HER2 testing across practices-Have we come to a consensus on the ideal method of testing? A systematic literature review.

Human epidermal growth factor (HER2) is an oncogene that codes for HER2 protein. The gene is amplified, and protein is overexpressed in 20% of patients and carries a poor prognosis. HER2-positive tumors tend to be more aggressive and highly proliferative. In 2006, trastuzumab, a monoclonal antibody targeting HER2, was approved for use with chemotherapy as an adjuvant treatment for women with HER2-positive breast cancer. The drug has shown improved survival rates for women with HER2-positive breast cancer. As promised for survival in HER2-positive patients continues with new research, and as novel drug approvals emerge, HER2 assessment plays a significant role in adjuvant and in metastatic setting. HER2 assays approved by the US Food and Drug administration include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and bright field dual in situ hybridization (DISH). Accuracy of HER2 testing across laboratories has an impact on treatment as false-negative testing can deprive the patients of trastuzumab therapy. The current review will focus on the variability of HER2 testing across laboratories and the potential impact on treatment.

Interobserver Reproducibility Among Gynecologic Pathologists in Diagnosing Heterologous Osteosarcomatous Component in Gynecologic Tract Carcinosarcomas.

Distinguishing hyalinized stroma from osteoid production by a heterologous osteosarcomatous component can be challenging in gynecologic tract carcinosarcomas. As heterologous components in a carcinosarcoma may have prognostic and therapeutic implications, it is important that these are recognized. This study examines interobserver reproducibility among gynecologic pathologists in the diagnosis of osteosarcomatous components, and its correlation with expression of the novel antibody SATB2 (marker of osteoblastic differentiation) in these osteosarcomatous foci. Digital H&E images from 20 gynecologic tract carcinosarcomas were reviewed by 22 gynecologic pathologists with a request to determine the presence or absence of an osteosarcomatous component. The 20 preselected cases included areas of classic heterologous osteosarcoma (malignant cells producing osteoid; n=10) and osteosarcoma mimics (malignant cells with admixed nonosteoid matrix; n=10). Interobserver agreement was evaluated and SATB2 scored on all 20 cases and compared with the original diagnoses. Moderate agreement (Fleiss' κ=0.483) was identified for the 22 raters scoring the 20 cases with a median sensitivity of 7/10 and a median specificity of 9/10 for the diagnosis of osteosarcoma. SATB2 showed 100% sensitivity (10/10) and 60% (6/10) specificity in discriminating classic osteosarcoma from osteosarcoma mimics. Utilizing negative SATB2 as a surrogate marker to exclude osteosarcoma, 73% (16/22) of the reviewers would have downgraded at least 1 case to not contain an osteosarcomatous component (range, 1-6 cases, median 1 case). Gynecologic pathologists demonstrate only a moderate level of agreement in the diagnosis of heterologous osteosarcoma based on morphologic grounds. In such instances, a negative SATB2 staining may assist in increasing accuracy in the diagnosis of an osteosarcomatous component.

Survival outcomes in endometrial cancer patients are associated with CXCL12 and estrogen receptor expression.

CXCL12 is a chemotactic cytokine that has pro-metastatic functions in several malignancies through interactions with its receptor, CXCR4. CXCL12 is an estrogen-regulated gene, and notably, estrogen is a major risk factor for endometrial cancer (EC) development. As few studies examine concurrent CXCL12, CXCR4, and estrogen receptor (ER) expression in EC patients, we examined this pathway in 199 EC patients with data from the University of Pittsburgh Medical Center Cancer Registry. Immunohistochemistry (IHC) was used to detect CXCR4, CXCL12 and ER protein expression. As CXCR4 expression was positive in all cases, this investigation focused on associations between CXCL12 and ER expression, clinicopathologic factors and survival outcomes using chi-square tests, Kaplan-Meier graphs, and log-rank tests. CXCL12 expression was negative in 63 cases (32%) and positive in 136 cases (68%). Negative CXCL12 expression was borderline significantly associated with metastasis (χ(2) p = 0.07). ER expression was negative in 75 cases (38%) and positive in 124 cases (62%). Positive ER expression was significantly associated with low grade and early stage tumors (χ(2) p < 0.001). CXCL12 and ER were not significantly associated (χ(2) p = 0.11). Positive CXCL12 expression was associated with longer overall survival (OS) (log-rank p = 0.006) and longer recurrence-free survival (RFS) (log-rank p = 0.01) in ER negative patients, but not in ER positive patients. We identified a unique molecular signature associated with better OS and RFS in EC patients. In addition to pathological characteristics of the tumor, expression of CXCL12 and ER may be clinically useful for assigning adjuvant treatment to EC cases.

Risk of malignancy when microscopic radial scars and microscopic papillomas are found at percutaneous biopsy.

OBJECTIVE: The objective of our study was to assess the incidence of associated malignancy when microscopic radial scars and microscopic intraductal papillomas are encountered at percutaneous biopsy for lesions that otherwise reveal benign histopathology. MATERIALS AND METHODS: A search of the pathology database for the period from December 14, 2006, through December 21, 2009, identified patients with a microscopic radial scar, a microscopic intraductal papilloma, or both at percutaneous biopsy. Patients whose percutaneous biopsy was performed for a lesion that revealed carcinoma or a high-risk pathology result were excluded to avoid confounding bias, as were patients who had only imaging follow-up. Only patients who underwent surgery solely for the study lesion were included. The lesion type that prompted core biopsy, biopsy guidance and device, sample number, and surgical outcomes were recorded. The incidences of benign, high-risk, and malignant pathology findings from surgery were calculated. RESULTS: The search revealed 35 patients (18 microscopic radial scars, 17 microscopic papillomas) who underwent surgery solely for the study lesion. Stereotactic guidance was used for 15 (43%); ultrasound, for 12 (34%); and MRI, for eight (23%). At surgery, 12 patients (34%) had high-risk histopathology results and 23 (66%) had benign results. No study lesions were upgraded to malignancy. CONCLUSION: Our study found no evidence of associated malignancy at surgical excision when microscopic radial scars and microscopic intraductal papillomas were encountered at percutaneous biopsy in patients who otherwise had benign histopathology results; thus, routine imaging follow-up may be performed.

Serous fluid: Metastatic sarcomas, melanoma, and other non-epithelial neoplasms.

While most tumors metastatic to the serous membranes are of epithelial origin, cytologists should be aware that non-epithelial neoplasms can also cause malignant effusions including sarcomas, melanomas, germ cell tumors, and, more rarely, brain tumors. The differential diagnosis of a malignant effusion is accordingly broad, especially for the small round blue cell tumors that includes not only mesenchymal tumors, but also non-mesenchymal tumors, such as neuroblastoma and Wilms tumor. Diagnosing non-epithelial malignancies in effusion specimens based entirely upon their cytomorphologic features is difficult because these neoplasms often exhibit considerable morphological overlap and their cytomorphology can differ from the original tumor. As malignant cells have a tendency to round up in body fluids these non-epithelial neoplasms can therefore mimic reactive mesothelial cells and metastatic adenocarcinoma. The use of ancillary studies including immunostaining, FISH, and molecular studies is thus often critical to reach a definitive diagnosis. This review article will be incorporated finally as one of the chapters in CMAS (CytoJournal Monograph/Atlas Series) #2. It is modified slightly from the chapter by the initial authors in the first edition of Diagnostic Cytopathology of Serous Fluids.

Prognostic utility of the breast cancer index and comparison to Adjuvant! Online in a clinical case series of early breast cancer.

INTRODUCTION: Breast Cancer Index (BCI) combines two independent biomarkers, HOXB13:IL17BR (H:I) and the 5-gene molecular grade index (MGI), that assess estrogen-mediated signalling and tumor grade, respectively. BCI stratifies early-stage estrogen-receptor positive (ER+), lymph-node negative (LN-) breast cancer patients into three risk groups and provides a continuous assessment of individual risk of distant recurrence. Objectives of the current study were to validate BCI in a clinical case series and to compare the prognostic utility of BCI and Adjuvant!Online (AO). METHODS: Tumor samples from 265 ER+LN- tamoxifen-treated patients were identified from a single academic institution's cancer research registry. The BCI assay was performed and scores were assigned based on a pre-determined risk model. Risk was assessed by BCI and AO and correlated to clinical outcomes in the patient cohort. RESULTS: BCI was a significant predictor of outcome in a cohort of 265 ER+LN- patients (median age: 56-y; median follow-up: 10.3-y), treated with adjuvant tamoxifen alone or tamoxifen with chemotherapy (32%). BCI categorized 55%, 21%, and 24% of patients as low, intermediate and high-risk, respectively. The 10-year rates of distant recurrence were 6.6%, 12.1% and 31.9% and of breast cancer-specific mortality were 3.8%, 3.6% and 22.1% in low, intermediate, and high-risk groups, respectively. In a multivariate analysis including clinicopathological factors, BCI was a significant predictor of distant recurrence (HR for 5-unit increase = 5.32 [CI 2.18-13.01; P = 0.0002]) and breast cancer-specific mortality (HR for a 5-unit increase = 9.60 [CI 3.20-28.80; P < 0.0001]). AO was significantly associated with risk of recurrence. In a separate multivariate analysis, both BCI and AO were significantly predictive of outcome. In a time-dependent (10-y) ROC curve accuracy analysis of recurrence risk, the addition of BCI+AO increased predictive accuracy in all patients from 66% (AO only) to 76% (AO+BCI) and in tamoxifen-only treated patients from 65% to 81%. CONCLUSIONS: This study validates the prognostic performance of BCI in ER+LN- patients. In this characteristically low-risk cohort, BCI classified high versus low-risk groups with ~5-fold difference in 10-year risk of distant recurrence and breast cancer-specific death. BCI and AO are independent predictors with BCI having additive utility beyond standard of care parameters that are encompassed in AO.

Endometrial leukocyte subpopulations associated with Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis genital tract infection.

OBJECTIVE: The objective of the study was to characterize endometrial inflammation associated with common genital tract pathogens. STUDY DESIGN: The design of the study was the immunohistochemical characterization of the endometrial leukocyte subpopulations from 37 controls and 45 women infected with Chlamydia trachomatis, Neisseria gonorrhoeae, or Trichomonas vaginalis. RESULTS: Compared with uninfected women, endocervical infection with C trachomatis, N gonorrhoeae, or T vaginalis was associated with significant increases in endometrial T cells, B cells, plasma cells, and polymorphonuclear leukocytes. Even more substantial increases in T cell, B cell, and plasma cell numbers were detected among women infected endocervically and endometrially with C trachomatis. CONCLUSION: Because lower genital tract C trachomatis, N gonorrhoeae, or T vaginalis infections were associated with comparable increases in the same endometrial leukocyte subpopulations, our results suggest the underappreciated involvement of T vaginalis in upper genital tract inflammatory processes. The more robust inflammatory infiltrate associated with C trachomatis endometrial ascension may offer insight into host inflammatory responses associated with pelvic inflammatory disease development.

Comparison of survival outcomes between patients with malignant mixed mullerian tumors and high-grade endometrioid, clear cell, and papillary serous endometrial cancers.

INTRODUCTION: Malignant mixed mullerian tumors (MMMTs) are an aggressive subtype of endometrial cancer (EC). Previous studies compare survival between high-grade endometrioid (EM), clear cell (CC), and papillary serous (PS) ECs; yet few studies compare MMMTs to these aggressive subtypes. The goal of this study was to compare recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) among EC subtypes. METHODS: We conducted a retrospective cohort study of EC cases treated at Magee-Women's Hospital between 1996 and 2008. Kaplan-Meier estimates of RFS, DSS, and OS as well as and log-rank tests were used to compare survival distributions between histologic subtypes. Cox regression was used to estimate hazard ratios for histologic subtypes, adjusted for other significant prognostic factors. Interactions between histologic subtype and prognostic factors were examined to assess effect modification. RESULTS: This cohort included 81 MMMT (15%), 254 high-grade EM (46%), 73 CC (13%), and 147 PS (26%) cases. Compared to high-grade EM (6%) and CC (7%) cases, relatively more MMMT (12%) and PS (12%) cases were nonwhite. Stage differed significantly among the subtypes, with 36%, 34%, 37%, and 51% of MMMT, high-grade EM, CC, and PS cases, respectively, diagnosed at advanced late stage (P<0.001). Kaplan-Meier curves and log-rank tests showed similar RFS, DSS, and OS between MMMT, high-grade EM, CC, and PS cases stratified by stage. In adjusted Cox regression models, RFS and DSS were not significantly different between MMMT and other subtypes. High-grade EM cases had a significantly better OS compared to MMMT cases (HR, 0.63; 95% confidence interval [CI], 0.41-0.98). CONCLUSIONS: This is the first retrospective study to suggest that certain survival outcomes are similar among MMMT, high-grade EM, CC, and PS subtypes. Other large-scale studies are needed to confirm these findings.

Factors associated with Type I and Type II endometrial cancer.

OBJECTIVE: We investigated risk factors for Type II (n = 176) vs. Type I (n = 1,576) endometrial cancer (EC) in cases treated at Magee-Womens Hospital between 1996 and 2008. METHODS: Clinical data were available from the University of Pittsburgh Medical Center (UPMC) Network Cancer Registry. Logistic regression was used to estimate the adjusted odds of having Type II EC vs. Type I EC. Risk factors of interest in this analysis were age, race, body mass index (BMI), year of diagnosis, parity, menopausal status, and history of additional primary tumors. RESULTS: Relative to women with Type I EC, women with Type II EC were more likely to be older at diagnosis (OR: 1.03 per 1 year increase in age, 95% CI 1.01-1.05), of non-white race (OR: 2.95, 95% CI 1.66-5.27), have a history of additional primary tumors (OR: 1.56, 95% CI 1.05-2.32), and less likely to be obese (OR: 0.45, 95% CI 0.29-0.70). CONCLUSION: In this large retrospective cohort of patients with EC, the striking difference in risk factors associated with Type II vs. Type I tumors suggests that these subtypes represent different disease entities that require different treatment modalities. Currently, Type II cases have a significantly worse prognosis compared to Type I. Further characterization of risk factors associated with developing Type II tumors is needed to prevent this aggressive malignancy.

PAX 2: a novel Müllerian marker for serous papillary carcinomas to differentiate from micropapillary breast carcinoma.

Ovarian serous papillary carcinoma, although rarely metastasizing to the breast, is often challenging based on morphology alone, particularly from the micropapillary variant of breast carcinoma. Gross cystic disease fluid protein-15, although a specific marker, can be negative in up to 50% of breast carcinomas. Wilm's tumor gene 1 (WT-1) has been identified as a useful marker to differentiate metastatic ovarian serous papillary carcinoma from primary breast carcinoma; however, it has recently been shown in the micropapillary variant of the primary breast carcinoma making it a less specific marker. PAX 2, a nuclear transcription factor, was recently observed in ovarian serous papillary carcinomas. In this study of 89 breast carcinoma cases, 26 micropapillary carcinoma, and 63 nonmicropapillary carcinoma types were retrieved from our pathology archives, represented on a single tissue microarray (TMA) with a 3-fold redundancy (TMA-1, TMA-2). In addition, whole tissue sections of a variety of benign and neoplastic müllerian tissues were surveyed with the PAX 2 immunostain. All cases were stained with rabbit polyclonal PAX 2 antibody and, in addition, the 5 metastatic ovarian serous carcinoma cases were stained with WT-1 as well for comparison. Only nuclear staining was considered positive. All primary breast carcinomas represented on TMA-1 and TMA-2 were entirely negative for PAX 2 100% (89/89), whereas 100% (5/5) of all metastatic ovarian serous carcinomas showed moderate-to-strong staining. PAX 2 expression was comparable with WT-1 as well in the metastatic ovarian serous carcinoma group. We therefore conclude that PAX 2 is a promising new, sensitive, and specific müllerian immunomarker for ovarian serous carcinomas (primary and metastatic).

Lobular versus ductal breast neoplasms: the diagnostic utility of p120 catenin.

The distinction between lobular and ductal lesions of the breast is important in several circumstances. Diagnostic reproducibility of lobular versus ductal lesions, based on histology alone, is less than optimal. The proper distinction between atypical lobular hyperplasia, lobular carcinoma in situ and low-grade ductal carcinoma in situ is critical for patient management. Patients who have a core biopsy of invasive lobular carcinoma often have preoperative magnetic resonance imaging to prepare the surgeon for proper margin attainment. E-cadherin, a negative membrane marker for lobular neoplasia, is useful in the distinction of lobular versus ductal neoplasia, but as a negative marker, can be difficult to interpret in particularly challenging cases. In this study, we surveyed primary and metastatic ductal lesions (62) and lobular lesions (64) of the breast to determine if P120 catenin is useful in the diagnostic distinction between lobular and ductal neoplasia. Primary breast ductal and lobular preneoplastic and neoplastic lesions were immunostained with E-cadherin and P120ctn and independently classified as ductal or lobular lesions. In addition, a wide array of carcinomas of different types were surveyed with P120ctn in tissue microarrays to ascertain whether the cytoplasmic P120ctn immunostaining pattern observed in lobular neoplasia was unique. Accurate categorization of ductal versus lobular neoplasia in the breast with P120ctn immunostaining was effective in all cases. Separation of low-grade ductal carcinoma in situ from lobular neoplasia was efficient. Diagnostically, P120ctn was particularly useful in identifying early lesions of lobular neoplasia. Of the other tumors that may morphologically mimic lobular carcinoma, only the diffusely infiltrating variants of rectal and gastric carcinomas showed diffuse cytoplasmic P120ctn immunostaining. Caution should be exercised when examining tumors in metastatic sites with P120ctn, with the incorporation of an appropriate panel of immunostains.

The spectrum of morphomolecular abnormalities of the E-cadherin/catenin complex in pleomorphic lobular carcinoma of the breast.

Pleomorphic lobular carcinoma of the breast is a high nuclear grade variant of lobular carcinoma. E-cadherin, a tumor-invasion suppressor gene, codes for a transmembrane protein that functions in intercellular adhesion. The E-cadherin protein internal domain binds with alpha, beta, gamma, and p120 catenins to anchor the E-cadherin complex to the actin cytoskeleton of the cell. The E-cadherin gene is routinely mutated in lobular neoplasia. This study examines the morphomolecular spectrum of the components of the E-cadherin-catenin complex in lobular neoplasia. Fifteen cases of pleomorphic lobular neoplasia, 8 cases of classic lobular neoplasia and 4 ductal carcinomas were studied. Normal breast epithelium and invasive ductal carcinomas all showed intense linear cell membrane immunostaining with antibodies to E-cadherin, alpha, beta, gamma, and P120 catenins. Membrane immunostaining of the catenin antibodies in lobular neoplasia was negative, except for rare cases that displayed beaded or dotlike patterns. Cytoplasmic immunostaining patterns for all lobular lesions included coarse paranuclear granules of beta catenin or diffuse intense cytoplasmic staining for P120 catenin. These immunostaining patterns demonstrate that catenins alpha, beta, gamma, and p120 are routinely dislocated from the cell membrane into the cytoplasm in lobular neoplasia and that the disrupted catenin patterns parallel absence of membrane E-cadherin in all cases. The diffuse cytoplasmic immunostaining of p120 in lobular neoplasia may be useful diagnostically as a positive marker for lobular neoplasia.

Evaluation and significance of hyperchromatic crowded groups (HCG) in liquid-based paps.

OBJECTIVE: Hyperchromatic crowded groups (HCG), a term first introduced into the cytology literature by DeMay in 1995, are commonly observed in Pap tests and may rarely be associated with serious but difficult to interpret lesions. In this study, we specifically defined HCG as dark crowded cell groups with more than 15 cells which can be identified at 10x screening magnification. METHODS: We evaluated consecutive liquid-based (Surepath) Pap tests from 601 women (age 17-74 years, mean age 29.4 yrs) and observed HCG in 477 cases. In all 477 HCG cases, Pap tests were found to be satisfactory and to contain an endocervical sample. HCG were easily detectable at 10x screening magnification (size up to 400 um, mean 239.5 um) and ranged from 1 to 50 (mean 19.5) per Pap slide. RESULTS: HCG predominantly represented 3-Dimensional groups of endocervical cells with some nuclear overlap (379/477--79%), reactive endocervical cells with relatively prominent nucleoli and some nuclear crowding (29/477--6%), clusters of inflammatory cells (25/477--5.2%), parabasal cells (22/477--4.6%), endometrial cells (1/477--0.2%). Epithelial cell abnormalities (ECA) were present in only 21 of 477 cases (4.6%). 18 of 21 women with HCG-associated ECA were less than 40 years old; only 3 were = or > 40 years. HCG-associated final abnormal Pap test interpretations were as follows: ASCUS (6/21--28%), LSIL (12/21--57%), ASC-H (2/21--9.5%), and HSIL/CIN2-3 (3/21--14%). The association of HCG with ECA was statistically significant (p = 0.0174. chi-square test). In patients with ECA, biopsy results were available in 10 cases, and 4 cases of biopsy-proven CIN2/3 were detected. Among these four cases, HCG in the Pap tests, in retrospect represented the lesional high grade cells in three cases (one HSIL case and two ASC-H cases). Interestingly, none of the 124 cases without HCG were found to have an epithelial cell abnormality. CONCLUSION: We conclude: a. HCG are observed in a high proportion of cervical smears. b. In the vast majority of cases, HCG are benign. c. ECA were only observed in cases with HCG. This observation is consistent with the hypothesis that the presence of HCG in Pap tests most often represents adequate sampling of the transformation zone, thus increasing the chances of detecting an epithelial cell abnormality. d. Only a few cases with HCG were associated with a serious ECA, but careful scrutiny of all HCG appears warranted to avoid the potential diagnostic pitfall of a significant false negative interpretation.

Introduction of the Thin Prep Imaging System (TIS): experience in a high volume academic practice.

OBJECTIVE: Since the introduction of the liquid-based ThinPrep testing in 1996, most cytology laboratories across the country have adopted the liquid-based cytology (LBC) for Pap test screening. Subsequent to wide-spread adoption of the ThinPrep Pap test, the ThinPrep Imaging System (TIS) Cytyc Corp, Marlborough, MA was introduced to improve the accuracy and efficiency of screening interpretation. We report our initial experience with the TIS at Magee Women's Hospital. We introduced the TIS in December 2004. METHODS: The imager assisted Pap test results over the first 12 months (December 2004 to December 2005) of implementation were reviewed and analyzed. Our implementation protocol included each cytotechnologist manually prescreening 200 negative slides to gain experience with the imager slides and serve as a quality check for the TIS. We re-screened 3400 slides (200 slides each for 17 cytotechnologists) manually which were initially determined to be negative using the TIS. 104,457 Pap tests were imaged on the TIS. 95,899 manually screened Pap tests, 12 months prior to the introduction of the TIS (December 2003-November 2004) are taken as the historic control group for our study. RESULTS: The mean ASC-US rate employing the automated imager was 8.70% [9088/104,457]. The mean LSIL detection rate was 4.22% [4409/104,457]. The imager did not miss any detectable high-grade lesions during these months, with a HSIL (+) detection rate of 0.68% in comparison to 0.60% by manual screening confirmed by follow-up biopsies. The difference is statistically significant with a p value of 0.022. The definition of false negative rate for purposes of this study is calculated as the number of false negative cases identified out of number of negatives re-screened. The TIS false negative rate was estimated at 0.012% [4/3400]. CONCLUSION: The overall performance of the TIS in our lab appears to be highly satisfactory in terms of improving sensitivity in screening cervical precursor lesions. The increased accuracy of detection of HSIL indicates a positive impact of the TIS in our laboratory.

ASC-H in Pap test--definitive categorization of cytomorphological spectrum.

OBJECTIVE: The American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines for management of ASC-H is colposcopic examination followed by biopsy. HPV testing (HPVT) is recommended after a negative biopsy result. More definitive interpretation of ASC-H could prevent discomfort and minimize the cost. The purpose of this study was to evaluate association of various cytomorphological patterns of ASC-H with various clinical scenarios. METHODS: We reviewed SurePath (TriPath Imaging, Inc. Burlington, NC, USA) cervical smears interpreted as ASC-H in 161 women (mean age, 37 {15 to 78} years), over 24 months (2002 to 2003). HPVT (Digene, Hybrid Capture II HPV test, Digene Corporation, Gaithersburg, MD, USA) was performed in 20% of cases (33/161) and biopsy results were available in 54 cases (19 with and 35 without HPVT). RESULTS: HPVT was positive in 64% (21/33) cases, and negative in 36% (12/33) cases. In the follow-up biopsies of 71% (15/21) of cases with positive HPVT, 27% showed HPV changes or CIN1, 27% showed CIN2-3, and 46% were negative for epithelial abnormality. Follow-up biopsies from cases with negative HPVT (33%, 4/12 cases), 8% showed CIN1 and 25% were negative for any epithelial abnormality. Six cytomorphological patterns of ASC-H correlated with different clinical categories in relation to HPVT and biopsy results. 35% (19 out of 54 ASC-H cases in which biopsy results were available) could be interpreted definitively as HSIL by cytopathology, 11% (6/54) cases as LSIL with cyanophilic atypical parakeratotic pattern, and 31% (17/54) cases as reactive, with HPV status. The interpretation had to be continued as ASC-H in 22% (12/54) cases. CONCLUSION: ASC-H demonstrated a spectrum of cytomorphological patterns. Some of these patterns in liquid-based cervical smears may be more specifically interpreted as LSIL, HSIL, or benign if HPV status is known.

FNAB cytology of extra-cranial metastasis of glioblastoma multiforme may resemble a lung primary: a diagnostic pitfall.

BACKGROUND: As extra-cranial metastasis of glioblastoma multiforme (GBM) is rare, it may create a diagnostic dilemma especially during interpretation of fine needle aspiration biopsy (FNAB) cytology. CASE PRESENTATION: We present transbronchial FNAB findings in a 62-year-old smoker with lung mass clinically suspicious for a lung primary. The smears of transbronchial FNAB showed groups of cells with ill-defined cell margins and cytological features overlapping with poorly differentiated non-small cell carcinoma. The tumor cells demonstrated lack of immunoreactivity for cytokeratin, thyroid transcription factor-1, and usual neuroendocrine markers, synaptophysin and chromogranin in formalin-fixed cellblock sections. However, they were immunoreactive for the other neuroendocrine immunomarker, CD56, suggesting neural nature of the cells. Further scrutiny of clinical details revealed a history of GBM, 13 months status-post surgical excision with radiation therapy and systemic chemotherapy. The tumor recurred 7 months earlier and was debulked surgically and with intra-cranial chemotherapy. Additional evaluation of tumor cells for glial fibrillary acidic protein (GFAP) immunoreactivity with clinical details resulted in final interpretation of metastatic GBM. CONCLUSION: Lack of clinical history and immunophenotyping may lead to a diagnostic pitfall with possible misinterpretation of metastatic GBM as poorly differentiated non-small cell carcinoma of lung in a smoker.

Immunohistochemical comparison of gastrointestinal stromal tumor and solitary fibrous tumor.

CONTEXT: The differential diagnosis of gastrointestinal stromal tumors (GIST) and solitary fibrous tumors (SFT) may be a diagnostic challenging because of overlapping clinicopathologic features. Many studies have shown consistent immunoreactivity for CD117 (c-Kit) in GIST. However, only a few studies have evaluated CD117 expression in SFT, and these studies have used an antibody from Santa Cruz Biotechnology. In non-GIST lesions, reactivity with this antibody has been shown to differ from that with a CD117 antibody from Dako Corporation. The immunoreactivity of SFT with the Dako CD117 antibody has not been reported. Conversely, CD99 is a marker for SFT, and its expression in GIST has not been evaluated. OBJECTIVE: To study the immunohistochemical profiles of GIST and SFT to evaluate their diagnostic overlap. DESIGN: We studied the immunoreactivity of 27 unequivocal GIST and 19 unequivocal extra-abdominal SFT for CD117, CD34, CD99, alpha-smooth muscle actin, vimentin, CD31, S100 protein, and muscle-specific actin. All antibodies, including CD117, were from Dako Corporation. RESULTS: We found positive immunoreactivity for CD117 in 100% of GIST and none of SFT; for CD34 in 89% of GIST, and 100% of SFT; for CD99 in 89% of GIST and 100% of SFT; for alpha-smooth muscle actin in 48% of GIST and 31% of SFT; for vimentin in 89% of GIST and 90% of SFT; and for muscle-specific actin in 22% of GIST and none of SFT. None of the GIST or SFT showed immunoreactivity for CD31 and S100 protein. CONCLUSIONS: The major difference between GIST and SFT was strong CD117 immunoexpression in all GIST and an absence of this expression in all SFT. With the exception of muscle-specific actin, the prevalence of immunoreactivity for the markers studied did not differ substantially between these 2 tumors. We conclude that GIST and SFT show distinctly divergent immunoprofiles with respect to CD117 and muscle-specific actin.