Katherine M. Scott

A new rabbit monoclonal antibody (4B5) for the immunohistochemical (IHC) determination of the HER2 status in breast cancer: comparison with CB11, fluorescence in situ hybridization (FISH), and interlaboratory reproducibility.

The 2 methodologies in current clinical use to assess HER2 status in breast cancer are: fluorescence in situ hybridization (FISH) (gene amplification) and immunohistochemistry (protein over-expression). A consistent finding has been that 3% to 15% of breast cancers over-express HER2 protein without evidence for gene amplification. Accurate determination of the HER2 status has implications for selecting patients most likely to respond to trastuzumab. We report here our preliminary experience with a new anti-HER2 rabbit monoclonal antibody, 4B5. The evaluation of HER2 status in 2 different cohorts of breast cancer cases (Single Institution (SI) and Multinational (MN)) with a total of 322 breast cancer cases was performed on an automated staining system (Ventana Medical Systems, Inc, Tucson, AZ) and scored by 3 pathologists (0-3+), for comparison with CB11 staining results (PATHWAY) and FISH (PathVysion). Interlaboratory reproducibility of automated staining results and interpretation was determined on a subset of the SI cohort at 3 separate laboratories. Rabbit monoclonal 4B5 demonstrated sharper membrane staining with less cytoplasmic and stromal background staining than CB11. In the SI cohort, the staining results for 4B5 were highly comparable with those obtained for CB11 with an overall concordance of 93.3%. In the multinational cohort, the overall concordance with CB11 was 84.7%. This lower level of concordance was associated with a much higher overall agreement of 4B5 with FISH (89.5%), compared with agreement of CB11 with FISH (81.2%). The difference in the performance of CB11 in the MN cohort versus the SI cohort may be due to differences in tissue fixation and processing in a centralized, high volume laboratory in an academic medical center versus multiple sites in the international community with potentially nonstandardized techniques. The staining results with 4B5 indicate that it has a more robust performance than CB11 because the correlation of 4B5 with FISH was nearly equivalent (88.2% MN; 89.3% SI) in both cohorts. Interlaboratory reproducibility was also excellent (κ 1.0). RMoAb 4B5 provides excellent sensitivity, specificity, and interlaboratory reproducibility for the detection of HER2 status in breast cancer.

Virtual slide telepathology for an academic teaching hospital surgical pathology quality assurance program.

Virtual slide telepathology is an important potential tool for providing re-review of surgical pathology cases as part of a quality assurance program. The University of Arizona pathology faculty has implemented a quality assurance program between 2 university hospitals located 6 miles apart. The flagship hospital, University Medical Center (UMC), in Tucson, AZ, handles approximately 20 000 surgical pathology specimens per year. University Physicians Healthcare Hospital (UPHH) at Kino Campus has one tenth the volume of surgical pathology cases. Whereas UMC is staffed by 10 surgical pathologists, UPHH is staffed daily by a single part-time pathologist on a rotating basis. To provide same-day quality assurance re-reviews of cases, a DMetrix DX-40 ultrarapid virtual slide scanner (DMetrix, Inc, Tucson, AZ) was installed at the UPHH in 2005. Since then, glass slides of new cases of cancer and other difficult cases have been scanned the same day the slides are produced by the UPHH histology laboratory. The pathologist at UPHH generates a provisional written report based on light microscopic examination of the glass slides. At 2:00 pm each day, completed cases from UPHH are re-reviewed by staff pathologists, pathology residents, and medical students at the UMC using the DMetrix Iris virtual slide viewer. The virtual slides are viewed on a 50-in plasma monitor. Results are communicated with the UPHH laboratory by fax. We have analyzed the results of the first 329 consecutive quality assurance cases. There was complete concordance with the original UPHH diagnosis in 302 (91.8%) cases. There were 5 (1.5%) major discrepancies, which would have resulted in different therapy and/or management, and 10 (3.0%) minor discrepancies. In 6 cases (1.8%), the diagnosis was deferred for examination of the glass slides by the reviewing pathologists at UMC, and the diagnosis of another 6 (1.8%) cases were deferred pending additional testing, usually immunohistochemistry. Thus, the quality assurance program found a small number of significant diagnostic discrepancies. We also found that implementation of a virtual slide telepathology quality assurance service improved the job satisfaction of academic subspecialty pathologists assigned to cover on-site surgical pathology services at a small, affiliated university hospital on a rotating part-time basis. These findings should be applicable to some community hospital group practices as well.

Long-term cyclophosphamide treatment for recurrent type I membranoproliferative glomerulonephritis after transplantation

The incidence of recurrent type I membranoproliferative glomerulonephritis (MPGN) after renal transplant is approximately 30%, and the rate of graft loss due to recurrent MPGN type I is higher than 50%. The treatment of this disease has not been defined. We report a case of recurrent MPGN type diagnosed 4 months after a cadaveric renal transplantation. The patient was treated with cyclophosphamide and was able to maintain her graft function. Cyclophosphamide was interrupted three times during the course. Each time her renal function deteriorated and her serum albumin decreased. The patient currently has a functional renal graft 3 years after transplantation while receiving low-dose therapy with cyclophosphamide. We suggest treating recurrent type I MPGN with cyclophosphamide while continuing the calcineurin inhibitor and prednisone.

Band 1p36 Abnormalities and t(1;17) in Ovarian Carcinoma

In a series of 128 karyotyped ovarian carcinomas, 42% of cases with chromosome 1 clonal structural abnormalities had breaks at band 1p36 (usually involving translocations of unknown material). Fluorescent in situ hybridization (FISH) studies using combinations of 1 centromere and 1p36.3-specific probes (16 cases) or 1 centromeric and 17 whole-chromosome paint probes (11 cases with 1p+) revealed a trend toward deletion of 1pter relative to 1 centromere (63%); intratumor heterogeneity; and the origin of 1p+ in 3/11 cases (27%) from chromosome 17 [t(1;17)(p36;?)]. The frequency of this specific breakpoint and its involvement in recurrent translocations suggest that these regions are loci for genes important in the pathogenesis of a subset of sporadic ovarian carcinomas.

The innovative bundling of teleradiology, telepathology, and teleoncology services

Teleradiolosy, telepathology, and teleoncology are important applications of telemedicine. Recent advances in these fields include a preponderance of radiology PACS (Picture Archiving and Communications System) users, the implementation of around-the-clock teleradiology services at many hospitals, and the invention of the first ultrarapid whole-slide digital scanner based on the array microscope. These advances have led to the development of a new health-care-delivery clinical pathway called the ultrarapid breast care process (URBC), which has been commercialized as the UltraClinics® process. This process bundles telemammography, telepathology, and teleoncology services and has reduced the time it takes for a woman to obtain diagnostic and therapeutic breast-care planning services from several weeks to a single day. This paper describes the UltraClinics process in detail and presents the vision of a network of same-day telemedicine-enabled UltraClinics facilities, staffed by a virtual group practice of teleradiologists, telepathologists, and teleoncologists.

Managing Henoch-Schonlein purpura in children with fish oil and ACE inhibitor therapy.

Background:  Henoch–Schonlein purpura (HSP) is a vasculitic syndrome with palpable purpura and renal involvement. The treatment for HSP with persistent renal disease remains controversial. The kidney biopsy in HSP shows IgA deposits and fish‐oil therapy has proven to be promising in halting the progression of IgA nephropathy.

Multicentric papillary renal carcinoma in renal allograft

A renal transplant recipient with 13 years of excellent allograft function was found incidentally to have a malignant mass in his transplanted kidney. After resection, pathological analysis showed 29 separate lesions of renal cell carcinoma. All tumors were confined within the renal capsule. The majority of tumors (21 of 29 tumors) were chromophil basophilic carcinoma with papillary architecture, 5 tumors were clear cell, 2 tumors were mixed cell type, and 1 tumor was chromophil eosinophilic papillary carcinoma. These histological findings are similar to those reported in hereditary papillary renal carcinoma. To our knowledge, this is the first case of multicentric papillary renal carcinoma occurring in the renal allograft. We speculate that the allograft in this case is predisposed to malignant changes because of preexisting genetic mutations, as well as prolonged immunosuppression.

Coccidioidomycosis in adolescents with lupus nephritis

Abstract Coccidioidomycosis, a fungal infection endemic in the southwestern United States, can cause life-threatening infections in immunosuppressed patients. We report the contrasting cases of two adolescents with lupus nephritis, treated with intravenous pulse cyclophosphamide and daily oral corticosteroids, who developed pulmonary coccidioidomycosis. One patient developed a fatal form of fulminant disseminated coccidioidomycosis, while the other patient developed a solitary pulmonary Coccidioides immitis abscess which was responsive to intravenous liposomal amphotericin and fluconazole therapy. Because serologies and initial X-ray studies can be negative, definitive diagnostic studies including bronchioaveolar lavage and needle aspiration should be performed when there is clinical suspicion of coccidioidomycosis in an immunocompromised patient. Immunosuppressed patients with coccidioidomycosis should receive early intravenous amphotericin therapy and may benefit from long-term suppressive antifungal therapy to prevent relapse.

Diagnostic frozen prostate sextant biopsies: An approach for preserving protein and RNA for additional studies

Primary prostate cancer represents 29% of newly diagnosed visceral cancers in men. Despite this common occurrence, relatively little is known about the pathogenesis of this malignancy. High‐grade prostatic intraepithelial neoplasia (HGPIN) is generally accepted as a precursor to invasive prostate carcinoma. There is a lack of adequate animal models, and the available cell culture lines are limited. Tissue from prostate needle core biopsies that have been frozen can provide adequate material for both diagnosis and research.

Acute myelo-monocytic infiltrate of the lower esophagus in a 4-year-old renal transplant recipient.

BACKGROUND Acute myeloid leukemia after solid organ transplantation is a rare phenomenon. Few achieve remission; most succumb to relapse and infection. METHODS A 4-year-old male renal transplant recipient on triple immunosuppression had culture-negative high spiking fever, persistent leukopenia, anemia and severe gastritis. Upper endoscopy showed 2 ulcerating masses in the lower esophagus. RESULTS Esophageal biopsy showed a highly atypical myelo-monocytic infiltrate. A blastic population of cells featuring convoluted nuclear envelopes with an open chromatin pattern and abundant cytoplasm were filling the submucosa and infiltrating into the muscularis propria. Extensive investigation including bone marrow aspiration showed no spread. Drastic reduction of immunosuppression except 4-mg/d (0.22 mg/kg/d) prednisone for 2 to 3 weeks led to resolution of the leukemic process proven on repeat biopsy. The patient still is in remission 2 years later. CONCLUSION This case provides evidence that early diagnosis and aggressive reduction of immunosuppression may remit a posttransplant locally invasive acute myelo-monocytic infiltrative process.