Giovanna M. Crisi

Invasive mammary carcinoma after immediate and short-term follow-up for lobular neoplasia on core biopsy.

Lobular neoplasia (LN), including atypical lobular hyperplasia (ALH) and lobular carcinoma in situ, may be encountered in breast core biopsies performed for mammographic abnormalities even though LN is often not, in itself, responsible for the abnormal mammogram. The need for surgical excision following a diagnosis of LN on core biopsy is not well defined. We examined pathologic and mammographic findings in a consecutive series of cases diagnosed as LN to address this issue. Radiology/pathology records were reviewed for cases with a pathology diagnosis of pure LN during the period 1998–2001. Specifically excluded were cases with associated atypical ductal hyperplasia, ductal carcinoma in situ, invasive mammary carcinoma, or any history of breast malignancy. Thirty-five women 39–76 years of age (mean 52 years) were identified. Specimens were obtained as stereotactic core (31) or limited wire-guided biopsy (four). The diagnoses were lobular carcinoma in situ (12), lobular carcinoma in situ/ALH (10), and ALH (13). Fourteen patients did not undergo excisional biopsy and had no subsequent clinical follow-up to warrant additional biopsy (follow-up 6 months to 3 years). Five patients had no immediate excision, but eventually during clinical follow-up for LN (1 month to 3 years), two developed mammographic lesions in the ipsilateral (one patient) or contralateral breast (one patient) that led to diagnoses of invasive mammary carcinoma (lobular and composite ductal–lobular types, 10 and 8 mm, respectively); three patients had subsequent mammographic findings in the ipsilateral or contralateral breast leading to biopsies showing only LN (two patients) or no neoplastic pathology (one patient). The remaining 16 patients (all core biopsied) underwent immediate wire-guided excisions. Thirteen (81%) showed additional foci of LN, one (6.3%) with atypical ductal hyperplasia, and two (12.5%) with invasive lobular carcinoma (3 mm and <1 mm). Three (19%) had no residual disease; however, additional clinical follow-up in one of these patients revealed an invasive mammary carcinoma in the contralateral breast (false-negative mammography). Radiographic findings were calcifications and density/mass lesions in 27 and 8 cases, respectively. Of 27 cases presenting with Ca2+, 10 showed colocalization of LN and Ca2+. In the eight cases presenting with density/mass, incidental microscopic microcalcifications colocalized to LN were found in two cases. When present, histologic Ca2+ was associated with LN in 12 of 29 cases studied (41%). Of the 21 patients with immediate or subsequent excision, five (24%) were found to have an associated invasive mammary carcinoma (two on immediate excision and three after short-term follow-up of up to 3 years). The bilaterality of cancer risk was expected; however, the number of invasive carcinomas was not. That the invasive carcinomas detected at follow-up were small implies that they might have been present (but occult) at initial presentation. We conclude that lobular carcinoma in situ detected on core biopsy is potentially a significant marker for concurrent and near-term breast pathology requiring complete intensive multidisciplinary clinical follow-up with specific individualization of patient care.

Mediators of the inflammatory response to joint replacement devices

Joint replacement surgery is one of the success stories of modern medicine, restoring mobility, diminishing pain and improving the overall quality of life for millions of people. Unfortunately, wear of these prostheses over time generates debris, which activates an innate immune response that can ultimately lead to periprosthetic resorption of bone (osteolysis) and failure of the implant. Over the past decade, the biological interactions between the particulate debris from various implant materials and the immune system have begun to be better understood. The wear debris induces a multifaceted immune response encompassing the generation of reactive oxygen species and damage-associated molecular patterns, Toll-like receptor signaling and NALP3 inflammasome activation. Acting alone or in concert, these events generate chronic inflammation, periprosthetic bone loss and decreased osteointegration that ultimately leads to implant failure.

Endosomal damage and TLR2 mediated inflammasome activation by alkane particles in the generation of aseptic osteolysis

Ultra-high molecular weight polyethylene is widely used as a bearing surface in prosthetic arthroplasty. Over time the generation of implant-derived wear particles can initiate an inflammatory reaction characterized by periprosthetic inflammation and ultimately bone resorption at the prosthetic bone interface. Herein we present evidence that the different sized particles as well as the different length alkane polymers generated by implant wear leads to a two component inflammatory response. Polymeric alkane structures, with side chain oxidations, directly bind and activate the TLR-1/2 signaling pathway. Whereas micron- and nanometer-sized particulate debris are extensively phagocyted and induce enlargement, fusion and disruption of endosomal compartments. The resulting lysosomal damage and subsequent enzymatic leakage induces the NALP3 inflammasome activation as determined by cathepsins S and B cytosolic release, Caspase 1 activation and processing of pro-IL-1beta, and pro-IL-18. These two processes synergistically results in the initiation of a strong inflammatory response with consequent cellular necrosis and extracellular matrix degradation.

Complex Cystic Breast Masses: Diagnostic Approach and Imaging-Pathologic Correlation

Complex cystic breast masses demonstrate both anechoic (cystic) and echogenic (solid) components at ultrasonography (US). US is used to identify and characterize such masses and to guide percutaneous biopsy. Numerous pathologic entities may produce complex cystic breast lesions or may be associated with them, and biopsy is usually indicated. Common benign findings include fibrocystic changes, intraductal or intracystic papilloma without atypia, and fibroadenoma. Common atypical findings include atypical ductal hyperplasia, atypical papilloma, atypical lobular hyperplasia, and lobular carcinoma in situ. Malignant findings include ductal carcinoma in situ, infiltrating ductal carcinoma, and infiltrating lobular carcinoma. If the biopsy approach is tailored to the individual patient and if the imaging features are closely correlated with findings at pathologic analysis, US-guided percutaneous biopsy may be used effectively to diagnose and to guide management of complex cystic masses.

Expression of c-Kit in adenoid cystic carcinoma of the breast

Breast adenoid cystic carcinoma (BACC) is a biologically distinct tumor with morphologic mimickers, which might make accurate classification problematic. Because c-kit expression has been reported in adenoid cystic carcinoma of various anatomic sites, we evaluated BACC for c-kit by immunohistochemical analysis, comparing the findings to similarly stained mimickers. Tested cases included 6 BACCs, 15 low-grade infiltrating ductal carcinomas (LGIDCs) chosen as potential mimickers, and 15 head-neck adenoid cystic carcinomas (HNACCs). All BACCs showed plasma membranous and cytoplasmic staining equal to or greater than that of adjacent benign epithelium. Five BACCs (83%) expressed c-kit in more than 50% of tumor cells. Only 2 of 15 LGIDCs expressed low-intensity, focal c-kit staining. Of the 15 HNACCs, 10 (67%) expressed c-kit. Hormone receptors were consistently negative in BACCs. All BACCs expressed c-kit, whereas LGIDCs infrequently expressed low-intensity c-kit. Immunohistochemical evaluation for c-kit might aid in accurately classifying carcinomas with histologic features overlapping adenoid cystic carcinoma and LGIDC.

Tolerogenic forms of auto-antigens and cytokines in the induction of resistance to experimental allergic encephalomyelitis

Resistance to experimental allergic encephalomyelitis (EAE) induction by homogenized myelin (MSCH) in complete Freunds adjuvant (CFA) and pertussigen (P) in SJL mice was seen 1 week after intravenous injection of PLP 139-151 coupled to spleen cells (PLP-ECDI-SP). Although this resistance could be transferred by spleen cells enriched for CD8+ T cells and thus had a component of immunoregulatory T cells, it was primarily due to anergy, as it was reversible by four daily injections of interleukin (II)-2 starting 3 days after the PLP-ECDI-SP. Earlier treatment with IL-2 did not reverse the tolerance. In view of the known higher sensitivity to anergy induction of Th1 than of Th2 cells, a change in the cytokine balance in the response to MSCH+CFA after anergy induction might be responsible for the resistance to EAE induction. The effect of treatment with cytokines alone on induction of EAE was therefore also determined. Short-term (1-2 weeks) daily pretreatment with IL-2 (4000 U) or TGF-beta 2 (1 micrograms) somewhat decreased the susceptibility to subsequent EAE induction, but IL-4 (5 ng), IL-10 (5 micrograms) or IL-12 (50-200 ng) had no effect under those conditions, even if low doses of PLP were injected simultaneously. Daily injections of IL-4 over an 8-week period prior to immunization, however, significantly lowered the incidence of EAE. Simultaneous injections of IFN-gamma (2000 U/day) completely abolished this effect of IL-4. The effect of these cytokines administered immediately after the immunization with MSCH + CFA + P was also examined. As shown earlier, TGF-beta 2 (100-1000 ng/day) caused a marked protection when it was given intraperitoneally on days 5-9 after injection of MSCH + CFA. IL-4 (5 ng/day), in contrast, was very protective when administered on days 0-4 and less so when given on days 5-9 or even on days 0-12. IL-10 (1 microgram/day) was not protective under these conditions and IL-12 (50 ng/day) significantly increased the severity and mortality of EAE when given on days 0-4 after MSCH + CFA.

Immunogenecity of Modified Alkane Polymers Is Mediated through TLR1/2 Activation

Background With the advancement of biomedical technology, artificial materials have been developed to replace diseased, damaged or nonfunctional body parts. Among such materials, ultra high molecular weight alkane or modified alkyl polymers have been extensively used in heart valves, stents, pacemakers, ear implants, as well as total joint replacement devices. Although much research has been undertaken to design the most non-reactive biologically inert polyethylene derivatives, strong inflammatory responses followed by rejection and failure of the implant have been noted. Methodology/Principal Findings Purification of the alkane polymers from the site of inflammation revealed extensive “in vivo” oxidation as detected by fourier transformed infra-red spectroscopy. Herein, we report the novel observation that oxidized alkane polymers induced activation of TLR1/2 pathway as determined by ligand dependent changes in intrinsic tyrosine fluorescence intensity and NF-κΒ luciferase gene assays. Oxidized polymers were very effective in activating dendritic cells and inducing secretion of pro-inflammatory cytokines. Molecular docking of the oxidized alkanes designated ligand specificity and polymeric conformations fitting into the TLR1/2 binding grooves. Conclusion/Significance This is the first report of a synthetic polymer activating immune responses through TLR binding.

Immunocytochemical analysis of breast cells obtained by ductal lavage.

Intraductal breast fluids containing exfoliated mammary epithelial cells can be harvested from the breast by ductal lavage to screen for disease‐associated cytologic abnormalities. In addition to epithelial cells, breast fluids contain large numbers of mammary foam cells, and the tissue of origin of these foam cells has been the subject of controversy for many years. Immunocytochemical, morphologic, and molecular studies variously have supported a mammary epithelial origin versus a histiocytic origin for this cell type. In the current study, the authors performed immunocytochemical analysis with epithelial specific and macrophage specific antibodies to characterize and quantify breast cells obtained by ductal lavage.

Conformational Variation of Surface Class II MHC Proteins during Myeloid Dendritic Cell Differentiation Accompanies Structural Changes in Lysosomal MIIC

Dendritic cells (DC), uniquely among APC, express an open/empty conformation of MHC class II (MHC-II) proteins (correctly folded molecules lacking bound peptides). Generation and trafficking of empty HLA-DR during DC differentiation are investigated here. HLA-DR did not fold as an empty molecule in the endoplasmic reticulum/trans-Golgi network, did not derived from MHC/Ii complexes trafficking to the cell surface, but was generated after invariant chain degradation within lysosomal-like MHC-II rich compartments (MIIC). In pre-DC, generated from monocytes cultured in the presence of GM-CSF, Lamp-1+MHC-II+ compartments are predominantly electron dense and, in these cells, empty MHC-II molecules accounts for as much as 20% of total surface HLA-DR. In immature DC, generated in presence of GM-CSF and IL-4, empty HLA-DR reside in multilamellar MIIC, but are scarcely observed at the cell surface. Thus, the morphology/composition of lysosomal MIIC at different DC maturational stages appear important for surface egression or intracellular retention of empty HLA-DR. Ag loading can be achieved for the fraction of empty HLA-DR present in the “peptide-receptive” form. Finally, in vivo, APC-expressing surface empty HLA-DR were found in T cell areas of secondary lymphoid organs.

Renal Sarcoidosis Presenting as Acute Kidney Injury With Granulomatous Interstitial Nephritis and Vasculitis

Among the various renal manifestations of sarcoidosis, granulomatous inflammation confined to the tubulointerstitial compartment is the most commonly reported finding. We present the case of a 66-year-old man with acute kidney injury, hypercalcemia, mild restrictive pulmonary disease, and neurologic signs of parietal lobe dysfunction. Kidney biopsy showed diffuse interstitial inflammation with noncaseating granulomas that exhibited the unusual feature of infiltrating the walls of small arteries with destruction of the elastic lamina, consistent with granulomatous vasculitis. The findings of granulomatous interstitial nephritis on kidney biopsy, hypercalcemia, and possible cerebral and pulmonary involvement in the absence of other infectious, drug-induced, or autoimmune causes of granulomatous disease established the diagnosis of sarcoidosis. Pulse methylprednisolone followed by maintenance prednisone therapy led to improvement in kidney function, hypercalcemia, and neurologic symptoms. Vasculocentric granulomatous interstitial nephritis with granulomatous vasculitis is a rare and under-recognized manifestation of renal sarcoidosis.