Calcifying fibrous pseudotumor of the breast.

Calcifying fibrous pseudotumor (CFP) is classified as a benign fibrous lesion, and is a rare pathologic entity. Previous reports have described CFPs in the extremities, chest wall, pleura, scrotum, mediastinum, neck, and visceral peritoneum. We present the first reported case of a CFP in the breast. CFP should be considered in the differential diagnosis for patients presenting with coarse indeterminate calcifications of the breast.

Tissue-specific transcripts of human steroid sulfatase are under control of estrogen signaling pathways in breast carcinoma.

Steroid sulfatase (STS) increases the pool of precursors of biologically active steroids, thereby playing an important role in breast cancer development. Mechanisms that control STS expression remain poorly understood. In present study we investigated alterations in the 5' region of STS gene to gain insight into the mechanism(s) that regulates its expression in mammary epithelial cells. We found that at least four alternatively spliced transcripts of STS gene can be produced from at least four different leader exons. Distinct expression patterns of the STS variants were observed in human tissues. Expression profiles of estrogen receptor alpha (ERalpha)-positive and ERalpha-negative breast carcinomas showed that these two categories of tumors and their adjacent benign tissues display remarkably different expression of STS isoforms. Coexpression of STS isoforms with ER isotypes suggests their cell-type specific coregulation. In addition, we identified ERalpha as essential regulator of STS transcription and provide evidence of direct estradiol-dependent binding of ERalpha to multiple STS cis-regulatory regions in vivo. Our results indicate that STS isoforms are under control of estrogen signaling pathways and their differential expression may play a significant role in breast cancer biology.

High-risk human papillomavirus detection: a split-sample comparison of hybrid capture and chromogenic in situ hybridization.

The American Society for Colposcopy and Cervical Pathology (ASCCP) has proposed high-risk human papillomavirus (HPV) testing as the "preferred" triage for women with atypical squamous cells of undetermined significance. We studied 401 atypical squamous cells of undetermined significance liquid-based cervicovaginal cytology split samples for HPV by chromogenic in situ hybridization (CISH) and by Hybrid Capture (HC) II (Digene, Gaithersburg, MD); 202 underwent HC II followed by CISH, and 199 underwent CISH followed by HC II. Of 401 vials, 101 (25.2%) were positive for HPV by 1 or more methods. HC II labeled 83 of 401 (20.7%) samples as positive, while 38 of 401 (9.5%) were positive by CISH. Positive attributes of CISH include the provision of a cytomorphologic link in assessing HPV positivity and comparative ease of use in laboratories without trained molecular diagnosticians. Greater efficacy and quantitative design are advantages of HC II. Comparing data by sequence of testing showed a lower likelihood of positive test results on the second ancillary test than on the first ancillary test, regardless of age or testing method (odds ratio, second/first = 0.58; P = .003). This finding suggests that liquid-based cervicovaginal cytology samples are not homogeneous throughout. Correlative studies with histology and polymerase chain reaction may clarify predictive values for both methods.

Enhanced metastasis suppression by targeting TRAIL receptor 2 in a murine model of triple-negative breast cancer.

PURPOSE: Metastatic breast cancer is a deadly disease which requires new therapeutic strategies. Endogenous TNF-related apoptosis-inducing ligand (TRAIL) functions as a metastasis suppressor by activating proapoptotic TRAIL receptors (TRAIL-R1/DR4 and/or TRAIL-R2/DR5) in transformed cells, making it an attractive pathway for antimetastatic therapies. However, it is unclear whether TRAIL-R1 or TRAIL-R2 is a better therapeutic target in metastatic breast cancer. EXPERIMENTAL DESIGN: Several metastatic, triple (estrogen receptor, progesterone receptor, and HER2)-negative cancer cell lines were treated with human agonistic monoclonal antibodies targeting TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab). The effects on cell viability, apoptosis, and caspase-8 activation were determined. An orthotopic model of triple-negative breast cancer in which fluorescently labeled breast cancer cells metastasize from the mammary gland to lymph nodes and lung was utilized to evaluate the effects of mapatumumab, lexatumumab, or doxorubicin on primary and metastatic tumor burden in vivo. RESULTS: Lexatumumab was more effective than mapatumumab in activating caspase-8, inducing apoptosis and inhibiting long-term survival of metastatic cancer cells, which expressed both TRAIL-R1 and TRAIL-R2. Human mammary epithelial cells transformed by oncogenic Ras were more sensitive to lexatumumab than nontransformed cells. Lexatumumab inhibited lymph node and lung metastases more robustly than mapatumumab in an orthotopic model of triple-negative breast cancer; both agents inhibited mammary tumor growth. In addition, lexatumumab was more effective than doxorubicin at suppressing metastases at doses of doxorubicin that were associated with toxicity, even though doxorubicin reduced primary tumor burden more robustly than lexatumumab. CONCLUSION: Targeting TRAIL-R2 receptor may be an effective therapeutic strategy for metastatic breast cancer.

Lobular carcinoma in situ variants in breast cores: potential for misdiagnosis, upgrade rates at surgical excision, and practical implications.

CONTEXT: Differentiating ductal carcinoma in situ (DCIS) from lobular carcinoma in situ (LCIS) on core biopsy has important clinical implications. Lobular carcinoma in situ variants, including LCIS with necrosis and pleomorphic LCIS, share morphologic features with solid DCIS that may lead to misclassification. OBJECTIVES: (1) To review all LCIS variants diagnosed in core biopsies at Northwestern University, Feinberg School of Medicine, and determine the frequency of misinterpretation of variant LCIS as solid DCIS in archival core biopsies, and (2) to determine the frequency of upgrade to invasive carcinoma or DCIS in the surgical excision. DESIGN: Consecutive core biopsies with original diagnoses of predominantly solid DCIS without invasion that were performed between January 2001 and December 2005 at Northwestern University, Feinberg School of Medicine, were selected for E-cadherin staining. The revised diagnosis of LCIS was based on E-cadherin negativity and morphology. The frequency of LCIS variants upgraded was then estimated from all core biopsies with original or revised diagnoses of pleomorphic LCIS or LCIS with necrosis. RESULTS: Among 75 cases of solid DCIS, 10 (13.3%) were reclassified as LCIS, including 9 variants (5 pleomorphic LCIS, 4 LCIS with necrosis) and 1 classic LCIS. Twenty-eight patients comprised the entire group of LCIS variant cases (both reclassified and originally diagnosed cases). Seven patients with LCIS variants (25%) were upgraded to invasive lobular carcinoma in surgical excision (4 of 11 cases of LCIS with necrosis [36%] versus 3 of 17 cases of pleomorphic LCIS [18%]). CONCLUSIONS: About one-tenth of solid DCIS diagnosed in core biopsies in the past may represent LCIS variants. These show a 25% upgrade to invasive lobular carcinoma in surgical excision. The distinction of an LCIS variant from DCIS is important because of its implications for radiation therapy, although it may not affect surgical management.

AlphaB-crystallin: a novel marker of invasive basal-like and metaplastic breast carcinomas.

Basal-like tumors are a newly recognized estrogen receptor (ER) negative and HER2 negative breast cancer subtype that express basal epithelial genes and are associated with poor survival. Metaplastic carcinomas are thought to belong within the basal-like group. We have recently demonstrated that the small heat shock protein alphaB-crystallin is commonly expressed in basal-like tumors and contributes to their aggressive phenotype. The current study examined the rates and patterns of alphaB-crystallin expression in whole tissue sections of human breast, including normal tissue, proliferative lesions, in situ and invasive carcinomas (ER positive, HER2 positive, basal-like, and metaplastic cancers). In normal breast tissue, proliferative lesions and in situ carcinomas, alphaB-crystallin expression was restricted to the myoepithelial cell compartment of ductal and lobular units. Most basal-like and metaplastic carcinomas demonstrated cytoplasmic expression of alphaB-crystallin (81% and 86%, respectively). Conversely, no staining for alphaB-crystallin was observed in nonbasal-like (ie, ER positive or HER2 positive) breast carcinomas. Taken together, our results indicate that alphaB-crystallin is a sensitive (81%) and specific (100%) marker for basal-like breast carcinomas. Moreover, the high rates of expression of alphaB-crystallin in metaplastic breast carcinomas (86%) suggest that these tumors may represent a histologically distinctive subset of basal-like breast tumors with a similar underlying molecular etiology.