Genomic alterations and phenotype of large compared to small high-grade ductal carcinoma in situ.

A clinically distinct subgroup of pure ductal carcinoma in situ presents as an extensive, high-grade lesion, which nevertheless lacks invasion. We sought to evaluate differences between those ductal carcinomas in situ presenting as large versus small lesions while controlling for high-grade, to determine whether there exist phenotypic and genetic differences between the 2 groups. Fifty-two cases of pure high-grade ductal carcinomas in situ were collected retrospectively, consisting of 27 large (>40 mm) and 25 small (<15 mm) cases. The 2 groups were compared based on genomic copy number assessed by array-based comparative genomic hybridization and by phenotype determined by immunohistochemistry for estrogen receptor, progesterone receptor, Ki-67, p53, cyclin D1, p16, cyclooxygenase 2, human epidermal growth factor receptor 2, and CD68. Large lesions presented at a younger age, with lower incidence of comedonecrosis and periductal macrophage response. Larger lesions also had significantly lower estrogen receptor expression, lower cyclin D1 expression, and lower Ki-67 index. The subset of 9 large palpable tumors had significantly lower p16/cyclooxygenase 2 expression and lower Ki-67 index compared to nonpalpable tumors. Genomically, larger lesions had fewer break points, fewer amplifications, and decreased copy number gains involving chromosome 8q and chromosome 20q when compared to the small lesions. Among pure high-grade tumors, small and large groups show specific genomic and phenotypic differences. Interestingly, larger tumors showed some molecular features associated with better prognosis. A more thorough evaluation of these differences could help identify the likelihood of recurrence or progression for in situ lesions.

Pathologic and biologic response to preoperative endocrine therapy in patients with ER-positive ductal carcinoma in situ.

BACKGROUND: Endocrine therapy is commonly recommended in the adjuvant setting for patients as treatment for ductal carcinoma in situ (DCIS). However, it is unknown whether a neoadjuvant (preoperative) anti-estrogen approach to DCIS results in any biological change. This study was undertaken to investigate the pathologic and biomarker changes in DCIS following neoadjuvant endocrine therapy compared to a group of patients who did not undergo preoperative anti-estrogenic treatment to determine whether such treatment results in detectable histologic alterations. METHODS: Patients (n = 23) diagnosed with ER-positive pure DCIS by stereotactic core biopsy were enrolled in a trial of neoadjuvant anti-estrogen therapy followed by definitive excision. Patients on hormone replacement therapy, with palpable masses, or with histologic or clinical suspicion of invasion were excluded. Premenopausal women were treated with tamoxifen and postmenopausal women were treated with letrozole. Pathologic markers of proliferation, inflammation, and apoptosis were evaluated at baseline and at three months.Biomarker changes were compared to a cohort of patients who had not received preoperative treatment. RESULTS: Median age of the cohort was 53 years (range 38-78); 14 were premenopausal. Following treatment, predominant morphologic changes included increased multinucleated histiocytes and degenerated cells, decreased duct extension, and prominent periductal fibrosis. Two postmenopausal patients had ADH only with no residual DCIS at excision. Postmenopausal women on letrozole had significant reduction of PR, and Ki67 as well as increase in CD68-positive cells. For premenopausal women on tamoxifen treatment, the only significant change was increase in CD68. No change in cleaved caspase 3 was found. Two patients had invasive cancer at surgery. CONCLUSION: Preoperative therapy for DCIS is associated with significant pathologic alterations. These changes may be clinically significant. Further work is needed to identify which women may be the best candidates for such treatment for DCIS, and whether best responders may safely avoid surgical intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00290745.

Inflammatory myofibroblastic tumor of the central nervous system and its relationship to inflammatory pseudotumor.

Inflammatory myofibroblastic tumor (IMT) is a distinctive spindle cell lesion and occurs primarily in soft tissue. Recent evidence suggests a neoplastic nature, although historically, both neoplastic and nonneoplastic processes were combined in this category. Originally described as a nonneoplastic process, the term inflammatory pseudotumor (IP) has been used synonymously with IMT. IMTs have been linked to ALK gene (2p23) rearrangements, and some have suggested an association with the human herpesvirus 8 (HHV-8). IMT in the central nervous system (CNS) is rare, its characteristics are poorly defined, and its relation to similar tumors at other sites is unclear. To better characterize IMT within the CNS, we studied clinicopathologic features of 6 IMTs and compared them with 18 nonneoplastic lesions originally classified as IP. The IMT group consisted of 2 male and 4 female patients with a median age of 29 years. Of the six IMTs, 5 occurred within the cerebral hemispheres, and one was in the posterior fossa. All tumors were composed of neoplastic spindle cells and a variable amount of inflammatory infiltrate. Eighteen IPs included in this study consisted of predominantly inflammatory masses occasionally seen in the setting of systemic diseases. Only 1 IMT and none of the IPs recurred during the follow-up period. Four IMTs had either ALK protein overexpression or 2p23 rearrangement, and 1 case demonstrated both. None of the IPs were positive for ALK. Neither IMT nor IP cases demonstrated HHV-8 expression. We suggest that IMT in the CNS is distinct from the nonneoplastic IP, and distinguishing IMT from nonneoplastic lesions should enable better decisions for patient management.

MRI tumor characterization using Gd-GlyMe-DOTA-perfluorooctyl-mannose-conjugate (Gadofluorine M), a protein-avid contrast agent.

The rationale and objectives were to define the MRI tumor-characterizing potential of a new protein-avid contrast agent, Gd-GlyMe-DOTA-perfluorooctyl-mannose-conjugate (Gadofluorine M; Schering AG, Berlin, Germany) in a chemically induced tumor model of varying malignancy. Because of the tendency for this agent to form large micelles in water and to bind strongly to hydrophobic sites on proteins, it was hypothesized that patterns of dynamic tumor enhancement could be used to differentiate benign from malignant lesions, to grade the severity of malignancies and to define areas of tumor necrosis. Gadofluorine M, 0.05 mmol Gd kg(-1), was administered intravenously to 28 anesthetized rats that had developed over 10 months mammary tumors of varying degrees of malignancy as a consequence of intraperitoneal administration of N-ethyl-N-nitrosourea (ENU), 45-250 mg kg(-1). These tumors ranged histologically from benign fibroadenomas to highly undifferentiated adenocarcinomas. Dynamic enhancement data were analyzed kinetically using a two-compartment tumor model to generate estimates of fractional plasma volume (fPV), apparent fractional extracellular volume (fEV*) and an endothelial transfer coefficient (K(PS)) for this contrast agent. Tumors were examined microscopically for tumor type, degree of malignancy (Scarff-Bloom-Richardson score) and location of necrosis. Eighteen tumor-bearing rats were successfully imaged. MRI data showed an immediate strong and gradually increasing tumor enhancement. K(PS) and fEV*, but not fPV obtained from tumors correlated significantly (p < 0.05) with the SBR tumor grade, r = 0.65 and 0.56, respectively. Estimates for K(PS) and fEV* but not fPV were significantly lower in a group consisting of benign and low-grade malignant tumors compared with the group of less-differentiated high-grade tumors (1.61 +/- 0.64 vs 3.37 +/- 1.49, p < 0.01; 0.45 +/- 0.17 vs 0.78 +/- 0.24, p < 0.01; and 0.076 +/- 0.048 vs 0.121 +/- 0.088, p = 0.24, respectively). It is concluded that the protein-avid MRI contrast agent Gadofluorine M enhances tumors of varying malignancy depending on the tumor grade, higher contrast agent accumulation for more malignant lesions. The results show potential utility for differentiating benign and low-grade malignant lesions from high-grade cancers.

Immunophenotypic overlap between adenoid cystic carcinoma and collagenous spherulosis of the breast: potential diagnostic pitfalls using myoepithelial markers.

Adenoid cystic carcinoma of the breast is a rare neoplasm whose cribriform architecture may mimic invasive cribriform carcinoma, cribriform ductal carcinoma in situ, and collagenous spherulosis. The diagnosis may be even more challenging in needle core biopsies. Immunohistochemical expression of p63 and c-kit distinguishes adenoid cystic carcinoma from invasive cribriform carcinoma and ductal carcinoma in situ. A formal comparison of the immunophenotype of adenoid cystic carcinoma to collagenous spherulosis has not been reported. Of concern is the overlap in myoepithelial markers between these two entities. Both may express S100, smooth muscle actin, and p63. This overlap may cause diagnostic confusion yet is under-emphasized in the literature. The expression profile of newer myoepithelial markers has not been studied in this setting. We evaluated smooth muscle actin, p63, calponin, smooth muscle myosin heavy chain, as well as c-kit, in nine cases of cribriform pattern adenoid cystic carcinoma of the breast in comparison to 12 cases of collagenous spherulosis. Both entities strongly expressed p63 and smooth muscle actin; in adenoid cystic carcinoma, the basaloid myoepithelial-like tumor cells expressed these markers, but the ductular epithelial cells did not. Neither calponin nor smooth muscle myosin heavy chain was expressed in adenoid cystic carcinoma but both were strongly expressed in collagenous spherulosis. Whereas the ductular epithelial cells of adenoid cystic carcinoma were positive for c-kit in all cases, collagenous spherulosis was negative for c-kit. Positive p63 expression by a cribriform breast lesion is not sufficiently specific to confirm a diagnosis of adenoid cystic carcinoma. A broader panel that includes calponin or smooth muscle myosin heavy chain and c-kit is required to exclude collagenous spherulosis in settings in which the distinctive morphologic features that separate these entities are not conspicuously present. Reliance on p63 or smooth muscle actin alone poses a potential diagnostic pitfall in evaluating cribriform breast lesions.