Indeterminate and erroneous fine-needle aspirates of breast with focus on the 'true gray zone': a review.

OBJECTIVE: To review our experience and the literature on inconclusive/erroneous fine-needle aspirates (FNAs) of breast with the focus on the 'true gray zone'. To describe the cytology, differential diagnosis, pitfalls and limitations of common and rare lesions. STUDY DESIGN: We conducted a literature search focusing on breast FNAs with statistical data of C3 and C4 categories including false-positive and false-negative cases. Similar data from 2003 to 2009 was obtained from our institution. RESULTS: C3 and C4 categories account for 3-17% of breast FNAs. Contributing factors are technical difficulties, inexperienced pathologists interpreting FNAs of breast and overlap of cytologic features of certain benign and malignant conditions; this last, 'true gray zone' accounts for 2% of cases. Fibroadenoma, proliferative breast lesions, gynecomastia, infiltrating and in situ low-grade adenocarcinomas and tubular, cribriform, lobular and mucinous carcinomas are the most common problematic lesions. Granular cell tumor, adenomyoepithelioma, pregnancy-related lesions, fat necrosis, inflammatory and radiation changes, adenoid cystic carcinoma, spindle-cell lesions and Phyllodes tumor are less common. CONCLUSION: Inconclusive/erroneous FNAs of breast due to the 'true gray zone' are rare. Most are due to the overlapping cytologic features of some benign and malignant conditions. Practical features that may help arrive at the correct diagnoses are elucidated.

Clinicopathologic characteristics of carcinomas that develop after a biopsy containing columnar cell lesions: evidence against a precursor role.

BACKGROUND: Columnar cell lesions are frequently associated with atypical ductal hyperplasia, lobular neoplasia, and tubular carcinoma, and have been suggested as a precursor lesion for low-grade carcinomas. However, in long-term follow-up studies, columnar cell lesions are associated with only a slight increase in later breast cancer development. If columnar cell lesions are precursor lesions, one would expect subsequent cancers to develop at the same site as the biopsy and to be preferentially of low grade. The goal of this article is to review the clinical and pathologic features of carcinomas that develop after a diagnosis of columnar cell lesion to try to establish whether these lesions are precursors to low-grade invasive carcinoma. METHODS: The authors reviewed biopsies containing columnar cell lesions, using the criteria of Schnitt and Vincent-Salomon, from 77 women in the Nashville Breast Cohort who developed subsequent breast carcinoma. Clinicopathologic features including laterality, type, and grade of the subsequent cancer were recorded. RESULTS: Breast cancer developed a median of 11 years after initial biopsy. The median age at diagnosis was 60 years. The majority of invasive carcinomas were of no special type and of intermediate grade. Moreover, the carcinomas were as likely to occur in the contralateral breast as in the breast that was originally diagnosed with columnar cell lesion, regardless of columnar cell lesion subtype (P = .48). CONCLUSIONS: Carcinoma subsequent to columnar cell lesions may occur in either breast and tends to show a similar grade and type distribution as sporadic breast cancer. These findings argue against columnar cell lesions being a true precursor for low-grade invasive carcinoma.

Variability in hormone and growth factor receptor expression in primary versus recurrent, metastatic, and post-neoadjuvant breast carcinoma.

The introduction of selective molecular targeted therapy, specifically tamoxifen and trastuzumab, has significantly altered the clinical behavior of breast carcinoma. Several questions remain, however, regarding potential phenotypic drifts in estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor (Her-2/neu) expression between the primary and metastatic site. Whether patients should be tested for ER, PR, and Her-2/neu expression in the nodal or distant metastatic site, local recurrence and following neoadjuvant therapy, and whether this has an effect on prognosis remains elusive. A review of 45 studies addressing ER, PR, and Her-2/neu expression in lymph node metastasis, distant metastasis, local recurrence, and post-neoadjuvant therapy revealed the following average phenotypic drift in ER, PR, and Her-2/neu expression, respectively: 13.1 % (median = 10.0 %), 13.8 % (median = 16.0 %), and 7.7 % (median = 5.0 %) for lymph node metastasis; 21.8 % (median = 19.5 %), 30.8 % (median = 33.5 %), and 7.6 % (median = 6.1 %) for distant metastasis; 19.8 % (median = 13.4 %), 27.1 % (median = 28.6 %), and 6.6 % (median = 1.6 %) for local recurrence; and 12.9 % (median = 8.0 %), 32.0 % (median = 20.0 %), and 8.9 % (median = 0 %) post-neoadjuvant therapy. The above findings support the notion of re-evaluating ER, PR, and Her-2/neu expression in distant metastasis, lymph node metastasis and to a lesser extent local recurrence. The effects of neoadjuvant therapy on receptor expression are more pronounced for PR, which may have a prognostic role in therapy efficacy.

Clinicopathologic and immunohistochemical characteristics of male breast cancer: a single center experience.

Male breast cancer (MaleBC) is a rare tumor that has been insufficiently described in the Middle East. The purpose of this study is to report the first MaleBC series in Lebanon, describing its clinicopathologic and immunohistochemical phenotype, and how it compares with MaleBC in the West and with female breast cancer in Lebanon and the Middle East. Forty-seven cases of MaleBC were reviewed. Results showed younger ages at presentation (62 years versus 67 years), higher incidence of lobular carcinoma (6% versus 1%), and more frequent p53 positivity and axillary node metastases in our series than in those reported about MaleBC. Other results such as higher estrogen receptor (ER) positivity and lower HER-2/neu over-expression were comparable to the literature. These findings suggest that MaleBC in our region may represent a biologically different tumor with potentially distinct prognostic and therapeutic implications.

Autofluorescence and diffuse reflectance spectroscopy and spectral imaging for breast surgical margin analysis.

BACKGROUND AND OBJECTIVE: Most women with early stage breast cancer have the option of breast conserving therapy, which involves a partial mastectomy for removal of the primary tumor, usually followed by radiotherapy. The presence of tumor at or near the margin is strongly correlated with the risk of local tumor recurrence, so there is a need for a non-invasive, real-time tool to evaluate margin status. This study examined the use of autofluorescence and diffuse reflectance spectroscopy and spectral imaging to evaluate margin status intraoperatively. MATERIALS AND METHODS: Spectral measurements were taken from the surface of the tissue mass immediately following removal during partial mastectomies and/or from tissues immediately after sectioning by surgical pathology. A total of 145 normal spectra were obtained from 28 patients, and 34 tumor spectra were obtained from 12 patients. RESULTS: After correlation with histopathology, a multivariate statistical algorithm classified the spectra as normal (negative margins) or tumor (positive margins) with 85% sensitivity and 96% specificity. A separate algorithm achieved 100% classification between neo-adjuvant chemotherapy-treated tissues and non-treated tissues. Fluorescence and reflectance-based spectral images were able to demarcate a calcified lesion on the surface of a resected specimen as well. CONCLUSION: Fluorescence and reflectance spectroscopy could be a valuable tool for examining the superficial margin status of excised breast tumor specimens, particularly in the form of spectral imaging to examine entire margins in a single acquisition.

Ratio between positive lymph nodes and total excised axillary lymph nodes as an independent prognostic factor for overall survival in patients with nonmetastatic lymph node-positive breast cancer.

BACKGROUND: The status of the axillary lymph nodes in nonmetastatic lymph node-positive breast cancer (BC) patients remains the single most important determinant of overall survival (OS). Although the absolute number of nodes involved with cancer is important for prognosis, the role of the total number of excised nodes has received less emphasis. Thus, several studies have focused on the utility of the axillary lymph node ratio (ALNR) as an independent prognostic indicator of OS. However, most studies suffered from shortcomings, such as including patients who received neoadjuvant therapy or failing to consider the use of adjuvant therapy and tumor receptor status in their analysis. METHODS: We conducted a single-center retrospective review of 669 patients with nonmetastatic lymph node-positive BC. Data collected included patient demographics; breast cancer risk factors; tumor size, histopathological, receptor, and lymph node status; and treatment modalities used. Patients were subdivided into four groups according to ALNR value (< .25, .25-.49, .50-.74, .75-1.00). Study parameters were compared at the univariate and multivariate levels for their effect on OS. RESULTS: On univariate analysis, both the absolute number of positive lymph nodes and the ALNR were significant predictors of OS. On multivariate analysis, only the ALNR remained an independent predictor of OS, with a 2.5-fold increased risk of dying at an ALNR of >or= .25. CONCLUSIONS: Our study demonstrates that ALNR is a stronger factor in predicting OS than the absolute number of positive axillary lymph nodes.

Severe hemophagocytic syndrome developing after treatment initiation for disseminated Mycobacterium tuberculosis: case report and literature review.

We describe a case of a young male with disseminated tuberculosis and severe secondary hemophagocytic syndrome. He presented with symptoms of tuberculosis and Mycobacterium tuberculosis was diagnosed. Later, while on anti-tuberculous treatment, he developed pancytopenia and bone marrow aspirate showed large macrophages with increased phagocytosis of mature and immature blood elements typical of hemophagocytic syndrome.

Prognostic significance of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase-1 (IDH-1) mutation in glioblastoma multiforme patients: A single-center experience in the Middle East region.

OBJECTIVES: To determine the prevalence and prognostic value of MGMT promoter methylation and IDH1 mutation in glioblastoma multiforme (GBM) patients from the Middle East. PATIENTS AND METHODS: Records of patients diagnosed between 2003 and 2015 were reviewed. MGMT promoter methylation was measured using methylation-specific polymerase chain reaction and IDH-1 mutation was reported. The primary endpoint was overall survival (OS). RESULTS: A total of 110 patients were included. The median age was 51 years and 71 patients (64.5%) were males. The median diameter of GBM was 4.6 cm and 29 patients (26.4%) had multifocal disease. Gross total resection was achieved in 38 patients (24.9%). All patients received adjuvant radiation therapy, and 96 patients (91.4%) received concomitant temozolomide. At a median follow up of 13.6 months, the median OS was 17.2 months, and the OS at 1 and 2 years were 71.6% and 34.8%, respectively. On multivariate analysis, age at diagnosis (HR 1.019; P = 0.044) and multifocality (HR 2.373; P = 0.001) were the only independent prognostic variables. MGMT promoter methylation was found in 28.2% of patients but did not significantly correlate with survival (HR 1.160; P = 0.635). IDH-1 mutation was found in 10% of patients was associated with a non-significant trend for survival improvement (HR 0.502; P = 0.151). CONCLUSION: Patients with GBM from the Middle East have adequate survival outcomes when given the optimal treatment. In our patient population, MGMT promoter methylation did not seem to correlate with outcomes, but patients with IDH1 mutation had numerically higher survival outcomes.

Comparison of autofluorescence, diffuse reflectance, and Raman spectroscopy for breast tissue discrimination.

For a given diagnostic problem, important considerations are the relative performances of the various optical biopsy techniques. A comparative evaluation of fluorescence, diffuse reflectance, combined fluorescence and diffuse reflectance, and Raman spectroscopy in discriminating different histopathologic categories of human breast tissues is reported. Optical spectra were acquired ex vivo from a total of 74 breast tissue samples belonging to 4 distinct histopathologic categories: invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), fibroadenoma (FA), and normal breast tissue. A probability-based multivariate statistical algorithm capable of direct multiclass classification was developed to analyze the diagnostic content of the spectra measured from the same set of breast tissue sites with these different techniques. The algorithm uses the theory of nonlinear maximum representation and discrimination feature for feature extraction, and the theory of sparse multinomial logistic regression for classification. The results reveal that the performance of Raman spectroscopy is superior to that of all others in classifying the breast tissues into respective histopathologic categories. The best classification accuracy was observed to be approximately 99%, 94%, 98%, and 100% for IDC, DCIS, FA, and normal breast tissues, respectively, on the basis of leave-one-sample-out cross-validation, with an overall accuracy of approximately 99%.

Dysregulated human myeloid nuclear differentiation antigen expression in myelodysplastic syndromes: evidence for a role in apoptosis.

Reduced levels of human myeloid nuclear differentiation antigen (MNDA) gene transcripts have been detected in both familial and sporadic cases of myelodysplastic syndromes (MDS). Numerous reports implicate elevated apoptosis/programmed cell death and death ligands and their receptors in the pathogenesis of MDS. MNDA and related proteins contain the pyrin domain that functions in signaling associated with programmed cell death and inflammation. We tested the hypothesis that MNDA is involved in the regulation of programmed cell death in human myeloid hematopoietic cells. Clones of K562 cells (MNDA-null) that expressed ectopic MNDA protein were established using retroviral transduction. MNDA-expressing K562 clones were resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis, but were not protected from programmed cell death induced with genotoxic agents or H(2)O(2). MNDA protein expression assessed in control and intermediate and high-grade MDS marrows showed several patterns of aberrant reduced MNDA. These variable patterns of dysregulated MNDA expression may relate to the variable pathophysiology of MDS. We propose that MNDA has a role regulating programmed cell death in myeloid progenitor cells, and that its down-regulation in MDS is related to granulocyte-macrophage progenitor cell sensitivity to TRAIL-induced programmed cell death.

Concordance between Immunohistochemistry and Microarray Gene Expression Profiling for Estrogen Receptor, Progesterone Receptor, and HER2 Receptor Statuses in Breast Cancer Patients in Lebanon.

INTRODUCTION: Accurate evaluation of estrogen and progesterone receptors and HER2 is critical when diagnosing invasive breast cancer for optimal treatment. The current evaluation method is via immunohistochemistry (IHC). In this paper, we compared results of ER, PR, and HER2 from microarray gene expression to IHC in 81 fresh breast cancer specimens. METHODS: Gene expression profiling was performed using the GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix Inc). Immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2 status was performed using standard methods at a CAP-accredited pathology laboratory. Concordance rates, agreement measures, and kappa scores were calculated for both methods. RESULTS: For ER, Kappa score was 0.918 (95% CI, 0.77.3-1.000) and concordance rate was 97.5% (95% CI, 91.4%-99.7%). For PR, Kappa score was 0.652 (95% CI, 0.405-0.849) and concordance rate was 86.4% (95% CI, 77%-93%). For HER2, Kappa score was 0.709 (95% CI, 0.428-0.916) and concordance rate was 97.5% (95% CI, 91.4%-99.7%). CONCLUSION: Our results are in line with the available evidence with the concordance rate being the lowest for the progesterone receptor. In general, microarray gene expression and IHC proved to have high concordance rates. Several factors can increase the discordance rate such as differences in sample processing.

Genomics and premalignant breast lesions: clues to the development and progression of lobular breast cancer.

Advances in genomic technology have improved our understanding of the genetic events that parallel breast cancer development. Because almost all mammary carcinomas develop in the terminal duct lobular units of the breast, understanding the events involved in mammary gland development make it possible to recognize those events that, when altered, contribute to breast neoplasia. In this review we focus on lobular carcinomas, discussing the pathology, development, and progression of premalignant lobular lesions from a genomic point of view. We highlight studies utilizing genomic approaches and describe how these investigations have furthered our understanding of the complexity of premalignant breast lesions.

Mesothelial Cells Within Vascular Transformation of Mediastinal Lymph Node Sinuses: An Unusual Benign Collision Mimicking Colliding Malignancies.

Vascular transformation of lymph node sinuses represents a rare benign entity mimicking malignant counterparts such as nodal Kaposi sarcoma. The presence of mildly atypical benign mesothelial cells within nodal sinuses raises the possibility of metastatic malignancy. Herein, a rare case of vascular transformation of lymph node sinuses with reactive sinusoidal mesothelial cells is outlined as a unique benign pathology and a potential mimicker of a malignant collision tumor.

Follicular dendritic cell sarcoma of the head and neck expressing thyroid transcription factor-1: a case report with clinicopathologic and immunohistochemical literature review.

Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm of follicular dendritic cells, most commonly affecting the lymph nodes and extranodal soft tissues of the head and neck, but also potentially arising in any visceral organ. FDCS with its diverse morphologies raises an occasionally challenging differential of primary and metastatic tumors with overlapping histologic and immunohistochemical features. When involving the head and neck, FDCS may be confused with squamous cell carcinoma, undifferentiated carcinoma, extracranial meningioma, and variants of papillary thyroid carcinoma. We describe here a case of FDCS showing nuclear grooves, intranuclear pseudoinclusions, diffuse epithelial membrane antigen and focal cytokeratin staining, and the first documented report of positivity for thyroid transcription factor-1. A discussion of the differential diagnosis and potential diagnostic pitfalls in FDCS brought forth by thyroid transcription factor-1 immunoreactivity and a full review of clinicopathologic and immunohistochemical features of head and neck FDCS are presented.

Inconclusive or erroneous fine-needle aspirates of breast with adequate and representative material: a cytologic/histologic study.

Adequately cellular and representative fine-needle aspirates (FNAs) of breast have a high diagnostic accuracy. There is, however, a recognized category designated as "gray zone" where a definitive diagnosis cannot be reached. We reviewed our experience in this category to identify useful diagnostic parameters. Twenty-four such FNAs with surgical follow-up were retrieved from AUBMC files (2003-2009). Cytology slides were reviewed blindly. All cases were females, 29-73 years. There were three erroneous and 21 inconclusive diagnoses. The majority (15) was invasive adenocarcinomas: two cribriform, four tubular, one lobular, and eight not otherwise specified. The remaining cases were papillary and fibroepithelial tumors (three each), ductal carcinoma in situ, cribriform (two), and one adenomyoepithelioma (AME). Useful diagnostic features included: (1) Biphasic cell population with focal nuclear atypia and intranuclear and cytoplasmic vacuolar inclusions (AME). (2) Complex clusters of epithelial cells with cribriform architecture (cribriform carcinoma). (3) Rigid tubular epithelial structures with abrupt change in diameter, ending in pointed tips with abnormal branching (tubular carcinoma). (4) Cellular stromal fragments (fibroepithelial tumors). (5) Papillary fibrovascular cores, columnar cells, and three-dimensional papillary epithelial fragments (papillary tumors). Myoepithelial cells classically described in benign aspirates were not always a discriminatory factor. The "gray zone" in breast FNA is usually due to overlapping cytologic features of some benign and malignant lesions. Useful distinguishing cytologic features are described.

Adult ocular toxocariasis mimicking ciliary body malignancy.

Purpose. To discuss an unusual presentation of ocular toxocariasis. Methods. Case report. Results. A 40-year-old woman presented with decreased vision in the left eye with a long history of recurrent red eye from uveitis. Eosinophilia and positive ELISA titers for Toxocara canis favored the diagnosis of ocular toxocariasis. Over 3 months, an anterior scleral mass had a rapid growth raising the possibility of medulloepithelioma, which rarely can mimic uveitic syndromes. Surgical plan changed from local excision to enucleation. Histopathology demonstrated a large homogeneous mass of chronic inflammatory cells with inflammation of the overlying thinned out sclera, medial rectus insertion, and limbal cornea. The triad of peripheral granuloma, eosinophilia, and positive blood serology established the diagnosis of ocular toxocariasis. Conclusions. Ocular toxocariasis can mimic ocular malignancy such as medulloepithelioma in adults and rarely presents as an anterior scleral mass.

Intranodal papillary epithelial proliferations: a local process with a spectrum of morphologies and frequent association with papillomas in the breast.

Lymph nodes, particularly those draining in major anatomic sites like axilla, pelvis, and neck are potential sites for the occasional presence of ectopic tissue, usually representative of the organ being drained. Owing to the uncertainty surrounding the processes causing such findings, and particularly in the setting of lymph node dissection and sampling for cancer staging, intranodal epithelial inclusions, rare as they may be, might be fertile soil for overdiagnosis of metastatic disease. Intranodal papillary inclusions are particularly problematic and challenging because of their complex architecture that may easily mimic a metastasis. From the files of the Breast Consultation Service, Department of Pathology at the Vanderbilt University Medical Center in Nashville, we identified 6 cases in which histopathologic examination of axillary lymph nodes revealed intranodal papillary inclusions (papillary epithelial proliferations). One case showed atypical ductal hyperplasia, 1 showed low-grade ductal carcinoma in situ, and 1 showed usual ductal hyperplasia. The corresponding breast lesions were papillomas in 5 of 6 cases, 2 of which displayed atypical ductal hyperplasia, whereas 3 showed low-grade ductal carcinoma in situ. One case showed intermediate-grade invasive ductal carcinoma, and the associated intranodal papilloma lacked atypia. Our findings suggest that intranodal papillary proliferations are often, although not exclusively, associated with papillary and noninvasive breast neoplasms, hence highlighting the origin of these intranodal lesions as independent de novo nodal processes rather than metastatic deposits.

Nerve sheath tumor with degenerative atypia and multivacuolated lipoblasts.

Lipoblastic nerve sheath tumor is a recently described benign soft tissue tumor consisting of lipoblasts in a neural/schwannian background. The 6 reported cases have exclusively comprised signet ring lipoblasts and showed no cellular atypia. The authors describe the first lipoblastic nerve sheath tumor to harbor multivacuolated lipoblasts and degenerative atypia, underscoring its important differential diagnosis with well-differentiated liposarcoma. The purpose of this report is to expand the morphologic spectrum of this unusual neoplasm, and reemphasize the potential of benign nonadipocytic tumors to harbor multivacuolated lipoblasts and mimic liposarcoma.

Ratio between positive lymph nodes and total excised axillary lymph nodes as an independent prognostic factor for overall survival in patients with nonmetastatic lymph node-positive breast cancer.

BACKGROUND.: The status of the axillary lymph nodes in nonmetastatic lymph node-positive breast cancer (BC) patients remains the single most important determinant of overall survival (OS). Although the absolute number of nodes involved with cancer is important for prognosis, the role of the total number of excised nodes has received less emphasis. Thus, several studies have focused on the utility of the axillary lymph node ratio (ALNR) as an independent prognostic indicator of OS. However, most studies suffered from shortcomings, such as including patients who received neoadjuvant therapy or failing to consider the use of adjuvant therapy and tumor receptor status in their analysis. METHODS.: We conducted a single-center retrospective review of 669 patients with nonmetastatic lymph nodepositive BC. Data collected included patient demographics; breast cancer risk factors; tumor size, histopathological, receptor, and lymph node status; and treatment modalities used. Patients were subdivided into four groups according to ALNR value (<.25, .25-.49, .50-.74, .75-1.00). Study parameters were compared at the univariate and multivariate levels for their effect on OS. RESULTS.: On univariate analysis, both the absolute number of positive lymph nodes and the ALNR were significant predictors of OS. On multivariate analysis, only the ALNR remained an independent predictor of OS, with a 2.5-fold increased risk of dying at an ALNR of ≥.25. CONCLUSIONS.: Our study demonstrates that ALNR is a stronger factor in predicting OS than the absolute number of positive axillary lymph nodes.