BRCA1/2 germline missense mutations: a systematic review.

Hereditary breast and ovarian cancer is an inherited syndrome associated with BRCA1/2 germline defects. The identified mutations are classified as missense, large deletion, insertion, nonsense and splice-site variants with a deleterious impact on BRCA1/2 function. Part of these forms the well-documented truncating mutations, and missense variants represent a clinical dilemma as the pathogenic role is yet to be clearly shown. In this systematic review, we collected these missense variations with a documented deleterious function. We focused on English language articles from MEDLINE. This study included all BRCA1/2 germline missense mutations identified in breast and ovarian cancer patients. The method of this study followed the 'PRISMA statement for reporting systematic reviews and meta-analyses'. A total of 61 BRCA1/2 germline and pathogenic missense mutations were identified: 70.5% affected BRCA1 and 29.5% BRCA2, respectively. In BRCA1, the majority of mutations were located in the BRCA C-terminus (48.8%), leading to a disruption of function. Conversely, no specific associations were verified between mutations and the BRCA2 gene. The European population was the most affected by BRCA1 and the Asian population by BRCA2 mutant patterns. The identification of novel BRCA1/2 missense mutations requires specific genetic tests to assess pathogenicity. With this systematic review, we are, to the best of our knowledge, the first to collect the overall amount of data on these pathogenic mutants with the aim of improving the management of carriers and their kindred.

Unnecessary axillary node dissections in the sentinel lymph node era.

In the sentinel lymph node era, axillary lymph node dissection (ALND) for uninvolved axillary lymph nodes should be considered unnecessary and inappropriate. Between January 2000 and August 2005, 3487 out of 10,031 invasive breast cancer patients consecutively operated at the European Institute of Oncology were considered not suitable for sentinel lymph node biopsy (SNB) and were directly submitted to ALND ('direct ALND'). In 2875 cases (82%) a variable grade of axillary involvement was shown, while in 612 patients (18%) no evidence of metastatic spreading was documented in the axilla. In particular, the presence of suspicious nodes at pre-operative clinical evaluation of the axilla (191 patients), neoadjuvant treatment (188 patients), large tumour >2 cm (88 patients), multifocality of disease (76 patients), previous excisional biopsy (49 patients), were considered the most frequent contraindications to SNB and led to an 'unnecessary ALND'. According to the wider extension of the indications for SNB over the time, the number of 'unnecessary ALNDs' progressively decreased from 26% (in 2000) to 9% of the 'direct ALNDs' (in 2005). As the clinical indications to SNB are progressively extending to encompass most breast cancer patients with non-metastatic disease who were previously excluded, great effort should be made to avoid 'unnecessary ALNDs'.

Sentinel node biopsy in male breast cancer.

OBJECTIVE: Male breast cancer is a rare disease and axillary status is the most important prognostic indicator. Lymphoscintigraphy associated with gamma-probe guided surgery has been proved to reliably detect sentinel nodes in female patients with breast cancer. This study evaluates the feasibility of the surgical identification of sentinel node by using lymphoscintigraphy and a gamma-detecting probe in male patients, in order to select subjects who would be suitable for complete axillary lymphadenectomy. METHODS: Colloid human albumin labelled with 99Tc was administered to 18 male patients with breast cancer and clinically negative axillary lymph nodes. Lymphoscintigraphy was performed the day before surgery. An intraoperative gamma-detecting probe was used to identify sentinel nodes during surgery. RESULTS: Lymphoscintigraphy and biopsy of the sentinel node were successful in all cases. A total of 20 sentinel nodes were removed. Pathological examinations showed 11 infiltrating ductal carcinomas, two intraductal carcinomas and five intracystic papillary carcinomas. Six patients (33%) had positive sentinel node (micrometastases were found in three patients). These patients underwent axillary dissection; in five of them (83%) the sentinel node was the only positive node. Twelve patients (67%) showed negative sentinel nodes; in all of them no further surgical treatments were planned. CONCLUSIONS: As in women, lymphoscintigraphy and sentinel node biopsy under the guidance of a gamma-detecting probe proved to be an easy method for the detection of sentinel nodes in male breast carcinoma. In male patients with early stage cancer, sentinel node biopsy might represent the standard surgical procedure in order to avoid unnecessary morbidity after surgery, preserving accurate staging of the disease in the axilla.

Stage migration after biopsy of internal mammary chain lymph nodes in breast cancer patients.

BACKGROUND: Involvement of the internal mammary chain lymph nodes (IMNs) is associated with worsened prognosis in breast cancer. Use of lymphoscintigraphy to visualize sentinel nodes reveals that IMNs often receive lymph from the area containing the tumor. METHODS: We biopsied IMNs in 182 patients because there was radiouptake to the IMNs or because the tumor was located in the medial portion of the breast. After tumor removal, pectoralis major fibers were divided to expose intercostal muscle. A portion of intercostal muscle adjacent to the sternum was removed. Lymph nodes and surrounding fatty tissue in the intercostal space were freed, removed, and analyzed histologically. The pleural cavity was breached in four cases (2.2%), with spontaneous resolution. RESULTS: IMNs were found in 160 (88%) of 182 patients; 146 (94.4%) were negative and 14 (8.8%) were positive. The latter received internal mammary chain radiotherapy. The axilla was negative in 4 of 14 cases and positive in 10. CONCLUSIONS: IMNs can be quickly and easily removed via the breast incision with insignificant risk and no increase in postoperative hospitalization. The patients with a positive IMN migrated from N0 (4 cases) or N1 (10 cases) to N3, prompting modification of both local (radiotherapy to internal mammary chain) and systemic treatment; without IMN sampling, they would have been understaged.