Pathologic changes after interstitial laser therapy of infiltrating breast carcinoma.

BACKGROUND: Interstitial laser therapy (ILT) is a technique of destroying tumor cells via thermal energy. Prior studies have shown that the procedure is safe and efficacious in laboratory animals and that complete cell death, as assessed by tetrazolium staining, is achieved in the laser treated area. DESIGN: Forty women with localized, mammographically detectable, T1 breast cancers consented to be treated with ILT and then have the treated area subsequently excised. The delay period ranged from 5 to 42 days. Prior to ILT, the diagnosis of breast carcinoma was established by stereotactic needle core biopsy. RESULTS: All 40 cases showed a characteristic gross appearance, which consisted of a series of concentric rings surrounding a cavity corresponding to the laser needle tip. The tissue immediately adjacent to the cavity appeared coagulated and showed the same "wind-swept" nuclei seen with cautery artifact. Surrounding this was a white-tan ring that histologically showed recognizable tumor. No necrosis, increased apoptosis or inflammatory infiltrate was noted in this area on hematoxylin-eosin sections. Immunostains for cytokeratin were negative in the recognizable tumor cells despite intense staining in the epithelial cells outside the laser treated area. A ring of red tan tissue which histologically consisted of necrotic tumor was seen next and this, in turn, was surrounded by a rim of vascular proliferation and fat necrosis. The breast tissue outside the zone of fat necrosis appeared to be unaffected by the laser therapy. CONCLUSIONS: ILT appears to be an effective way to treat small localized breast cancer. It is important for the pathologist to recognize the changes seen after ILT, especially the zone containing pseudoviable tumor. Cytokeratin may be a marker to identify these likely non-viable but recognizable tumor cells. The extent of the laser affected area is defined by vascular proliferation and fat necrosis.

Status of HER-2 in male and female breast carcinoma.

BACKGROUND: HER-2 overexpression is seen in 20% to 30% of invasive female breast carcinomas. Besides being prognostic, HER-2 may also be predictive of response to therapy. Similar studies in male breast carcinoma are lacking. We compared the overexpression and amplification of HER-2 in female and male breast carcinoma. DESIGN: Formalin-fixed, paraffin embedded archival material from 58 invasive male breast carcinomas and 202 invasive female breast carcinomas were immunostained for HER-2. Scoring was performed according to established guidelines. Each case was also assessed for HER-2 gene amplification by fluorescence in-situ hybridization (FISH) utilizing the PathVysion assay (Vysis corporation, Downers Grove, Illinois). RESULTS: There were 58 male patients who ranged in age from 38 to 92 years (mean 63). Thirty-five (60%) were T1 lesions and 23 (40%) were T2 lesions. Twenty-five patients (43%) had positive lymph nodes. One (1.7%) of the 58 cases showed 3+ staining of HER-2. The remaining 57 cases did not show overexpression. There was no amplification of the HER-2 gene in any of the cases. There were 202 female patients who ranged in age from 26 to 96 years (mean 52). In all, 129 (64%) were T1 lesions, 61 (30%) were T2 lesions, and 13 (6%) were T3 lesions. Fifty-two (26%) showed positive staining with HER-2 (44 cases 3+, 8 cases 2+). The remaining 150 (74%) did not show overexpression. There was amplification of HER-2 gene in 55 (27%) of the cases. Two of the cases negative by FISH were 3+ positive by IHC. CONCLUSIONS: HER-2 is overexpressed in approximately 27% of female breast carcinomas. A high level of correlation is demonstrated between IHC and FISH techniques. Gene amplification of HER-2 does not play a role in male breast carcinoma. The rate of single-copy overexpression of HER-2 appears identical in male and female breast carcinoma.

Image-guided surgery of small breast cancers.

BACKGROUND: Widespread screening mammography has resulted in detection of many breast cancers smaller than one cm. Image-guided percutaneous needle sampling provides accurate diagnostic and prognostic information for adjuvant therapy. Less invasive methods based on imaging techniques are emerging as an alternative to wire localization and lumpectomy. DATA SOURCES: Information presented in this overview was provided by seven investigators from five medical centers in the United States. These researchers are currently developing various techniques of image-guided percutaneous therapy of small (Tis, 1) breast cancers. CONCLUSIONS: Several percutaneous treatment modalities for treatment of early breast cancer, either excisional or in-situ ablative, are described in this overview and their potential applications are discussed.

Occult metastases in sentinel nodes of 200 patients with operable breast cancer.

BACKGROUND: Up to 30% of patients with operable breast cancer and negative regional lymph nodes experience disease recurrence within 10 years. Serial sectioning and immunohistochemical staining of these nodes have revealed 9% to 30% occult metastases. METHODS: Sentinel nodes from 200 patients with T1 and T2 invasive breast carcinoma were step-sectioned at 2- to 3-mm intervals, fixed in 10% formalin, and embedded in paraffin. Sections were taken from the face of the blocks and stained with hematoxylin and eosin (H&E). The blocks were then cut completely, and sections at .25-mm intervals were stained with cytokeratin and examined. RESULTS: Tumor metastases were found in 34 patients when the sentinel nodes were examined at 2- to 3-mm intervals and in an additional 51 patients when the nodes were sectioned in their entirety at .25-mm intervals and stained with cytokeratin, bringing the total number of patients with metastases to 85. Of the 51 patients whose metastases were detected by 2- to 3-mm sectioning and cytokeratin staining, 27 had isolated tumor cells and 24 had clusters of innumerable malignant cells, all of which were visualized and confirmed by H&E staining of the adjacent sections. CONCLUSIONS: Histologic examination of sentinel nodes of patients with invasive breast cancer sectioned at 2- to 3-mm intervals and stained with H&E significantly underestimates nodal metastases. Sectioning of the entire sentinel nodes at .25-mm intervals and staining with cytokeratin detects metastases as either isolated cells or as clusters.

Stereotactically guided laser therapy of occult breast tumors: work-in-progress report.

HYPOTHESIS: Mammographically detected breast tumors can be completely ablated with laser energy. DESIGN: Nonrandomized control trial. SETTING: A university hospital ambulatory care center. PATIENTS: Thirty-six patients with mammographically detected well-defined breast tumors were selected. INTERVENTIONS: The diagnosis of malignant neoplasms and determination of prognostic factors were established by image-guided needle-core biopsy. Patients were treated on a stereotactic table, using a 16- to 18-gauge laser probe, with an optic fiber transmitting a predetermined amount of laser energy. A multisensor thermal probe was inserted into the breast adjacent to the laser probe to monitor treatment. In the last 10 patients, the tumor blood flow was evaluated before and after laser therapy with contrast-enhanced color Doppler ultrasound. One to 8 weeks after laser therapy, the tumors were surgically removed and serially sectioned. MAIN OUTCOME MEASURE: Complete necrosis in 66% of tumors. RESULTS: Total tumor ablation with negative margins was observed whenever 2500 J/mL of tumor was given or the thermal sensors recorded 60 degrees C. Microscopic examination at 1 week showed disintegration of malignant cells, with peripheral acute inflammatory response and at 4 to 8 weeks extensive fibrosis. Contrast-enhanced color Doppler ultrasound revealed loss of tumor circulation after therapy, and positron emission tomography scan correlated well with histologic findings. There were no systemic adverse effects. Two patients sustained 3 x 4-mm skin burns around the laser needle. CONCLUSION: A stereotactically guided minimally invasive technique may be effective for the treatment of mammographically detected breast cancer.

Occult metastases in the sentinel lymph nodes of patients with early stage breast carcinoma: A preliminary study.

BACKGROUND: Thirty percent of lymph node negative patients with operable breast carcinoma experience disease recurrence within 10 years. Retrospective serial sectioning of axillary lymph nodes has revealed undetected metastases in 9-30% of these patients. These occult metastases have been shown to have an adverse effect on survival. Serial sectioning (SS) is impractical for all axillary lymph nodes harvested from Levels I and II, but it is feasible if applied only to sentinel lymph nodes. METHODS: Sentinel lymph nodes from 52 patients with invasive breast carcinoma were cut at 2 mm intervals, fixed in 10% formalin, and embedded in paraffin. Sections were taken from the blocks, stained with hematoxylin and eosin (H & E), and compared with cytokeratin-stained sections taken at 0.25 mm intervals throughout the entire blocks. RESULTS: Tumor metastases were found in 6 patients (12%) when the sentinel lymph nodes were sectioned at 2 mm intervals and stained with H & E, compared with 30 patients (58%) when the same lymph nodes were serially sectioned at 0.25 mm intervals and stained with cytokeratin. Of 24 patients whose metastases were detected by SS and cytokeratin staining, 12 had isolated tumor cells and 12 had colonies of several thousand malignant cells. CONCLUSIONS: Routine histologic examination of axillary lymph nodes, including sentinel lymph nodes, in cases of breast carcinoma significantly underestimates lymph node metastases. This deficiency may be overcome by SS of the entire lymph nodes and staining with a specific monoclonal antibody. The percentage of patients found to have colonies of cells that were missed by routine sectioning corresponds closely to the percentage of "lymph node negative" patients who would be expected to relapse. The true clinical significance of these occult metastases will be determined by long term follow-up. [See editorial on pages 905-7, this issue.]

Systemic calciphylaxis in a patient with end-stage renal disease and a normal parathyroid hormone level taking erythropoietin intramuscularly.

OBJECTIVE: To describe a patient with systemic calciphylaxis. METHODS: We present a case of a 26-year-old woman with end-stage renal disease taking intramuscular injections of erythropoietin in whom systemic calciphylaxis subsequently developed. Both clinical and laboratory findings are reviewed. RESULTS: In a 26-year-old woman with end-stage renal disease who was taking erythropoietin intramuscularly, multiple, superficial ulcerative lesions developed on both lower extremities. Despite aggressive treatment, new lesions subsequently developed. Laboratory values showed an increased calcium-phosphate product and a normal parathyroid hormone level. A skin biopsy specimen showed necrotic skin and subcutaneous fat with foci of calcification around the vessels, findings that confirmed the diagnosis of calciphylaxis. The patient then underwent subtotal parathyroidectomy and responded with initial improvement; however, her condition later deteriorated, and she died of uncontrolled pulmonary hemorrhage. CONCLUSION: Systemic calciphylaxis is a rare but devastating complication of end-stage renal disease. This condition mimics many different disorders; therefore, a high index of suspicion is essential for early recognition and diagnosis, which is assisted by biopsy specimens of skin lesions. Treatment includes subtotal or total parathyroidectomy in conjunction with autotransplantation, administration of phosphate binders, aggressive treatment with antibiotics, and lowering of the calcium-phosphate product. Even though a successful outcome is possible when this disease is recognized early and treated aggressively, the morbidity and mortality associated with systemic calciphylaxis still remain high.

Increased numbers of cytokeratin-positive interstitial reticulum cells (CIRC) in reactive, inflammatory and neoplastic lymphadenopathies: hyperplasia or induced expression?

A total of 291 enlarged lymph nodes showing a range of reactive-inflammatory processes, primary and metastatic neoplasms were studied to determine the distribution and immunoprofile of their cytokeratin-positive interstitial reticulum cells (CIRC) in comparison with normal nodes. In 258/291 nodes (89%), CIRC numbers were distinctly increased in the subcapsular, paracortical and, occasionally, in the medullary zones; often, these increased CIRC formed networks around follicles, sinuses and vessels. CIRC had comparatively small, irregularly shaped bodies and dendritic processes; occasionally, giant forms were noted. CIRC contained cytokeratins (CK) 8 and 18 but not 19, as shown by immunohistochemistry, and by gel electrophoresis with subsequent immunoblotting. They co-expressed vimentin consistently, alpha-smooth-muscle actin frequently, and desmin less frequently. They did not contain desmoplakins, Factor VIII, S-100, LCA, B and T lymphocyte- and macrophage-associated antigens, chromogranin A, synaptophysin or the A-80 glycoprotein. We found no clear correlation between the increased CIRC and given nodal disease processes. However, CIRC were most abundant in nodes free of but draining malignant tumours; bizarre CIRC assemblies were noted in HIV lymphadenopathy. CIRC appear to represent a subset of the so-called "fibroblastic reticulum cells" of lymph nodes. Their function remains undetermined; their increase in diverse lymphadenopathies suggests that they partake in nodal reactions to injury. It remains unclear whether the increase in CIRC relative number is due to proliferation or to CK gene induction processes but their presence and potential capability to undergo hyperplasia with dysplastic forms should alert pathologists to possible diagnostic pitfalls. In addition, we discuss that CIRC may undergo transformation and represent the "cell of origin" of certain CK-positive tumours restricted to lymph nodes.

Human performance studies of the video microscopy component of a dynamic telepathology system.

Human performance studies were performed to evaluate the video microscopy component of a proposed dynamic telepathology system. Frozen sections from breast biopsies of 115 patients were evaluated by both conventional light microscopy and video microscopy by 6 pathologists. Receiver operator characteristic (ROC) curve studies showed nearly identical levels of discrimination between benign and malignant breast lesions for both viewing modalities. Viewing times were significantly greater (p < 0.001) for video microscopy but within a time frame that rendered the technology of potential value for pathology diagnostic applications. Large degrees of interobserver viewing time variability were found for light and video microscopy.

Telepathology. Long-distance diagnosis.

Telepathology is defined as the practice of pathology at a distance, by visualizing an image on a video monitor rather than viewing a specimen directly through a microscope. Components of a telepathology system include the following: (1) a workstation equipped with a high-resolution video camera attached to a remote-controlled light microscope; (2) a pathologist workstation incorporating controls for manipulating the robotic microscope as well as a high-resolution video monitor; and (3) a telecommunications link. Progress has been made in designing and constructing telepathology workstations and fully motorized, computer-controlled light microscopes suitable for telepathology. In addition, components such as video signal digital encoders and decoders that produce remarkably stable, high-color fidelity, and high-resolution images have been incorporated into the workstations. Resolution requirements for the video microscopy component of telepathology have been formally examined in receiver operator characteristic (ROC) curve analyses. Test-of-concept demonstrations have been completed with the use of geostationary satellites as the broadband communication linkages for 750-line resolution video. Potential benefits of telepathology include providing a means of conveniently delivering pathology services in real-time to remote sites or underserviced areas, time-sharing of pathologists' services by multiple institutions, and increasing accessibility to specialty pathologists.

An algorithm for hematuria.

Two algorithms are presented to help clarify the diagnostic evaluation of hematuria. Utilizing an anatomic framework for adults and an etiologic framework for children, this complex clinical problem can be approached in a logical manner.

Telepathology and the networking of pathology diagnostic services.

Telepathology is the practice of pathology over a long distance. Components of a telepathology system include the following: a remote-controlled light microscope attached to a high-resolution video camera; a pathologist workstation incorporating controls for manipulating the microscope and a high-resolution video monitor; and a telecommunications linkage. An immediate challenge is to establish the specifications for a telepathology system. Breast tissue has served as a model. Receiver operator characteristic curve studies show that the pathologist's ability to discriminate benign from malignant breast tumors is similar using either a conventional light microscope or a video monitor with approximately 1000 lines of resolution. The percentage of cases for which pathologists render an "equivocal" diagnosis is the same for the two modalities. Telepathology may be an effective way to provide on-line consultations in difficult cases and to provide hospitals in remote areas with immediate access to anatomic pathology services.

Cell-to-cell fusion of lens fiber cells in situ: correlative light, scanning electron microscopic, and freeze-fracture studies.

We have discovered cell-to-cell fusion between fiber cells of adult frog lenses in situ. Stereo scanning electron microscopy (SEM) revealed fusion between neighboring fiber cells in radial cell columns (RCCs) and in the same growth ring, respectively. Cell-to-cell fusion of fiber cells in the lens produced fusion zones that in cross-section were larger and of different polygonal shapes than unfused fiber cells. The shape and sizes of fiber cells surrounding fusion zones and the alignment of RCCs were also altered. Serial sectioning through fusion zones confirmed that they were areas of cell-to-cell continuity established by the union of neighboring fiber cells as seen by SEM. Fusion zones represent a previously unrecognized intercellular pathway in the adult frog lens. Although numerous fusion zones were seen throughout the lens cortex and nucleus, cell-to-cell fusion was rarely observed to have occurred between elongating fiber cells. Interestingly, communicating junctions with an unusual ultrastructure that closely resembles the appearance of membranes in the process of fusion demonstrated in other systems were frequently seen in the region of the superficial cortex where fusion zones were most numerous. The fact that such unusual communicating junctions were not found in any other region of the lens leads us to speculate that structural changes in fiber cell communicating junctions may herald the formation of fusion zones and that the initial site of cell-to-cell fusion between fiber cells may be within communicating junctional plaques.