceeding 5 MV, 3-4 fields, 45 Gy/25 fractions/5 weeks plus a boost delivered to the site of resected disease with 3-4 fields, 9 Gy/5 fractions/1 week to a total dose of 54 Gy. The boost dose was administered after complete exclusion of the small bowel from the treatment volumes; if this was not possible a total dose of 50.4 Gy was given. Raltitrexed was administered intravenously at a dose of 3 mg/m2 as a bolus injection on days 1 and 22 of radiotherapy one hour before treatment, for a total of two cycles. Each patient underwent weekly clinical evaluation and laboratory tests. Toxicity was assessed by the WHO scale., Results: Forty-five (90%) patients completed the established treatment. Acute severe toxicity included grade III proctitis in 4/50 (8%), grade III-IV diarrhea in 4/50 (8%), grade III perineal dermatitis in 4/50 (8%) and grade III leukopenia in 2/50 (4%) patients; five patients (10%) experienced a transient grade Ill increase in their liver biochemistry values., Conclusions: Our data related to acute toxicity and patient compliance proved the feasibility of this adjuvant radiochemotherapy treatment. A longer follow-up is necessary to evaluate the effectiveness of this new regimen in terms of disease-free and overall survival.

Aims and Background: Giant cell tumor of tendon sheath (GCTTS) is a common tumor occurring on the tendon sheaths of the fingers. The nature of this lesion is still controversial: some researchers consider it a reactive process arising from chronic inflammation while others regard it as a tumor of presumed synovial cell or monocytic macrophage system origin. In an effort to clarify the histogenesis we decided to further investigate the immunophenotypic profile of this tumor., Study Design: We studied 20 GCTTS of the fingers using a panel of 18 antibodies, 13 monoclonal and 5 polyclonal., Results: The immunohistochemical investigation revealed that the mononuclear cells of this lesion can be divided into two groups. The cells of the first and more numerous group were positive for vimentin, PG-M1 and KP1 but also for muscle actin (HHF35 monoclonal antibody) and neuron-specific enolase. A second population of mononuclear cells, usually arranged around the giant cells, were positive for PG-M1, KP1, LCA and occasionally for alpha-1-antitrypsin and alpha-1-antichymotrypsin. Multinucleated giant cells were also positive for KP1, PG-M1 and LCA monoclonal antibodies. A variable but usually weak positivity for alpha-1-antitrypsin, alpha-1-antichymotrypsin and lysozyme was also observed., Conclusions: Our results suggest a synovial cell origin for GCTTS and do not support the hypothesis that it could be a neoplasm with a true histiocytic origin. The positivity of some cells for the HHF35 antibody, together with electron microscopic evidence of filament bundles with focal dense bodies, suggests that at least part of the mononuclear cells may have a myofibroblastic differentiation.

Aims and Background: Granular cell tumor, usually a benign neoplasm, has been the object of many studies because of its uncertain histogenesis and based on many immunohistochemical and ultrastructural studies it has been suggested that it originates from the Schwann cell. Our recent observation that granular cell tumor is positive with PG-M1, a new anti-macrophage monoclonal antibody, led us to further investigate the immunophenotypic profile of the tumor., Study Design: We studied 11 granular cell tumors using a panel of 20 antibodies, 13 monoclonal and 7 polyclonal., Results: The immunohistochemical study showed in all cases a constant diffuse positivity for S-100 protein, neuron-specific enolase, vimentin, KP1 and PG-M1, as well as occasional and focal positivity for alpha-1-antitrypsin, alpha-1-antichymotrypsin and lysozyme., Conclusions: The immunophenotypic profile constantly observed could be the expression, on one hand, of the neuroectodermic nature of the neoplasm, proven by positivity for S-100 protein, neuron specific enolase and vimentin, and on the other could be the expression of the phagocytic activity of the tumor cell, proven by positivity for KP1 and PG-M1 antibodies and also by the presence of numerous phagolysosomes.

Fifty colorectal carcinomas were investigated to demonstrate distal intramural spread (DIS). In 17 cases (34%) a DIS ranging from 0.25 to 3.5 cm was present. DIS was positively correlated with stage C2 (p less than 0.01), lymph node metastasis (p less than 0.03) and infiltrative growth of the tumor (p less than 0.05). Our results show that DIS is a relatively frequent event but of limited extension. In fact, a distal clearance margin of 2 cm was considered safe for all patients but one C2 mucoid case. No pathologic feature can predict preoperatively the presence and extent of DIS.

A case of bilateral primary malignant lymphoma of the breast in a 30 year old woman is described. The tumors were first discovered during a self-examination of the breast at the 7th month of pregnancy. Thereafter they rapidly increased in size. The patient underwent simple bilateral mastectomy, and histological examination revealed a centroblastic/centrocytic lymphoma. The patient is alive and well 9 months after mastectomy.

In order to document any modifications in age and sex distributions, tumor locations and histological types, a retrospective study was performed comparing 377 consecutive cases of gastric cancers observed from 1942 to 1956 with 359 cases diagnosed from 1986 to 1987. The mean age at diagnosis rose from 57 to 66 years with no significant male/female ratio variations (1.6 vs 1.7). Tumors located in the proximal stomach increased from 13 to 23% (p less than 0.001) whereas those arising in the distal stomach decreased from 66 to 50% (p less than 0.001). Intestinal type gastric carcinoma decreased from 65.6 to 52.6% (p less than 0.001). The diffuse type rose from 24 to 43% (p less than 0.001) and the mucoid type fell from 10.3 to 4.4% (p less than 0.001). In spite of the overall decline in intestinal type carcinomas, this form remained more common in the upper third area and increased from 55 to 70% (p less than 0.001). Significant modifications in the distribution of diffuse, mucoid and signet ring cell type carcinomas were also noted. The possible significance and implications of these observations are discussed.