Detailed Reanalysis of 500 Breast Cancers With Equivocal HER2 Immunohistochemistry and Borderline ERBB2 Fluorescence In Situ Hybridization Results.

OBJECTIVES: We investigated the impact of our laboratory's reflex testing process for resolving ERBB2 (HER2) status on breast cancer samples that require additional workup after fluorescence in situ hybridization (FISH), per guideline recommendations published in 2018 by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). METHODS: In total, 500 breast cancer specimens with ERBB2 FISH results in groups 2 through 4 (all reported as immunohistochemistry [IHC] equivocal [2+] at external laboratories) were resubmitted for IHC testing in our laboratory. Per the ASCO/CAP guideline, FISH was rescored when internal IHC was also equivocal (2+), targeted to tumor areas demonstrating more intense IHC staining, if observed. RESULTS: Reflex IHC/FISH testing changed the final reported ERBB2 status in 185 of 500 (37.0%) samples. Result changes included discordant IHC (n = 4 score 0, n = 132 score 1+, and n = 16 score 3+) and discordant FISH (n = 33). Numerical differences in FISH scores were comparable for targeted vs nontargeted FISH rescoring (P = .086 for ERBB2 copy number; P = .49 for ERBB2 ratio). Two cases showed larger differences in FISH scores, suggesting heterogeneity. CONCLUSIONS: Retesting of breast cancer samples with equivocal IHC frequently changes IHC results, but targeted reanalysis of borderline FISH results rarely identifies significant differences in ERBB2 copy number or ratio.

PLEKHA7, an Apical Adherens Junction Protein, Suppresses Inflammatory Breast Cancer in the Context of High E-Cadherin and p120-Catenin Expression.

Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers express high levels of E-cadherin, the major mediator of adherens junctions, which enhances formation of tumor emboli. Previous studies suggest that E-cadherin promotes cancer when the balance between apical and basolateral cadherin complexes is disrupted. Here, we used immunohistochemistry of inflammatory breast cancer patient samples and analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We used viral transduction to re-express PLEKHA7 in inflammatory breast cancer cells and examined their aggressiveness in 2D and 3D cultures and in vivo. We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in most patient samples and very low expression in cell lines. Re-expressing PLEKHA7 suppressed proliferation, anchorage independent growth, spheroid viability, and tumor growth in vivo. The data indicate that PLEKHA7 is frequently deregulated and acts to suppress inflammatory breast cancer. The data also promote the need for future inquiry into the imbalance between apical and basolateral cadherin complexes as driving forces in inflammatory breast cancer.

Association of Event-Free and Distant Recurrence-Free Survival With Individual-Level Pathologic Complete Response in Neoadjuvant Treatment of Stages 2 and 3 Breast Cancer: Three-Year Follow-up Analysis for the I-SPY2 Adaptively Randomized Clinical Trial.

Importance: Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial. Objective: To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents. Design, Setting, and Participants: Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019. Interventions: Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide. Main Outcomes and Measures: Pathologic complete response and 3-year EFS and DRFS. Results: Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS. Conclusions and Relevance: The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.

Genomic profiling proves metastasis of cutaneous melanoma to vitreal fluid.

Cutaneous melanoma metastases can contribute to visual disturbances through a variety of factors, including metastasis to the vitreal fluid. The optimum management of metastatic cutaneous melanoma to the vitreal fluid is unknown, but can include radiation therapy or systemic therapy including immunotherapy. A high degree of suspicion is necessary to consider this complication while working with patients with cutaneous melanoma.

Characteristics and Management of Male Breast Parenchymal Cysts.

OBJECTIVE: Parenchymal breast cysts are considered to be rare in men and are sparsely described in the literature. The purpose of this study was to review our institution's experience with male breast cysts in an effort to improve overall understanding and management of this rare entity. METHODS: An institutional review board-exempt retrospective study was performed. Radiology reports for males who underwent mammogram and/or breast ultrasound at any of our institution's primary or satellite locations from January 1995 to January 2020 were screened to find males with breast cysts. If cysts were reported and images were available, case review was performed to confirm parenchymal breast cyst(s) and patient characteristics were collated. RESULTS: Of 5425 male cases presenting for breast imaging, 19 (0.4%) cases of male breast cysts were confirmed, with a mean patient age of 41.6 years (range: 2-81 years). The most common indication leading to cyst discovery was a palpable lump, corresponding to the site of the cyst in 5 (26.3%) patients and near the site where cyst(s) were ultimately discovered in 7 (36.8%) patients. There were 8 (42.1%) instances of cysts without concurrent gynecomastia. Three (15.8%) men underwent needle sampling. There were no cases of atypia or malignancy on needle biopsy or on subsequent clinical follow-up, with median clinical follow-up of 70.3 months (range: 3.3-259.4 months). CONCLUSION: Male breast parenchymal cysts are rare, but their prevalence is likely underestimated. If detected incidentally or upon targeted evaluation, biopsy may be averted if classic benign cyst features are identified.

Breast MRI phenotype and background parenchymal enhancement may predict tumor response to neoadjuvant endocrine therapy.

Neoadjuvant endocrine therapy (NET) is increasingly used for the treatment of estrogen receptor positive, HER2 negative breast cancer. We evaluated whether MRI phenotype and background parenchymal enhancement (BPE) can predict response to NET. Patients with localized breast cancer treated with NET and had a pre-treatment breast MRI were identified. Baseline MRI phenotype and BPE was interpreted by a single radiologist blinded to the results of systemic therapy. Response was defined as stable disease or reduction in tumor size on clinical and/or ultrasound examination. Of the 21 patients identified, 17 were responders; all patients with minimal/mild BPE had a response compared to 5/9 (56%) patients with moderate/marked BPE (P = 0.02). All four nonresponders had moderate/marked BPE as compared to 5/17 (29%) responders (P = 0.02). This pilot study suggests that minimal/mild BPE may be predictive of a positive response to NET. A higher degree of background enhancement was significantly predictive of negative response to NET.

Update on the College of American Pathologists Experience With High-Risk Human Papillomavirus Proficiency Testing for Cytology.

CONTEXT: - Since 2008, the College of American Pathologists has provided the human papillomavirus for cytology laboratories (CHPV) proficiency testing program to help laboratories meet the requirements of the Clinical Laboratory Improvement Amendments of 1988. OBJECTIVES: - To provide an update on trends in proficiency testing performance in the College of American Pathologists CHPV program during the 4-year period from 2011 through 2014 and to compare those trends with the preceding first 3 years of the program. DESIGN: - Responses of laboratories participating in the CHPV program from 2011 through 2014 were analyzed using a nonlinear mixed model to compare different combinations of testing medium and platform. RESULTS: - In total, 818 laboratories participated in the CHPV program at least once during the 4 years, with participation increasing during the study period. Concordance of participant responses with the target result was more than 98% (38 280 of 38 892). Overall performance with all 3 testing media-ThinPrep (Hologic, Bedford, Massachusetts), SurePath (Becton, Dickinson and Company, Franklin Lakes, New Jersey), or Digene (Qiagen, Valencia, California)-was equivalent (P = .51), and all 4 US Food and Drug Administration (FDA)-approved platforms-Hybrid Capture 2 (Qiagen), Cervista (Hologic), Aptima (Hologic), and cobas (Roche Molecular Systems, Pleasanton, California)-outperformed laboratory-developed tests, unspecified commercial kits, and other (noncommercial) methods in ThinPrep medium (P < .001). However, certain off-label combinations of platform and medium, most notably Cervista with SurePath, demonstrated suboptimal performance (P < .001). CONCLUSIONS: - Laboratories demonstrated proficiency in using various combinations of testing media and platforms offered in the CHPV program, with statistically significant performance differences in certain combinations. These observations may be relevant in the current discussions about FDA oversight of laboratory-developed tests.

Back to Basics: Traditional Nottingham Grade Mitotic Counts Alone are Significant in Predicting Survival in Invasive Breast Carcinoma.

BACKGROUND: Newer multigene molecular profiling assays for breast carcinoma rely heavily on the quantification of genes of proliferation, whereas traditional histological grading reports the mitotic count. The mitotic activity of invasive breast carcinomas may be undervalued; therefore, an evaluation of the prognostic significance of mitotic score in predicting prognosis was performed. METHODS: Retrospective analysis of a single institutional cohort of newly diagnosed estrogen receptor positive (ER+), HER2 negative (HER2-) unilateral invasive breast carcinomas was performed. Mitotic scores from the 3-part Nottingham combined histological grade were compared with clinical parameters. Mitoses were counted on Olympus BX50 microscopes and assigned scores of 1-3 based on observed mitoses. RESULTS: A total of 1292 ER+, HER2- invasive breast carcinoma patients were identified, with a median follow-up time of 2.6 years (range 0-14 years). Higher mitotic score was significantly associated with younger age, larger tumor size, angiolymphatic invasion, node-positive disease, higher stage, and the use of hormonal and cytotoxic chemotherapy. Mitotic score was significant in modeling time to local/regional recurrence (p = 0.02), recurrence-free survival/RFS (p < 0.001), and overall survival/OS (p = 0.01) with higher mitotic scores associated with worse outcomes. Higher mitotic score correlated significantly with intermediate/high risk Oncotype Dx recurrence scores (p = 0.009). CONCLUSIONS: First-generation molecular profiling assays for estrogen receptor positive invasive breast carcinomas derive much of their predictive power from quantifying genes of proliferation into a single score. Sometimes overlooked in the profusion of molecular data, the time-tested, mitotic count in the Nottingham combined histological grade is a good single-parameter predictor of survival.

Rates of residual disease with close but negative margins in breast cancer surgery.

OBJECTIVES: A recent multidisciplinary consensus defined an adequate breast cancer margin as no ink on tumor. The purpose of this study was to analyze rates of residual disease at re-excision by margin width. MATERIALS AND METHODS: A prospective database at a single institution was reviewed from 2000 to 2012. Institutional protocol had been to perform re-excision surgery when margins were <2 millimeters (mm). RESULTS: There were 2520 procedures. Re-excision surgery was performed for 12% of breast conserving therapy (BCT) procedures and 2% of mastectomies; residual disease was present in 38% and 26%, respectively. The rates of residual disease for all patients with positive, 0.1-0.9 mm, and 1.0-1.9 mm margins were 40%, 38%, and 33%, respectively. Age, race, menopause status, width of closest final margin, tumor histology, hormone receptor status, triple-negative disease and presence of lymphovascular invasion (LVI) were not significantly associated with the presence of residual disease. The presence of multiple margins <2 mm trended toward significance (p = 0.06). Median follow-up was 43 months. The five-year local recurrence rates (5-year LR) were 1.1% for mastectomy patients and 1.9% for BCT patients. CONCLUSIONS: Breast cancer patients with margins of excision <2 mm have a substantial risk of residual disease but the rates far exceed LR rates. These findings suggest that using residual disease rates to determine the appropriate margin width is not reliable, but also serve as a note of caution to track LR rates as institutions conform to new national guidelines for margin management.

Human papillomavirus testing and reporting rates in 2012: results of a College of American Pathologists national survey.

CONTEXT: College of American Pathologists (CAP) surveys are used to establish national benchmarks for laboratory parameters. OBJECTIVE: To evaluate changes in laboratory human papillomavirus (HPV) testing patterns in laboratories incorporating HPV testing with Papanicolaou tests in 2012. DESIGN: Data were analyzed from the CAP HPV Supplemental Questionnaire distributed to 1771 laboratories participating in either CAP HPV or CAP Papanicolaou proficiency testing in 2013. RESULTS: A total of 1022 laboratories (58%) responded. There were more high-risk (HR) HPV tests performed per institution as compared to previous surveys. There were more HPV tests performed within an institution as compared to previous surveys. Hybrid Capture 2 (HC2) remains the most common method (42.4%, 239 of 564); Cervista and cobas methods are used in 37.2% (210 of 564) and 14.9% (84 of 564) of laboratories, respectively. Human papillomavirus testing is offered as a reflex test after a Papanicolaou test result of atypical squamous cells of undetermined significance (ASC-US) in 89.6% of laboratories (476 of 531); as a cotest for women aged 30 years and older in 60.3% (404 of 531); as reflex testing after atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) in 42.7% (320 of 531); and as reflex testing after atypical glandular cells (AGC) in 27.3% (145 of 531). The HPV-positive rates for ASC-US and ASC-H were similar in 2012 and 2006. Cervista (49.2%, 88 of 179) and Roche cobas (27.4%, 49 of 179) are the most common methods used for genotyping. Most laboratories use the CAP Human Papillomavirus for Cytology Program for proficiency testing. CONCLUSIONS: There was an increase in annual volume of HR-HPV testing with a shift toward in-house HR-HPV testing. Genotyping volumes also increased. HC2 and Cervista are most commonly used, with an increasing volume of Roche cobas testing. The most common indication for HPV testing among all laboratories was ASC-US reflex testing, but an increase in HPV cotesting was observed. The data provide an update into persisting and newer trends in HPV testing practices.

Pseudomembranous tracheobronchitis caused by Rhizopus sp. After allogeneic stem cell transplantation.

Invasive fungal infections are a major cause of morbidity and mortality in allogeneic stem cell transplant recipients. They can occasionally involve the tracheobronchial tree with serious clinical consequences. Tracheobronchial involvement is often an unexpected finding during diagnostic bronchoscopy. Herein, we report a case of pseudomembranous tracheobronchitis caused by Rhizopus sp. in an allogeneic stem cell transplant recipient.

Histologic characteristics of vaginal cuff tissue from patients with vaginal cuff dehiscence.

STUDY OBJECTIVE: To describe the histologic characteristics of vaginal tissue in patients with vaginal cuff dehiscence (VCD) after robotic hysterectomy and to compare this group with patients without dehiscence. DESIGN: Retrospective analysis (Canadian Task Force classification II-3). SETTING: Academic center. PATIENTS: Seven patients with VCD and 6 patients without VCD. INTERVENTIONS: Vaginal cuff tissue was obtained from all patients and was stained using hematoxylin-eosin and evaluated for acute and chronic inflammation markers including neutrophils, lymphocytes, and plasma cells. Immunohistochemical staining was performed and evaluated using the semiquantitative method for collagen types I and III, smooth muscle actin, and SM22α (myofibroblast) content. Grading was performed by 4 blinded investigators. The Mann-Whitney test was used to evaluate the 2 groups, and correlation coefficients for interobserver variability. MEASUREMENTS AND MAIN RESULTS: The VCD group, compared with the non-VCD group, demonstrated significantly greater numbers of neutrophils (1.71 vs 1.0; p = .04), lymphocytes (2.85 vs 1.33; p = .002), and plasma cells (2.2 vs 1.0; p = .001). There was no statistical difference between the groups in amounts of collagen I (1.71 vs 1.27; p = .09) and collagen III (1.66 vs 1.38; p = .37), smooth muscle actin (1.23 vs 1.33; p = .65), and SM22α (1.85 vs 1.27; p = .09). Interobserver variability was low (κ = 0.86; p = .76). CONCLUSION: Compared with the control group, patients with VCD demonstrated significantly higher levels of acute and chronic inflammatory cells. This finding suggests that a prolonged inflammatory phase may be delaying normal progression to reparation in patients with dehiscence.

Malignant peripheral nerve sheath tumors (MPNST): the Mayo Clinic experience.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are a rare form of soft tissue sarcoma with few studies reporting on patient outcomes and prognostic variables. METHODS: A retrospective review of 175 patients diagnosed with MPNST from 1985 to 2010 was performed. Patient, tumor, and treatment characteristics were evaluated to identify prognostic variables. RESULTS: The median age of our study population was 44 years, and 51% were female. Median tumor size was 6 cm, and 61% of patients had high-grade tumors. Tumors were most commonly located on the extremities (45%), then trunk (34%) and head/neck (19%). The majority of patients underwent surgical resection (95%) and adjuvant treatment with chemotherapy (6%), radiation (42%) or both (22%). Margin status was R0 in 69%, R1 in 2%, R2 in 9%, and unknown in 20%. The local recurrence rate was 22%, and 5- and 10-year disease-specific survival (DSS) were 60% and 45%, respectively. On univariate analysis, no predictors for local recurrence were identified. Tumor size ≥ 5 cm, high tumor grade, tumor location, presence of neurofibromatosis type 1, local recurrence, and adjuvant chemotherapy were all associated with DSS. On multivariate analysis, size ≥ 5 cm [hazard ratio (HR)= 6.1, 95% confidence interval (CI) 1.5-25.0], local recurrence (HR = 4.4, 95% CI 1.7-11.4), high tumor grade (HR = 3.8, 95% CI 1.1-13.2), and truncal location (HR = 3.7, 95% CI 1.1-12.7) were poor prognostic indicators for DSS. CONCLUSIONS: High tumor grade and tumor size ≥ 5 cm predict adverse DSS for MPNST. In the context of a multidisciplinary treatment regimen, local recurrence and survival outcomes at 5 and 10 years were better than previously reported for MPNST.

Cytologic features of epithelioid hemangioendothelioma.

To determine cytologic features of epithelioid hemangioendothelioma (EHE) that would enable accurate diagnosis, we evaluated fine-needle aspiration biopsy (FNAB) smears from 11 histologically confirmed EHEs. The variably cellular smears comprised dispersed single cells and occasional cell aggregates. Dense stromal fragments were present in association with some tissue fragments. The cells were epithelioid, containing moderate or large amounts of dense cytoplasm. Nuclei exhibited mild pleomorphism, and nuclear grooves were identified in all cases. At least occasional intranuclear pseudoinclusions (INPIs) and intracytoplasmic lumina (ICLs) were present in all cases and in 9 cases (82%), respectively, and rare erythrocytes were seen within ICLs in 5 cases (45%). Mitotic figures were identified in 4 cases (36%). The background was bloody in 6 cases (55%) and contained hemosiderin and/or hemosiderin-laden macrophages in 5 cases (45%). The combination of the following features in FNAB samples should raise strong suspicion for EHE: predominantly dispersed single cells with occasional cohesive cell clusters; epithelioid cytomorphology; dense cytoplasm with well-defined cytoplasmic borders; ICLs (with or without erythrocytes), INPIs, and nuclear grooves. The presence of these features should prompt correlation with clinical, radiologic, and histologic features and immunohistochemical evaluation using vascular markers.

Use of preoperative magnetic resonance imaging for invasive lobular cancer: good, better, but maybe not the best?

BACKGROUND: Invasive lobular cancer (ILC) of the breast is difficult to diagnose clinically and radiologically. It is hoped that preoperative magnetic resonance imaging (MRI) can improve evaluation of extent of disease. METHODS: Patients diagnosed with ILC at a single institution from 2001 to 2008 who underwent clinical breast examination (CBE), mammography, ultrasound, and MRI were studied retrospectively. Concordance between tumor size on imaging/CBE and pathologic size was defined as size within ± 0.5 cm. Pearson correlation coefficients (R) were calculated for each modality. Local recurrence and re-excision rates were compared with those patients with ILC who did not undergo preoperative MRI. RESULTS: Seventy patients with ILC had all imaging modalities, including CBE, performed preoperatively. The sensitivity for detection of ILC by MRI was 99%. MRI-based tumor size was concordant with pathologic tumor size in 56% of tumors. MRI overestimated tumor size by >0.5 cm in 31% of tumors. Correlation of tumor size on imaging with final pathology was better for MRI (R = 0.75) than for mammography (R = 0.65), CBE (R = 0.63), or ultrasound (R = 0.45, all P < 0.01). Preoperative MRI was associated with lower reoperation rates for close/positive margins (P > 0.05). CONCLUSIONS: For ILC, MRI has better sensitivity of detection and correlation with tumor size at pathology than CBE, mammography, or ultrasound. However, 31% of cases are overestimated by MRI, and correlation remains only at 0.75. The select use of MRI for preoperative estimation of tumor size in ILC is supported by our data, but the need for improvement and refinement of imaging remains.

The natural history of a branch duct intraductal papillary mucinous neoplasm in a patient with Lady Windermere syndrome: a case report.

CONTEXT: "Low-risk" branch duct intraductal papillary mucinous neoplasm (IPMN) is defined as pancreatic epithelial cellular proliferation of small branch ducts that lack malignant characteristics. At present, our understanding of the natural history of "low-risk" branch duct IPMN is still evolving. Lady Windermere syndrome is a disorder seen in non-smoking women with no pre-existing pulmonary disease affecting the lingula and/or right middle lobe with Mycobacterium avium-intracellulare complex. We present a case with pancreatic adenocarcinoma after a six-year surveillance of "low-risk" branch duct IPMN in an asymptomatic elderly white woman with Lady Windermere syndrome. CASE REPORT: A 79-year-old woman was referred to our institution because of pancreatic cystic abnormalities and elevated carbohydrate antigen 19-9 (CA 19-9). While at our institution, she was also diagnosed with Lady Windermere syndrome. Multiple abdominal imaging studies, endoscopic retrograde cholangiopancreatography, computer tomography, and magnetic resonance cholangiopancreatography (MRCP) were performed in the ensuing 6 years, all consistent with "low-risk" branch duct IPMN. No progression was seen until year 6 when MRCP showed a 2 cm pancreatic cancer. Because of multiple comorbidities, the patient chose chemotherapy over a pancreaticoduodenectomy. She developed respiratory failure and died after one cycle of gemcitabine. CONCLUSIONS: "Low-risk" branch duct IPMN may be a heterogeneous disease in which some cases can transform into malignant pancreatic neoplasms despite the absence of the so-called "high risk" features on imaging studies. Clinical management, therefore, requires individualized flexibility. In addition, when there is coexistence of Lady Windermere syndrome and pancreatic cancer, prompt diagnosis and treatment of Lady Windermere syndrome should be considered prior to chemoradiotherapy or surgery.

Special variants of differentiated thyroid cancer: does it alter the extent of surgery versus well-differentiated thyroid cancer?

INTRODUCTION: Recently, more aggressive variants of so-called well-differentiated thyroid carcinomas have been identified such as the tall cell variant, columnar cell variant, diffuse sclerosing variant, insular carcinoma, and Hürthle cell (oncocytic, oxyphilic) carcinomas. METHODS: An evidence-based review was performed to identify the optimal treatment recommendations for these thyroid cancers of intermediate differentiation. CONCLUSIONS: Although some variation exists within the group, aggressive surgical and medical management are recommended for these neoplasias. Any such recommendations should, however, be viewed in the light of the fact that the current literature mainly consists of case reports, case series, and limited reviews. The clinical presentation, pathophysiology, diagnosis, and surgical and medical management for these thyroid cancers with intermediate differentiation are discussed.

Gene expression profiling of benign and malignant pheochromocytoma.

There are currently no reliable diagnostic and prognostic markers or effective treatments for malignant pheochromocytoma. This study used oligonucleotide microarrays to examine gene expression profiles in pheochromocytomas from 90 patients, including 20 with malignant tumors, the latter including metastases and primary tumors from which metastases developed. Other subgroups of tumors included those defined by tissue norepinephrine compared to epinephrine contents (i.e., noradrenergic versus adrenergic phenotypes), adrenal versus extra-adrenal locations, and presence of germline mutations of genes predisposing to the tumor. Correcting for the confounding influence of noradrenergic versus adrenergic catecholamine phenotype by the analysis of variance revealed a larger and more accurate number of genes that discriminated benign from malignant pheochromocytomas than when the confounding influence of catecholamine phenotype was not considered. Seventy percent of these genes were underexpressed in malignant compared to benign tumors. Similarly, 89% of genes were underexpressed in malignant primary tumors compared to benign tumors, suggesting that malignant potential is largely characterized by a less-differentiated pattern of gene expression. The present database of differentially expressed genes provides a unique resource for mapping the pathways leading to malignancy and for establishing new targets for treatment and diagnostic and prognostic markers of malignant disease. The database may also be useful for examining mechanisms of tumorigenesis and genotype-phenotype relationships. Further progress on the basis of this database can be made from follow-up confirmatory studies, application of bioinformatics approaches for data mining and pathway analyses, testing in pheochromocytoma cell culture and animal model systems, and retrospective and prospective studies of diagnostic markers.