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The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only approximately 30% of breast tumors, indicating that either very few molecular alterations are common to the majority of breast cancers, or that they have not yet been identified. In striking contrast, we now show that 19 of 19 stage I breast tumors tested with the functional unscheduled DNA synthesis assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls (n = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis. By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples versus normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNase protection. These results were confirmed at the protein level for five NER gene products. Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early-stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis-platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium. human primary breast cell explant culture | human breast tumor explant culture | breast epithelial attached epispher | hypermutability doi/ 10.1073/pnas.0914772107

Abstract Background Screening mammography has had a positive impact on breast cancer mortality but cannot detect all breast tumors. In a small study, we confirmed that low power magnetic resonance imaging (MRI) could identify mammographically undetectable tumors by applying it to a high risk population. Tumors detected by this new technology could have unique etiologies and/or presentations, and may represent an increasing proportion of clinical practice as new screening methods are validated and applied. A very important aspect of this etiology is genomic instability, which is associated with the loss of activity of the breast cancer-predisposing genes BRCA1 and BRCA2. In sporadic breast cancer, however, there is evidence for the involvement of a different pathway of DNA repair, nucleotide excision repair (NER), which remediates lesions that cause a distortion of the DNA helix, including DNA cross-links. Case presentation We describe a breast cancer patient with a mammographically undetectable stage I tumor identified in our MRI screening study. She was originally considered to be at high risk due to the familial occurrence of breast and other types of cancer, and after diagnosis was confirmed as a carrier of a Q1200X mutation in the BRCA1 gene. In vitro analysis of her normal breast tissue showed no differences in growth rate or differentiation potential from disease-free controls. Analysis of cultured blood lymphocyte and breast epithelial cell samples with the unscheduled DNA synthesis (UDS) assay revealed no deficiency in NER. Conclusion As new breast cancer screening methods become available and cost effective, patients such as this one will constitute an increasing proportion of the incident population, so it is important to determine whether they differ from current patients in any clinically important ways. Despite her status as a BRCA1 mutation carrier, and her mammographically dense breast tissue, we did not find increased cell proliferation or deficient differentiation potential in breast epithelial cells from this patient which might have contributed to her cancer susceptibility. Although NER deficiency has been demonstrated repeatedly in blood samples from sporadic breast cancer patients, analysis of blood cultured lymphocytes and breast epithelial cells for this patient proves definitively that heterozygosity for inactivation of BRCA1 does not intrinsically confer this type of genetic instability. These data suggest that the mechanism of genomic instability driving the carcinogenic process may be fundamentally different in hereditary and sporadic breast cancer, resulting in different genotoxic susceptibilities, oncogene mutations, and a different molecular pathogenesis.

* Context.--Cervical screening in the United States increasingly involves newer US Food and Drug Administration-approved cytologic methods and adjunctive high-risk human papillomavirus (hrHPV) DNA testing. Objective.--To document cervical screening test performance preceding histopathologic cervical intraepithelial neoplasia (CIN) 2/3 diagnoses. Design.--Preceding screening test results with computer-imaged, liquid-based cytology (LBC) and hrHPV results were analyzed for 2827 patients with histopathologic CIN 2/3 diagnoses. Results.--Of 2827 patients with CIN 2/3 diagnoses, 2074 (73.4%) had system LBC findings within 4 months of CIN 2/3 diagnoses: high-grade squamous intraepithelial lesion (n = 862; 41.6%), low-grade squamous intraepithelial lesion (n = 464; 22.4%), atypical squamous cells of undetermined significance (n = 445; 21.5%), atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (n = 288; 13.9%), and atypical glandular cells/adenocarcinoma in situ (n = 15; 0.7%). Of the 2827 patients, 1488 (52.6%) also had earlier system LBC results at more than 4 months to 3 years before CIN 2/3 diagnoses: one or more abnormal LBC results (n = 978; 65.7%), one or more negative LBC results (n = 911; 61.2%), both abnormal and negative LBC (n = 401; 26.9%). Of 807 patients with hrHPV cotest results within 4 months of CIN 2/3 diagnoses, 786 (97.4%) had hrHPV+ results. Of 454 patients who also had earlier hrHPV results at more than 4 months to 3 years before CIN 2/3 diagnoses: 377 (83.0%) had one or more [hrHPV.sup.+] result, 110 (24.2%) had one or more hrHPV' result, and 33 (7.3%) had both positive and negative HPV results. Conclusion.--Patients with histopathologic CIN 2/3 had recent abnormal LBC results, most often, high-grade squamous intraepithelial lesions. Among cotested patients, 97.4% (786 of 807) tested hrHP[V.sup.+}]. However, a significant number of patients tested during an extended period of several years had earlier negative Papanicolaou or negative HPV test results, suggesting the recent development of some CIN 2/3 lesions and supporting the value of cotesting for enhanced detection of other developing, small, inaccessible, or nondiagnostic precursor lesions. (Arch Pathol Lab Med. 2013;137:942-947; doi:10.5858/arpa.2012-0307-OA), The primary goal of cervical screening is the identification and removal of intraepithelial precancerous lesions, which, if left untreated, would, at some future time, become invasive cervical cancer. (1) The [...]

Herein, we present a case of a 76-year-old Caucasian man with a very large fungating, ulcerating mass, involving the right neck and parotid area, which developed while he was being treated for chronic lymphocytic leukemia/small lymphocytic lymphoma. Resection of the fungating right neck tumor, right modified radical neck dissection, and right superficial parotidectomy with flap reconstruction were performed. The final pathological diagnosis was high-grade leiomyosarcoma of the skin and the subcutaneous tissue, with invasion into the skeletal muscle, skin, and soft tissue. Additionally, the sarcoma had metastasized to the lymph nodes that were involved diffusely by lymphoma. The most interesting fact for this case is coincidence of three rare occurrences which were soft tissue sarcomas of subcutaneous leiomyosarcoma form and its metastasis to same lymph nodes that were involved with lymphoma. [ABSTRACT FROM AUTHOR]

BACKGROUND: The presence of pigment in axillary lymph nodes (LN) secondary to migration of tattoo ink can imitate the appearance of a blue sentinel lymph node (SLN) on visual inspection, causing the operator to either miss the true SLN or excise more than is needed. OBJECTIVE: We present patients with tattoos ipsilateral to an early stage breast cancer who underwent a SLN biopsy. METHODS: Patients were retrospectively reviewed from medical records and clinicopathologic data was collected. A total of 52 LNs were retrieved from 15 patients for sentinel mapping and 29 of them had tattoo pigmentation on pathologic evaluation. RESULTS: Of those 29 SLNs, 2 of them (6.9%) were pigmented, but did not contain either blue dye or Tc-99m (pseudopigmented SLN). Two (3.8%) SLNs were positive for metastasis; both of these had either blue dye or Tc99m uptake, and 1 demonstrated tattoo pigment in the node. CONCLUSIONS: In this cohort of patients with ipsilateral tattoos, removed more LNs lead to unnecessary excision which may important for increasing the risk of arm morbidity from SLN biopsy. However, the presence of tattoo pigment did not interfere with understaging for axillary mapping and it did not effect of pathological identification of SLNs positivity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Atypical Ductal Hyperplasia (ADH) is a disease of the proliferative breast lesion characterized with atypia and when diagnosed on core needle biopsy (CNB), excisional biopsy is the current management to exclude adjacent cancer, which may found 10 to 20%. OBJECTIVE: The purpose of the study is to investigate the role of biomarkers on surgical decision after the diagnosis of ADH on CNB. METHODS: Patients with pure ADH on core biopsy were retrospectively selected, and categorized according to final pathology after excision into three groups: Group I (n: 39) ADH; Group II (n: 27) ductal carcinoma in situ (DCIS), and Group III (n: 9) invasive cancer (IC). Immunohistochemical analyses were performed using biomarkers MUC1, Ki67, Cyclin B1, and Cyclin D1. RESULTS: Only Cyclin D1 was significant in between group analysis by one-way ANOVA (64.74, 49.44, and 51.11, respectively; p = 0.01). However when appropriate cut-off levels (2%-50%) were used for each biomarkers using X2 test, no statistical significance was found. CONCLUSION: MUC1, Ki67, Cyclin B, and Cyclin D1have failed to predict adjacent cancer on core biopsy specimens with ADH. Further surgery is warranted for all ADH cases diagnosed on core biopsies until a new predictor is identified. [ABSTRACT FROM AUTHOR]

Background: Screening mammography has had a positive impact on breast cancer mortality but cannot detect all breast tumors. In a small study, we confirmed that low power magnetic resonance imaging (MRI) could identify mammographically undetectable tumors by applying it to a high risk population. Tumors detected by this new technology could have unique etiologies and/or presentations, and may represent an increasing proportion of clinical practice as new screening methods are validated and applied. A very important aspect of this etiology is genomic instability, which is associated with the loss of activity of the breast cancer-predisposing genes BRCA1 and BRCA2. In sporadic breast cancer, however, there is evidence for the involvement of a different pathway of DNA repair, nucleotide excision repair (NER), which remediates lesions that cause a distortion of the DNA helix, including DNA cross-links. Case presentation: We describe a breast cancer patient with a mammographically undetectable stage I tumor identified in our MRI screening study. She was originally considered to be at high risk due to the familial occurrence of breast and other types of cancer, and after diagnosis was confirmed as a carrier of a Q1200X mutation in the BRCA1 gene. In vitro analysis of her normal breast tissue showed no differences in growth rate or differentiation potential from disease-free controls. Analysis of cultured blood lymphocyte and breast epithelial cell samples with the unscheduled DNA synthesis (UDS) assay revealed no deficiency in NER. Conclusion: As new breast cancer screening methods become available and cost effective, patients such as this one will constitute an increasing proportion of the incident population, so it is important to determine whether they differ from current patients in any clinically important ways. Despite her status as a BRCA1 mutation carrier, and her mammographically dense breast tissue, we did not find increased cell proliferation or deficient differentiation potential in breast epithelial cells from this patient which might have contributed to her cancer susceptibility. Although NER deficiency has been demonstrated repeatedly in blood samples from sporadic breast cancer patients, analysis of blood cultured lymphocytes and breast epithelial cells for this patient proves definitively that heterozygosity for inactivation of BRCA1 does not intrinsically confer this type of genetic instability. These data suggest that the mechanism of genomic instability driving the carcinogenic process may be fundamentally different in hereditary and sporadic breast cancer, resulting in different genotoxic susceptibilities, oncogene mutations, and a different molecular pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Objective.: To determine if percent surface area involvement (SAI) of tumor in endometrial cancer is predictive of lymph node metastasis. Methods.: A retrospective study was performed of all patients diagnosed with endometrial cancer at Magee Women''s Hospital between January 1990 and December of 1995. Papillary serous and clear cell histologic subtypes were excluded. Pathology reports were reviewed for percent SAI, myometrial invasion, grade, histologic subtype, lymphvascular space invasion, and lymph node metastasis. Percent SAI was categorized into three groups: <35%, 35–80%, and >80%. The primary outcome variables were pelvic or periaortic lymph node metastasis. Univariate and multivariate analysis logistic regression models were used to determine predictors of nodal metastasis. Results.: Of 558 patient records reviewed, 319 had lymph node dissections performed and 42 (13%) of those patients had positive lymph nodes. Two of 79 (3%) patients with <35% SAI had lymph node metastasis, 17 of 165 (10%) patients with 35–80% SAI had lymph node metastasis, and 23 of 75 (31%) patients with >80% SAI had lymph node metastasis. The percent SAI was significantly associated with lymph node metastasis (p <0.001). Multivariate logistic regression indicated that for patients with >80% SAI, the odds of having lymph node metastasis were 10.8 times (CI 1.3–90.4) that for patients with similar tumor histology, grade, and invasion, but <35% SAI (p =0.03). A subset analysis of patients with superficial myometrial invasion was performed and 16% of patients with <50% myometrial invasion and >80% SAI had positive lymph nodes, while only 1.4% of patients with <50% myometrial invasion and <35% SAI had positive lymph nodes (p =0.02). Conclusion.: Our analysis indicates that percent SAI is an independent risk factor for lymph node metastasis. Furthermore, assessing SAI with myometrial invasion gives a more accurate prediction of lymph node metastasis than myometrial invasion alone. This becomes clinically relevant when assessing risk factors for lymph node metastasis intraoperatively. [Copyright &y& Elsevier]

Mutations in the p53 tumor suppressor gene are frequent in breast tumors but the implication of p53 mutations in breast cancer development remains poorly understood. In this study, we applied laser capture microdissection (LCM) microscope to histologically review and sample cells from paraffin-embedded breast tissue sections obtained from six cases of ductal carcinoma in situ (DCIS) and ten cases of atypical ductal hyperplasia (ADH). p53 mutations were detected, using single stranded conformational polymorphism (SSCP) and sequencing, in cell samples of three cases with DCIS and five cases with ADH. p53 mutations are therefore present in DCIS and ADH of the breast, considered as pre-malignant precursors to breast cancer, and some of them may represent early events in breast cancer development. [Copyright &y& Elsevier]