What modifies the relation between tumour size and lymph node metastases in T1 breast carcinomas?

AIMS: To evaluate which pathological and clinical parameters modify the relation between tumour size and lymph node metastases in invasive breast carcinomas < 20 mm. METHODS: In a retrospective study, 1075 patients with pT1 invasive breast carcinoma and with known nodal status were analysed. The size of the infiltrating tumour was microscopically evaluated, and the in situ component was not considered. The additional pathological parameters considered were: tumour grade, peritumoral vascular invasion, multicentricity, and angiogenesis. The immunophenotype of the tumour was determined as: the expression of oestrogen (ER) and progesterone (PR) receptors, p53, and c-erbB2. The patients were grouped by age as follows: < 50, 51-70, and > 70 years old. RESULTS: Three hundred and seventy four patients (34.8%) were node positive. Univariate analysis showed that nodal positivity was significantly correlated with large tumour size (> 10 mm), vascular invasion, grade 2-3, multicentricity, and high angiogenesis (> 100 microvessels/x20 high power frame). No significant correlation was found between nodal positivity and ER, PR, p53, or c-erbB2 status. Interestingly, the association with in situ carcinoma was correlated with lower nodal positivity in tumours presenting equally sized infiltrating components. Age was an independent variable and significantly modified the risk of nodal positivity in tumours < 1 cm. In fact, in patients under 51 years of age, the proportion of nodal positivity in pT1a tumours was sevenfold higher than in older patients. In patients from 51 to 70 years old, nodal positivity correlated with tumour size, and multicentricity was an additional risk factor. CONCLUSIONS: These data suggest that, together with tumour size, the presence of in situ carcinoma, and vascular invasion, age is one of the most important predictors of metastatic diffusion in breast carcinomas.     

Caveolin-1 expression in lung carcinoma varies according to tumour histotype and is acquired de novo in brain metastases

Aims:  To study caveolin-1 (Cav-1) expression in metastatic lung carcinomas.
Methods and results:  Cav-1 expression was investigated in a series of 121 lung carcinomas and it was shown that 18/121 tumours (14.9%) were Cav-1+. None of the pure bronchioloalveolar carcinomas proved to be positive, vs. 42.8% of the large cell carcinomas (neuroendocrine subtype excluded). Adenocarcinomas (8.5%), large cell neuroendocrine carcinomas (20%) and squamous cell carcinomas (29.6%) displayed an intermediate percentage of positive cases, suggesting a gradient of Cav-1 expression according to tumour histotype-related aggressiveness. Moreover, the percentage of Cav-1+ tumours with distant metastases was almost double that of non-metastatic tumours (17.8% vs. 8.1%), irrespective of the histotype. In 34 tumours metastatic to the brain, primary and secondary lesions were compared and 53% of brain metastases were Cav-1+ vs. 20.6% of primaries, indicating a de novo acquisition of Cav-1 expression. This pattern was exclusive to the brain, as it was not acquired in adrenal metastases. In our series, the presence of epidermal growth factor receptor amplification, determined by fluorescence in situ hybridization, was not related to Cav-1 reactivity.
Conclusions:  Cav-1 immunoreactivity in lung carcinoma is histotype-dependent and acquired de novo in brain metastases, suggesting a site-specific phenotypic shift in secondary lesions.     

Spontaneous and pronase‐induced HER2 truncation increases the trastuzumab binding capacity of breast cancer tissues and cell lines

A subgroup of HER2‐overexpressing breast tumours co‐expresses p95 $^{{\rm{HER2}}}$ , a truncated HER2 receptor that retains a functional HER2 kinase domain but lacks the extracellular domain, thus impairing trastuzumab binding. We evaluated p95 $^{{\rm{HER2}}}$ expression in 99 frozen breast carcinoma samples by western blot analysis. The HER2‐positive cell line BT474 treated with pervanadate or pronase was used as a positive control for p95 $^{{\rm{HER2}}}$ expression. Immunohistochemistry was performed on parallel formalin‐fixed, paraffin‐embedded sections of the same case series using antibodies directed against either the intra‐ or extra‐cellular binding domain of HER2. In particular, biotinylated trastuzumab (BiotHER) was used to evaluate the binding capacity of the humanized antibody. To avoid a subjective evaluation of the score values and the percentage of immunostained cells, the slides were scanned and automatically analysed. The number of cases with HER2 overexpression (score 3+) and HER2 gene amplification was higher in the p185 $^{{\rm{HER2}}}$ ‐positive/p95 $^{{\rm{HER2}}}$ ‐positive samples than in the p185 $^{{\rm{HER2}}}$ ‐positive/p95 $^{{\rm{HER2}}}$ ‐negative group. Automated analysis confirmed a significantly higher percentage of 3+ scored cells in p95 $^{{\rm{HER2}}}$ ‐positive cases. Conversely, the percentage of 2+ scored cells was higher in p95 $^{{\rm{HER2}}}$ ‐negative cases. The status of the HER2 extracellular domain was then studied using flow cytometry on BT474 cells after pronase enzymatic digestion using trastuzumab and pertuzumab, while the presence of HER2‐HER3 dimers was studied using a proximity‐ligation assay. In vitro experiments showed that short‐term pronase digestion of BT474 cells produced two HER2 fragments (of 95 and 150 kDa, detectable in tissue specimens as well), increased the binding affinity of trastuzumab, reduced the rate of HER2–HER3 dimers, and did not interfere with pertuzumab‐binding capacity. In conclusion, the presence of p95 $^{{\rm{HER2}}}$ as detected by western blot analysis does not compromise the immunohistochemical detection of HER2. Our data suggest that a reduction of the receptor steric hindrance as induced by enzymatic shedding may facilitate the binding capacity of trastuzumab. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Intramasseterin-infiltrating angiolipoma: a challenging diagnosis

Angiolipomas are benign mesenchymal tumors infrequently affecting the head and neck region, manifesting themselves as small (<4 cm), slow-growing mass that are painful or tender to palpation. Ultrasonography, fine needle aspiration biopsy, computed tomography, and magnetic resonance imaging can be used to make a diagnosis. Surgical excision is the treatment of choice in both infiltrating and noninfiltrating forms, even if liposuction can be considered in multiple forms. We describe a case of infiltrating intramasseterin angiolipoma, in which diagnosis was suspected after magnetic resonance imaging with gadolinium; then a transoral surgical excision was performed. To the best of our knowledge, only 1 other case of intramasseterin-infiltrating angiolipoma has been previously described.     

Bone‐to‐Implant Contact Around Immediately Loaded Direct Laser Metal‐Forming Transitional Implants in Human Posterior Maxilla

Objective: Direct laser metal forming (DLMF) is a procedure in which a high‐power laser beam is directed onto a metal powder bed and programmed to fuse particles according to a computer‐aided design file, generating a thin metal layer. This histologic study evaluated the bone‐to‐implant contact (BIC%) around immediately loaded DLMF transitional implants retrieved after 2 months from posterior human maxillae. Methods: Twelve totally edentulous individuals (mean age, 66.14 ± 2.11 years) received DLMF transitional implants divided in twelve immediately loaded (IL) and twelve unloaded (UI) implants. These transitional implants were placed between conventional implants to support the interim complete maxillary denture during the healing period. After 8 weeks, the transitional implants and the surrounding tissue were removed and prepared for histomorphometric analysis. Results: Mature woven preexisting bone lined by newly formed bone in early stages of maturation were found around all retrieved implants. Histometric evaluation indicated that the mean BIC% was 45.20 ± 7.68% and 34.10 ± 7.85% for IL and UI, respectively (P <0.05). Conclusion: The present data obtained in humans showed that, although both IL and UI presented good BIC%, IL DLMF implants had a higher BIC% in the posterior maxilla.