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Objectives Pathology and laboratory medicine (PALM) services in low- and middle-income countries are essential to combat the increasing prevalence of cancer in addition to providing documentation of cancer types and trends for future allocation of public health resources. There are many ways PALM as a whole can engage on the global health front. This study summarizes the efforts and results of a global health educational and clinical elective for pathology residents in Quetzaltenango, Guatemala. Methods Pathology residents led and implemented the project, working alongside an in-country pathologist and project collaborator to instill project sustainability and allow for future capacity building. Results An educational elective was established between the pathology departments of the University of Virginia and Hospital Regional de Occidente in Quetzaltenango, Guatemala. Two residents at a time engaged in a month-long educational elective assisting and learning from the in-country pathologist in anatomic pathology clinical work. Conclusions The project is an example of a global health initiative centering on the enhancement of PALM services in a low-resource environment via a bidirectional, sustainable educational exchange.

Hereditary amyloidosis is a challenging but critical diagnosis, with serious implications with regard to treatment and disease surveillance for both patients and their families. Systemic symptomology is often vague. As vitreous amyloid deposition is strongly linked to the systemic, hereditary disease, its cytodiagnosis in the vitreous may be the incipient finding of hereditary amyloidosis. We describe a 64-year-old man with a history of heart disease and peripheral neuropathy who presented with asymmetric visual disturbances and vitreous opacities, leading to diagnostic vitrectomy. Amyloid was identified on a ThinPrep slide of the vitreous sample via Congo red stain. Creation of a cell block from the residual ThinPrep sample allowed for amyloid protein typing, identifying ATTR (transthyretin)-type amyloid and strongly suggesting hereditary amyloidosis. Subsequent sequencing of the patient's TTR gene identified a pathogenic variant that is associated with autosomal dominant hereditary transthyretin-mediated amyloidosis.

Programmed death ligand 1 (PD-L1) is a transmembrane protein that plays a major role in immune suppression. Its interaction with the receptor PD-1 results in downregulation of antitumoral immunity. Humanized monoclonal antibodies that interrupt the PD-L1/PD-1 interaction have shown therapeutic efficacy in patients with advanced urothelial cancer. However, immunohistochemical staining of PD-L1 in bladder tumors and its relationship to tumor histologic type, grade, and overall survival has been incompletely analyzed. Slides from 165 cystectomy specimens were reviewed for tumor type, grade of urothelial carcinoma, pathologic stage, and overall survival. A tissue microarray (TMA) using four 0.6 mm cores from each case was constructed. Immunohistochemistry was performed on the TMA using a variety of new PD-L1 antibodies and platforms now widely available. For each case, the percent of tumor cells positive for PD-L1 and the percent of positive immune cells were scored. The overall number of bladder cancers positive for PD-L1 depended on the antibody/platform combination used and the threshold for considering a tumor "PD-L1-positive." Squamous cell carcinomas (SCCs) of the bladder demonstrated PD-L1 positivity more frequently than urothelial cell carcinomas (UCCs). High-grade UCCs were positive for PD-L1 on tumor cells more frequently than low-grade UCCs. There was no difference in survival between PD-L1-positive and PD-L1-negative bladder cancers in our study. Further studies should consider examining the predictive significance of PD-L1 IHC in bladder cancers.

Objectives The insulin-like growth factor-1 receptor (IGF1R) has been implicated in therapeutic resistance in head and neck squamous cell carcinoma (HNSCC), and small molecule tyrosine kinase inhibitors (TKIs) of IGF1R activity may have anticancer activity. Therefore, the relationship between survival and IGF1R expression was assessed for oral cavity (OC) cancer, and the antitumor effects of two IGF1R-TKIs, OSI-906 and BMS-754807, were evaluated in HNSCC cell lines in vitro. Methods Clinical outcome data and tissue microarray immunohistochemistry were used to generate IGF1R expression-specific survival curves. Immunoblot, alamarBlue proliferation assay, trypan blue exclusion viability test, clonogenic assay, flow cytometry, and reverse phase protein array (RPPA) were used to evaluate in vitro responses to IGF1R-TKIs. Results For patients with stage III/IV OCSCC, higher IGF1R expression was associated with poorer overall 5-year survival (P = 0.029). Both BMS-754807 and OSI-906 caused dose-dependent inhibition of IGF1R and Akt phosphorylation and inhibited proliferation; BMS-754807 was more potent than OSI-906. Both drugs reduced HNSCC cell viability; only OSI-906 was able to eliminate all viable cells at 10 μM. The two drugs similarly inhibited clonogenic cell survival. At 1 μM, only BMS-754807 caused a fourfold increase in the basal apoptotic rate. RPPA demonstrated broad effects of both drugs on canonical IGF1R signaling pathways and also inhibition of human epidermal growth factor receptor-3 (HER3), Src, paxillin, and ezrin phosphorylation. Conclusion OSI-906 and BMS-754807 inhibit IGF1R activity in HNSCC cell lines with reduction in prosurvival and proliferative signaling and with concomitant antiproliferative and proapoptotic effects. Such antagonists may have utility as adjuvants to existing therapies for HNSCC. Level of evidence NA Laryngoscope, 130:1470-1478, 2020.

Background: Tenosynovial giant cell tumor (TSGCT), also known as giant cell tumor of tendon sheath or pigmented villonodular synovitis, is the most common benign tumor of the tendon and synovium. The intra-articular diffuse type can present as a large infiltrative mass involving adjacent soft tissue and sometimes causes secondary destruction of bone, which leads to radiographic and clinical concern for malignancy. The tumor may also be purely extra-articular. Case: Here, we report the fine needle aspiration cytology findings of 2 cases of diffuse-type TSGCT with large mononuclear cells with eccentric nuclei, finely granular cytoplasm, and a peripheral well-defined cytoplasmic rim of hemosiderin (“ladybird cells”). Conclusion: Although the presence of ladybird cells has been described in tissue sections of TSGCT, their identification in cytological specimens has not been reported to our knowledge. When observed, their presence may aid in differentiating TSGCT from other lesions with multinucleated osteoclast-type giant cells occurring at or near joints.

Cyclin D1 and FADD (Fas-associated protein with death domain) regulate the cell cycle and apoptosis, respectively, and are located on chromosome 11q13, which is frequently amplified in head and neck squamous cell carcinoma (HNSCC). This study evaluates these proteins as predictors of clinical outcomes for HNSCC.Historical cohort study.Academic tertiary care center.Two hundred twenty-two patients with upper aerodigestive HNSCC.Patients with tumors that were strongly positive for cyclin D1 and FADD had reduced overall (OS; P = .003 and P.001), disease-specific (DSS; P = .039 and P.001), and disease-free (DFS; P = .026 and P.001) survival, respectively. Together, the 2 markers effectively stratified OS (P.001), DSS (P.001), and DFS (P = .002). Strong FADD staining correlated with greater alcohol consumption and varied significantly with primary tumor site: 56% of hypopharynx tumors expressed high levels of FADD but only 7% of glottis tumors. Using Cox regression analysis, FADD and N stage were significant independent predictors of DSS and DFS, whereas cyclin D1, FADD, and N stage were independently significant for OS.Cyclin D1 and FADD may have utility as predictors of long-term outcomes for patients with HNSCC. Further study is needed to determine if these proteins predict response to different treatment approaches or assist in selecting patients for multimodality therapy.

Oncogenic (tumor-induced) osteomalacia is a rare paraneoplastic syndrome of phosphate wasting that is frequently associated with phosphaturic mesenchymal tumor (PMT). As the cytologic features of this tumor apparently have not been reported, we describe the fine-needle aspiration (FNA) findings for PMT that arose from the gluteal soft tissue in a patient with hypophosphatemia and multiple fractures secondary to osteomalacia. Smears from the computerized tomography (CT)-guided FNA showed groups of spindle cells having elongated nuclei, fine to moderately coarsely granular chromatin, inconspicuous nucleoli, and delicate cytoplasm. Marked nuclear atypia, mitotic figures, and necrosis were absent. The differential diagnosis included a variety of benign and malignant spindle cell neoplasms such as monophasic synovial sarcoma, leiomyoma, peripheral nerve sheath tumor, fibrosarcoma, and, less likely, metastatic melanoma and sarcomatoid carcinoma. The bland-appearing cytologic features of a spindle cell tumor in a patient with osteomalacia should suggest the diagnosis of PMT.

OBJECTIVES. Many noninvasive methods (using breath, blood, and stool samples) are available to diagnose Helicobacter pylori. However, because the noninvasive tests are proxy measures of the infection, they need validation before use. Factors that may affect test validity include patient age, gender, and geographic location. Because no data were available on the validation of noninvasive tests for the diagnosis of H pylori among children in the Middle East, this study was performed.METHODS. Children between 2 and 17 years of age evaluated at the Cairo University School of Medicine pediatric gastroenterology clinic who were already scheduled for upper endoscopy were eligible for enrollment in the study. At the time of endoscopy, 3 biopsies were collected and used for rapid urease, histology, and culture, respectively. All children also donated a sample of stool and blood and had a urea breath test performed. Stool and serum samples were tested for the presence of H pylori by using commercially available enzyme-linked immunosorbent assay–based technology. The sensitivity, specificity, and positive and negative predictive values were calculated for each noninvasive test used in the study. Receiver operating curves also were charted to determine optimal cut points for the various tests when used in the current study cohort.RESULTS. One hundred eight children were enrolled in the study, with 52 children being under 6 years of age. The urea breath test and HpStar (DakoCytomation, Norden, Denmark) stool enzyme-linked immunosorbent assay kit had the highest sensitivity and specificity (sensitivity and specificity: 98 and 89 [urea breath test] and 94 and 81 [HpStar], respectively), whereas the serologic kit had an unacceptably low sensitivity (50%). The sensitivity of neither the urea breath test nor the HpStar tests was affected by subject age, but specificity of the HpStar test, although still high, was significantly lower among children under 6 years. Receiver operating curves found optimal cut points of the urea breath test at 6.2 δ over baseline and of the HpStar at 0.25 enzyme-linked immunosorbent assay units.CONCLUSION. The urea breath test and HpSTAR stool antigen kit are reliable tests for the noninvasive diagnosis of H pylori among children living in the Middle East.

Summary Background Non-invasive methods for diagnosis of urothelial carcinoma have reduced specificity in patients with non-malignant genitourinary disease or other disorders. We aimed to use mass spectrometry and bioinformatics to define and validate a cancer-specific proteomic pattern. Methods We used capillary-electrophoresis-coupled mass spectrometry to obtain polypeptide patterns from urine samples of 46 patients with urothelial carcinoma and 33 healthy volunteers. From signatures of polypeptide mass, we established a model for predicting the presence of cancer. The model was refined further by use of 366 urine samples obtained from other healthy volunteers and patients with malignant and non-malignant genitourinary disease. We estimated the proportion of correct classifications from the refined model by applying it to a masked group containing 31 patients with urothelial carcinoma, 11 healthy individuals, and 138 patients with non-malignant genitourinary disease. We also sequenced several diagnostic polypeptides for urothelial carcinoma. Findings We identified a diagnostic urothelial-carcinoma pattern of 22 polypeptide masses. On masked assessment, prediction models based on these polypeptides correctly classified all samples of urothelial carcinoma (sensitivity 100% [95% CI 87–100) and all healthy samples (specificity 100% [84–100]). Correct identification of patients with urothelial carcinoma from those with other malignant and non-malignant genitourinary disease ranged from 86% to 100%. A prominent polypeptide from the diagnostic pattern for urothelial carcinoma was identified as fibrinopeptide A—a known biomarker of ovarian cancer and gastric cancer. Interpretation Validation of a highly specific biomarker pattern for urothelial carcinoma in a large group of patients with various urological disorders could be used in the diagnosis of other diseases that are identified in urine samples or in other body fluids.

The ability to use archival tissue to test externally valid hypotheses of carcinogenesis is dependent on the availability of population-based samples of cancer tissue. Tissue microarrays (TMAs) provide an efficient format for developing population-based samples of tissue. A TMA was constructed consisting of archival tissue from patients diagnosed with invasive colorectal cancer in the state of Hawaii in 1995. The population representativeness of the TMA was evaluated by comparing patient and clinical characteristics of TMA cases to that of all cases of colorectal carcinoma diagnosed statewide in 1995. Cytokeratin 20 (CK20) and cytokeratin 7 (CK7) immunohistochemistry was used to validate the utility of the TMA, and the expression of these proteins was correlated with patient and tumor characteristics. The TMA comprised tissue specimens from 286 patients representing 47% of all invasive cases diagnosed statewide in 1995. TMA cases were comparable to all invasive colorectal cases statewide with respect to age, sex, race/ethnicity, anatomic site, and survival. There were some differences between TMA cases and all cases with respect to tumor stage, histological classification, and treatment. There were significant differences in the relative expression of CK20 and CK7 proteins between malignant and normal tissues and by tumor stage. Advanced cancers were more likely to have CK20+/cytokeratin 7+ (CK7+) profiles than early-stage cancers, which were predominantly CK20+/cytokeratin 7- (CK7-). CK7+ expression was not correlated with anatomic location of carcinomas. This well-characterized TMA offers a powerful tool for testing hypotheses regarding colorectal carcinogenesis, including the identification of potential markers of neoplastic development and progression.

Purpose: RhoGDI2 was recently shown to be a metastasis suppressor gene in models of bladder cancer. We sought to further understand its importance in human cancer by determining the level of its expression and the distribution of its encoded protein in normal human tissues and cell lines and to evaluate whether its protein expression is a determinant of human bladder cancer progression. Experimental Design: RhoGDI2 mRNA and protein expression was evaluated in cell lines and human tissues using Affymetrix and tissue microarrays, respectively. Tissue microarrays represented most human normal adult tissues and material from 51 patients that had undergone radical cystectomy for bladder cancer. In these 51 patients, the χ2 test was used to test for associations between RhoGDI2 and stage, grade of urothelial carcinoma, histological type, and disease-specific survival status. Cox proportional hazards regression analyses were used to estimate the effect of RhoGDI2 expression level on time to development of metastatic disease and disease-specific survival time, adjusting for grade, stage, and histological type. Results: In normal tissues, there was strong RhoGDI2 protein expression in WBCs, endothelial cells, and transitional epithelium. RhoGDI2 mRNA expression was inversely related to the invasive and metastatic phenotype in human bladder cancer cell lines. In patients with bladder cancer, univariate analysis indicated that reduced tumor RhoGDI2 protein expression was associated with a lower actuarial 5-year disease-free and disease-specific survival (P = 0.01). In addition, patients with tumors that had low or absent RhoGDI2 had a shorter time to disease-specific death (P ≤ 0.01). When tumor grade, stage, histological type, and RhoGDI2 staining level were examined using multivariate analysis, RhoGDI2 expression was found to be an independent predictive factor for disease-specific death (P = 0.03). Conclusions: These results suggest that RhoGDI2 is an independent predictor of prognosis for patients with bladder cancer and provide clinical evidence in support of its involvement in cancer metastasis.

BACKGROUND With the advent of the prostate specific antigen (PSA) assay, an increased detection rate of prostate carcinoma has ensued. This has been associated with a downward stage migration. In contrast, grade has shifted heavily toward moderate differentiation. The authors sought to test the hypothesis that such changes in grade in part may be because of trends among pathologists to upgrade similar specimens over time. METHODS Two expert genitourinary pathologists regraded 23 prostate biopsies and 15 radical prostatectomy specimens during a 3-year period (1989–1991). Each pathologist then regraded 32 prostate biopsies and 15 radical prostatectomies from 1998 to 2000. For both time periods, each pathologist regraded only specimens that they personally had graded initially. All specimens were scored using the Gleason system, the predominant system used in describing prostate carcinoma grade. In evaluating original and regraded scores, the authors classified score changes between less than or equal to 6 and greater than or equal to 7 or between 7 and greater than or equal to 8 as significant because such changes have a high probability of altering clinical management. The results were analyzed using the two-tailed Fisher exact test. RESULTS Of 23 prostate biopsies from 1989 to 1991, 10 of 23 (44%) had a clinically significant Gleason score change when regraded, whereas 2 of 15 (13%) radical prostatectomy specimens from the same period had a clinically significant Gleason score change. A significant change in the distribution of biopsy Gleason scores on regrading was observed (P < 0.04). In comparison, when the prostate biopsies from 1998–2000 were regraded, 10 of 32 (31%) had a clinically significant grade change. Radical prostatectomy specimens from the same period revealed 3 of 15 (20%) with a clinically significant grade change. After regrading the biopsies from 1989–1991, 8 of 23 (35%) of were upgraded, whereas 2 of 23 (9%) were downgraded. In comparison, of the biopsies with significant changes from 1998 to 2000, 3 of 32 (9%) were upgraded, whereas 7 of 32 (22%) were downgraded. Of the radical prostatectomy specimens with significant change, only 2 of 15 from each period were upgraded. Significant upgrading (P < 0.005) occurred only in the biopsy specimens from 1989 to 1991. CONCLUSIONS The authors' data suggest that rates of upgrading and downgrading of biopsy specimens differ between the 1989–1991 cases and the 1998–2000 cases, with the 1989–1991 samples exhibiting a significant change toward higher grades. Although not excluding the possibility of a change in the biology of prostate carcinoma over time, these findings suggest that the apparent trend toward higher biopsy grades in part may be because of how pathologists interpret these specimens today as compared with 10 years ago. Therefore, outcome studies including a biopsy Gleason score from older specimens as a risk variable have a significant chance of being vulnerable to this phenomenon. Based on the authors' data, all such specimens should undergo rereview. Cancer 2002;94:2282–7. © 2002 American Cancer Society. DOI 10.1002/cncr.10457

Penile squamous cell carcinoma (SCC) is sometimes an aggressive disease that has a variable worldwide incidence, in part due to differing rates of inflammatory and infectious risk factors. In the developed world, penile SCC is a rare malignancy, and most studies therefore originate in less developed countries. The current study was undertaken to examine the morphologic and immunohistochemical features of penile SCC from a region with low disease incidence. Sixty-two complete or partial penectomy specimens from 59 patients were reviewed. Twenty-six patients had metastasis, 3 had recurrent disease, and 7 were dead due to tumor. Most patients were uncircumcised (72%). Twenty-two percent of carcinomas were associated with lichen sclerosis. Perineural invasion was significantly associated with metastasis (P=0.007). Most SCCs (65%) had the usual keratinizing morphology, and these tumors were significantly associated with the differentiated form of intraepithelial lesion (P

Objectives. Angiogenesis has been shown to be related to p53 and retinoblastoma gene function as well as to neuroendocrine differentiation (as measured by chromogranin A staining) in prostate tumors. Studies have indicated that immunohistochemical assessment of p53, retinoblastoma, and chromogranin A in prostate cancers treated by radical prostatectomy can be useful in predicting disease-specific survival, whereas the degree of microvessel density (MVD), a measure of angiogenesis, correlates with disease recurrence. The ability of MVD, however, to predict disease-specific survival either alone or in conjunction with other prognostic factors has not yet been evaluated. The purpose of our study was to determine the relative importance of p53, retinoblastoma, and chromogranin A as well as MVD in the prediction of disease-specific survival following radical prostatectomy in conjunction with classical pathologic assessment. Methods. From 1970 to 1984, radical prostatectomy was performed on 75 patients with clinical Stage A2 to B2 adenocarcinoma of the prostate. No neoadjuvant or adjuvant treatments were given, and patients were followed until death. Prostatectomy specimens were examined to evaluate conventional pathologic parameters. In addition, the tissue was immunohistochemically stained for p53, retinoblastoma, chromogranin A, and endothelial cells. A previously described computerized imaging system analyzed the microvessels and computed both “optimized” and “area-weighted” MVD scores. Proportional hazard models were used to investigate the simultaneous association of these variables with disease-specific survival. Results. Of the 75 patients, 4 had follow-up of less than 3 months, and 29 patients had inadequate tissue for analysis of all immunohistochemical markers. The analyzed subset of 42 patients was found to be representative of the cohort of 71 patients. Multivariate analysis revealed that p53 and retinoblastoma have the greatest prognostic importance regarding disease-specific survival. Chromogranin A and optimized or area-weighted MVD scores were of no additional value when p53 and retinoblastoma were assessed. Conclusions. Microvessel density, as a determinant of angiogenesis and chromogranin A, does not seem to add significantly to the prognostic disease-specific survival information provided by conventional pathology combined with p53 and retinoblastoma assessment.

Purpose: Status of the surgical margins after radical prostatectomy is a key factor for predicting postoperative outcome. Current methods used to determine margin status are tedious, costly and vary among institutions. Sensitive and inexpensive detection of prostate cells in the circulation of patients with prostate cancer has been achieved using reverse transcriptase (RT) polymerase chain reaction (PCR) for prostate specific antigen and prostate specific membrane antigen. Therefore, we designed and tested a novel and objective molecular assay for assessing surgical margins at radical prostatectomy based on the detection of prostate specific markers using RT-PCR. We also compared this assay to standard pathological examination.Materials and Methods: A total of 30 consecutive patients with local prostate cancer underwent radical prostatectomy. At the completion of gland excision 5 biopsies of the prostatic fossa were obtained for histopathological and molecular analysis. We performed RT-PCR analysi...

Background: We sought to evaluate the predictive value of preoperative fine-needle aspiration (FNA) on surgical decision making by evaluating the final pathologic diagnosis and comparing it to the preoperative diagnosis. Further, we wished to calculate the predictive accuracy of each of several types of preoperative FNA diagnosis. Study Design: A retrospective chart review of 151 thyroid resections between July 1990 and April 1996 at the University of Virginia was undertaken. The mean age was 45 years (range, 11 to 85 years). Preoperative laboratory values, presenting symptoms, imaging studies, and predictive values of preoperative FNA and intraoperative frozen section were analyzed. Results: Symptomatology was poorly predictive of a benign versus malignant postoperative final pathologic diagnosis. Sensitivity, specificity, and accuracy of frozen section versus FNA was 86% versus 86%; 99% versus 93%, and 96% versus 92%, respectively, if the reading "cancer" or "suspicious" were predicted as positive for malignancy and "benign" or "follicular" were predicted as negative for malignancy. If only the reading "cancer" was predicted as positive for malignancy and only "benign" was predicted as negative for malignancy, sensitivity and specificity for FNA were 100% and 96%, respectively, and 100% and 99%, respectively, for frozen section. Forty-nine "follicular" lesions obtained by preoperative FNA resulted in 46 benign diagnoses after surgical resection. Conclusions: The use of preoperative FNA is a powerful diagnostic tool in the hands of skilled pathologists. There is increasing evidence that intraoperative frozen section adds little to intraoperative decision making in patients diagnosed with thyroid cancer by preoperative FNA. Less definitive interpretations decrease the sensitivity, specificity, and accuracy of the FNA diagnosis.

OBJECTIVE: γ-Glutamyl transpeptidase activity has been shown to be essential for the nephrotoxicity of cisplatin. The purpose of this study was to determine whether expression of γ-glutamyl transpeptidase in ovarian carcinomas is necessary for the antitumor effect of cisplatin. STUDY DESIGN: Tumor tissue from 18 patients with stage III or IV ovarian serous papillary carcinoma or poorly differentiated adenocarcinoma was analyzed for expression of γ-glutamyl transpeptidase by histochemical or immunohistochemical staining. Response to cisplatin-based combination chemotherapy was evaluated on the basis of clinical response, progression-free interval, and survival. RESULTS: γ-Glutamyl transpeptidase expression in the tumors ranged from 0% to 100% of the tumor cells γ-glutamyl transpeptidase positive. Patient survival ranged from 15 months to 9 years. Twelve of the 18 patients had a complete response to the initial course of cisplatin-based combination chemotherapy. There was no statistically significant correlation between either response or time to relapse and γ-glutamyl transpeptidase expression. However, there was a correlation between high levels of γ-glutamyl transpeptidase in the tumor and acute ototoxicity in patients treated with cisplatin. Expression of high levels of γ-glutamyl transpeptidase in the tumor was also found to be associated with shorter patient survival, suggesting that γ-glutamyl transpeptidase might have a role in resistance to drugs used in second- and third-line therapy. CONCLUSIONS: Expression of γ-glutamyl transpeptidase in ovarian serous papillary or poorly differentiated adenocarcinomas is not necessary for the antitumor activity of cisplatin. A correlation was found between high levels of γ-glutamyl transpeptidase in the tumor and both increased ototoxicity from cisplatin and decreased patient survival. These data suggest that administering an inhibitor of γ-glutamyl transpeptidase activity to block the nephrotoxicity of cisplatin would not interfere with its therapeutic effect. (Am J Obstet Gynecol 1998;179:363-7.)

BACKGROUND The accumulation of chromogranin A (Chr A) and cathepsin D (Cath D) gene products may be important in prostate carcinoma progression. This study assessed whether the levels of immunoreactivity for Chr A and Cath D are better predictors of disease specific survival than conventional pathologic parameters of the primary tumor such as Gleason score, capsular penetration, seminal vesicle invasion, and percent tumor in the specimen for patients with clinically localized prostate carcinoma managed by radical prostatectomy. METHODS Seventy-one patients with modified Jewett clinical stages A1 to B2 adenocarcinoma of the prostate underwent a radical prostatectomy after a negative metastatic workup. No neoadjuvant or adjuvant treatments were given and all disease recurrences and causes of death were recorded. Analysis of prostatectomy specimens was undertaken to determine the conventional pathologic parameters of the primary tumor and Chr A and Cath D immunohistochemical staining. Univariate and multivariate analyses were performed to determine the independent contributions of Chr A and Cath D in predicting survival. RESULTS On univariate analysis Chr A was the only variable that reached statistical significance for disease specific survival (P = 0.035). Cath D nearly reached significance with a P value of 0.079 for disease specific survival. On multivariate analysis, the only independent factor predicting disease specific survival was the Chr A staining score (P < 0.05). In patients with unequivocal foci of Chr A immunoreactivity, the 14-year disease specific survival was 50% compared with 68% for patients lacking such foci. CONCLUSIONS The level of Chr A immunohistochemical staining is a strong predictor of disease specific survival and is superior to standard pathologic prognostic factors. Such findings lay the groundwork for future prospective study of the utility of such markers on biopsy specimens to predict patient outcome. Cancer 1997; 80:2109-19. © 1997 American Cancer Society.

Acute lung injury is associated with pulmonary hypertension, intrapulmonary shunting, and increased microvascular permeability, leading to altered oxygenation capacity. Thromboxane A2 has been found to be a central mediator in the development of septic and oleic acid (OA)-induced acute lung injury. Our previous study demonstrated a beneficial effect of preinjury thromboxane A2 receptor blockade. The current study examines the efficacy of postinjury receptor blockade on oxygenation capacity and pulmonary hemodynamics in an isolated lung model of OA-induced acute lung injury.Four groups of rabbit heart-lung preparations were studied for 60 minutes in an ex vivo perfusion-ventilation system. Saline control lungs received saline solution during the first 20 minutes of study. Injury control lungs received an OA-ethanol solution during the first 20 minutes. Two treatment groups were used: T10, in which the thromboxane receptor antagonist, SQ30741, was infused 10 minutes after the initiation of OA infusion; and T30, in which the thromboxane receptor antagonist was infused 30 minutes after OA infusion.Significant differences were found in oxygenation (oxygen tension in T10 = 62.6 +/- 11.7 mm Hg, T30 = 68.2 +/- 21.2 mm Hg; injury control = 40.2 +/- 9.0 mm Hg, saline control = 123.5 +/- 16.01 mm Hg; p0.001) and percentile change in pulmonary artery pressure (T10 = 1.1% +/- 19.4% increase, T30 = 11.2% +/- 7.3% increase; injury control = 47.6% +/- 20.5%, saline control = 4.2% +/- 6.81%; p0.001).This study demonstrates that blockade of the thromboxane A2 receptor, even after the initiation of acute lung injury, eliminates pulmonary hypertension and improves oxygenation.

An unusual breast carcinoma with prominent spindle cells, intracytoplasmic mucin, and argyrophilia in an 82-yr-old woman was sampled preoperatively by fine-needle aspiration (FNA). The smears contained highly cellular sheets and fragments of uniform spindle cells with abundant vacuolated cytoplasm. The cells were mucicarmine positive and contained many cytoplasmic argyrophilic granules. The findings were confirmed by histologic examination of the excised tumor, which was also studied with a panel of immunohistochemical stains. A review of the literature indicated that spindle-cell argyrophilic mucin-producing carcinoma (SCAMPC) of the breast is a very rare neoplasm presenting primarily in elderly patients. The FNA cytologic features seem to be unique and should allow distinction from other primary breast lesions.

Leukemias and lymphomas involving the lung were diagnosed by means of exfoliative cytology in 31 specimens from 20 patients. Initial diagnostic categorizations included 29 specimens "positive for malignancy," including two thought to represent "carcinoma vs. lymphoma," and two considered suspicious for lymphoma. Previous diagnoses of lymphoma (13 patients) and acute myelogenous leukemia (AML) (2 patients) were available. In 5 additional patients, exfoliative respiratory cytology yielded the first diagnosis of hematopoietic malignancy. Cytologic diagnosis included nine large-cell and six small-cell non-Hodgkin's lymphomas (NHL), three Hodgkin's lymphomas (HD), and two AML. Key cytologic features included markedly pleomorphic and monomorphic cell populations in HD and NHL, respectively, as well as lack of tumor cell cohesion and necrosis in all cases. Cytologically, acute leukemia may be difficult to differentiate from large-cell NHL, and small-cell NHL from reactive/benign small lymphocytes. Blood, scant cellularity, crush artifacts, and apparent molding may affect diagnostic accuracy. Immunocytochemistry in cell block sections of sputa and washings is useful in the diagnostic workup in selected cases. Although involvement of the respiratory system by leukemias and lymphomas is uncommon and not always preceded by a history of malignancy, cytologic diagnosis is usually prompt, reliable, and accurate.

BACKGROUND Fine needle aspiration in lieu of needle biopsy is widely used for the diagnosis of pancreatic neoplasms. The cytologic features of ductal carcinomas are well characterized, but the appearances of less common pancreatic neoplasms, such as acinar cell carcinoma (ACC), are not well described. CASES We present the cytologic, histologic, immunocytochemical and ultrastructural features of two cases of ACC. The tumors occurred in a 36-year-old woman and 43-year-old man. The aspirate from one case contained neoplastic cells with smooth-contoured nuclei containing one or two prominent nucleoli. The aspirated material from the second case was necrotic, with numerous neutrophils and scattered nests of tumor cells similar to those present in the first case. Histologically, both tumors manifested solid and acinar patterns, and each contained some cells with periodic acid-Schiff-positive granules that were resistant to diastase. The neoplasms were immunochemically positive for trypsin and negative for neuroendocrine markers. Ultrastructurally, the aspirate from one case demonstrated apical microvilli, zymogenlike granules and abundant rough endoplasmic reticulum. CONCLUSION Uncommon pancreatic neoplasms may be difficult to diagnose due to their cytologic and histologic subtleties. Supplemental studies including immunocytochemistry, cytochemistry and electron microscopy are important in facilitating their identification.

We reviewed the clinical and fine-needle aspiration (FNA) findings in 20 patients with poorly differentiated carcinomas presenting initially as parotid or as submandibular masses. There were 11 primary tumors and nine metastatic malignancies in 14 males and six females ranging in age from 39 to 89 yr (median = 66). The tumor types included three primary carcinomas with oncocytic features, three additional cases of high-grade parotid carcinoma, one case of primary neuroendocrine carcinoma, two examples of malignant mixed tumor, one high-grade mucoepidermoid carcinoma, and a single example of malignant lymphoepithelial lesion. Six patients with metastatic carcinoma had previous diagnoses of malignancy. In the three remaining individuals, primary carcinomas of the lung (two cases), and an unknown primary site presented initially as parotid masses. Five examples of metastatic squamous cell carcinoma, one metastatic basal cell carcinoma, and two metastatic renal cell carcinomas were identified. One parotid lymphoepithelioma was interpreted cytologically as an atypical lymphoproliferative process suggestive of Hodgkin's disease. Nineteen cases (95%) were correctly classified as carcinoma at the time of FNA. High-grade carcinomas aspirated from the parotid may be primary, but are frequently metastatic to either the gland, or to an intraparotid lymph node. Our experience indicates that some metastatic carcinomas present at this site, without a previous history of malignancy. Distinguishing primary from metastatic lesions has important therapeutic implications.

Background: Standard treatment for muscle-invasive bladder cancer (MIBC) includes chemotherapy with either gemcitabine-cisplatin (GC) or methotrexate, vinblastine, adriamycin and cisplatin (MVAC). These regimens have similar clinical complete response rates of approximately 30%. While no targeted treatment has been approved for bladder cancer, clinical trials have identified biochemical markers that predict the chemoresponsiveness of MIBC tumors to specific chemotherapeutic agents. For example, patients with high hENT1 and low RRM1 expression responded better to GC-based chemotherapy than their counterparts, and HER2 overexpression predicted resistance to cisplatin-based therapy. To quantify targets that are known indicators of tumor behavior, we used targeted proteomic analysis to assess 30 different protein biomarkers in formalin-fixed paraffin-embedded (FFPE) MIBC tumor tissue. Methods: Twelve FFPE MIBC tissue blocks were obtained and a pathologist marked a minimum 8mm2 of tumor area from 1 or 2 slides. Following laser microdissection of the marked areas, proteins were extracted using the Liquid-Tissue® process and subjected to selected reaction monitoring mass spectrometry to quantify the amounts of 30 different targeted proteins in each patient sample. Results: Of the 12 patient samples, 7 (58%) expressed high levels of hENT1 and 11 (92%) expressed low levels of RRM1, indicating that gemcitabine-based therapy would be an appropriate choice. A single patient expressed high levels of RRM1, an indication for non-gemcitabine based therapy. All 12 patients expressed TUBB3, a marker of resistance to taxane (vinblastine) and 10 patients (83%) lacked expression of FR-alpha, a marker of sensitivity to methotrexate. The majority of patients expressed a marker of sensitivity to anthracycline (TOPO2A) and did not express a resistance biomarker for platinum therapy (ERCC1). Of 3 patients whose tumors expressed HER2, 2 had overexpression (>750 amol/ug) and would thus be eligible for HER2 basket trials. Further, multiplex-targeted proteomics discovered patients expressing FGFR1 (17%), cMET (33%), Axl (17%) and IDO1 (25%), which would make them eligible for clinical trials of targeted or immunotherapies. Conclusion: MIBC is heterogeneous and expresses a wide range of proteins. Yet, it continues to be treated with only 2 chemotherapeutic regimens. Multiplexed proteomics is currently being used in clinical practice to inform personalized patient care decisions with identification and the relative quantities of actionable proteins known to predict tumor behavior. Citation Format: Fabiola Cecchi, Sheeno Thyparambil, Adele Blackler, Todd Hembrough, Shahrooz Rabizadeh, Patrick Soon-Shiong, Henry Frierson, Daniel Theodorescu. Targeted proteomic analysis for personalized treatment of muscle invasive bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 449.

CD30 (Ki-1)-positive anaplastic large cell lymphoma (CD30 + ALCL) is a morphologically and immunophenotypically distinct subset of non-Hodgkin's lymphoma. Although the presence of Epstein-Barr virus (EBV) has been well documented in a significant proportion of cases of Hodgkin's disease, another CD30 + malignancy, few studies have examined the association of EBV with CD30 + ALCL. These latter studies have produced conflicting findings. To further investigate the existence of a putative association of EBV with CD30 + ALCL, and whether this association, if present, shows geographic variation, we examined 34 formalin-fixed, paraffin-embedded specimens from cases of CD30 + ALCL from the United States and Hong Kong. Immunophenotypically, 15 cases were of B lineage, 15 cases were of T lineage, one case expressed both B- and T-cell markers, and three were of null lineage. A highly sensitive in situ hybridization method was performed with use of an antisense oligonucleotide probe to the EBV-encoded RNA (EBER-1). EBV-RNA was identified in 3 of 14 CD30 + ALCL specimens from Hong Kong patients and in 1 of 20 from the American patients. The EBER-1 signal was present in all or virtually all of the tumor cell nuclei in the three EBV-RNA-positive CD30 + ALCL Hong Kong cases, but was only focally present in the single EBV-positive American case. The latent membrane protein-1 (LMP1) of EBV was identified in only one of the four positive cases, a Hong Kong case. Our results suggest that in contrast to Hodgkin's disease, EBV has no significant association with CD30 + ALCL

This study compares the use of immunohistochemistry (IHC) for diagnosing carcinoma in private practice and commercial settings with use in a single academic center. HE the former group used IHC stains in 11% and the latter in 26% of cases (P < .0001). Pathologists from commercial laboratories (12% of referrals) used IHC in 38% of cases, whereas private/hospital-based community laboratories (86% of referrals) used them in 24%. The average number of stains ordered per case was similar among all groups. We suggest that the use of IHC may reflect both the degree of experience of the pathologist and the pathology practice setting. For more than 25 years, immunohistochemistry (IHC) has greatly assisted surgical pathologists in the diagnosis of neoplastic diseases. Currently, IHC has a wide variety of uses, including, but not limited to, confirmation of diagnosis, determination of the primary site of origin for metastatic tumors, classification of neoplasms, use as a prognostic and predictive biomarker, and identification of infectious organisms.

Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumor- and stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis.

Multiagent chemotherapy is often used to treat patients with locally advanced infiltrating breast carcinoma before mastectomy. One of the most important prognostic factors, histologic grade, may be altered by induction chemotherapy. Because locally advanced infiltrating breast carcinomas are frequently diagnosed by fine-needle aspiration, histologic grade can be determined in the mastectomy specimens only after chemotherapy. Histologic grade, with its three components, was examined in 30 mastectomy specimens after induction chemotherapy for infiltrating ductal carcinoma and compared with findings in available pretreatment incisional biopsy specimens. Histologic grade for the 24 axillary lymph node-positive carcinomas treated with induction chemotherapy was compared with the grade for 24 axillary lymph node-positive ductal cancers that had been treated by surgery only. Complete, partial, or no clinical response was seen in 4 (13%), 21 (70%), and 5 (17%) patients after chemotherapy. In six of seven tumors, there was complete agreement between biopsy and postchemotherapy mastectomy specimens in grade and in scores for the three components. Half of the 24 node-positive tumors from patients treated with chemotherapy and 21% of node-positive neoplasms from patients treated initially with surgery had a mitotic count score of 1. In these two node-positive groups, 71% of tumors from patients treated with surgery and 92% of cancers from patients treated with induction chemotherapy showed a nuclear pleomorphism score of 3. For these two groups, however, there were no statistically significant differences in histologic grade or in any of its three components.

Sinonasal non-Hodgkin's lymphomas (SNHL) of B- or T-cell immunophenotype have been associated with the Epstein-Barr virus (EBV) in Asian patients. We investigated eight sinonasal and 10 Waldeyer's ring NHL from Western patients for evidence of EBV genomes using a sensitive in situ hybridization technique. EBV DNA was detected in each of three sinonasal NHL with a T-cell immunophenotype and two of five cases with a B-cell immunophenotype. Two of 10 B-cell Waldeyer's ring NHL were positive for EBV genomes. In each positive case, EBV genomes were evenly distributed among the neoplastic cells, whereas no evidence of EBV in associated nonneoplastic lymphocytes or epithelium was seen. The results indicate that B-cell and T-cell sinonasal NHL are associated with EBV in Western as well as in Asian patients, and that EBV may have a role in oncogenesis in NHL of the upper aerodigestive tract. The strong association of EBV with nasopharyngeal carcinoma suggests that the anatomic site is important in the development of EBV-related neoplasms.

Previous studies have shown that patients with nonpalpable invasive breast cancer have a favorable prognosis. These studies, however, have not analyzed pathologic features of mammographically detected tumors according to tumor size. We describe the histopathologic features of 77 nonpalpable invasive breast cancers, comparing neoplasms less than or equal to 1 cm with larger clinically occult tumors. Forty-seven lesions (61%) were less than or equal to 1 cm (group A) and 30 (39%) were greater than 1 cm (group B). In group A, there were 30 infiltrating ductal carcinomas (IDC); seven infiltrating lobular carcinomas (ILC); and two cases each of mixed ILC and IDC, mixed tubular carcinoma and ILC, and infiltrating cribriform carcinoma. There was one case each of mucinous carcinoma, apocrine carcinoma, tubular carcinoma, and mixed mucinous and IDC. In group B, there were 23 (77%) IDC, five (17%) ILC, and two mixed IDC and ILC. Tumors in group B were more frequently grade 3 (22% versus 7%), but this was not statistically significant (p = 0.21). There were no important differences in the frequency, subtypes and location of carcinoma in situ, or other histopathologic parameters evaluated in the biopsy specimens. Mastectomy specimens with axillary lymph node dissections were available for review in 64 cases (83%). Group B patients had a higher rate of residual invasive carcinoma (31% versus 13%) and lymph node metastases (31% versus 16%), but these differences were not statistically significant. Residual carcinoma in situ was more frequent in group B (54%) compared with group A (26%) (p = .036). Of seven group B cases with negative biopsy margins, residual invasive carcinoma was present in five (71%). We conclude that small nonpalpable invasive breast cancers differ from larger nonpalpable tumors primarily in size. The finding of negative biopsy margins should not be construed as conclusive evidence for the absence of residual infiltrating disease.

A 66-year-old man with squamous cell carcinoma of the tongue and vallecula had massive lower gastrointestinal hemorrhage. Colonoscopy examination results were normal, but angiography revealed a 3 x 6-cm hypervascular mass in the right lower quadrant. Persistent bleeding required resection of a large ileal ulcer, which proved to be an isolated ulcer containing cells with cytomegalovirus (CMV) inclusion bodies. Massive gastrointestinal hemorrhage due to an isolated CMV ileal ulcer in adults without acquired immunodeficiency syndrome has not been previously reported. This case illustrates that hemorrhage due to CMV infection of the ileum may occur in the absence of endoscopic evidence of colonic involvement.

Rosai-Dorfman disease is rare and typically presents with cervical lymphadenopathy, but may manifest as extranodal disease. This disease is generally indolent and self-limited, but it carries a poor or fatal prognosis when it is advanced or when it involves and compresses vital structures. We present a case of Rosai-Dorfman disease affecting the pulmonary arteries in a 22-year-old woman with severe, symptomatic right heart failure.

Unusual tissue changes in needle tracts after fine-needle aspiration were studied in two specimens. One specimen, a 3.0 x 2.5 cm mesenteric nodule, was found six days after a nondiagnostic transabdominal fine-needle aspiration of a retroperitoneal mass. At frozen-section examination, the nodule had proliferating spindle-shaped cells interspersed with adipocytes that raised the possibility of well-differentiated liposarcoma. On permanent sections, however, there was fat necrosis and reactive spindle-shaped cells that immunohistochemically were consistent with myofibroblasts. In the second case, a needle tract was noted in breast tissue on which a biopsy was performed two days after a cytologic diagnosis of carcinoma. The 0.4-mm-wide tract contained neutrophils, foamy histiocytes, and clumps of intact, atypical epithelial cells without a desmoplastic or elastotic component. Aside from these epithelial cells, nothing in the biopsy specimen suggested invasive carcinoma. The cells were identical to those from a comedocarcinoma present in the biopsy and mastectomy specimens. These two cases provide examples of pitfalls that may arise during the examination of biopsy specimens obtained after fine-needle aspiration.

A diffuse, well-differentiated, malignant peritoneal mesothelioma (MPM) developed in a nine-year-old girl. She received limited chemotherapy and radiation therapy and is alive and well without clinical evidence of disease 109 months after diagnosis. The neoplastic cells stained immunohistochemically for cytokeratin and epithelial membrane antigen but were unreactive with B72.3, anti-carcinoembryonic antigen, and anti-Leu-M1. Ultrastructurally, the tumor cells had abundant desmosomes, numerous tonofilament bundles, and variable-length microvilli. These findings confirm the mesothelial nature of the cells. Features consistent with malignancy included DNA aneuploidy by flow cytometric analysis and diffuse peritoneal involvement. The three previously described survivors with MPM were also premenarchal girls. Some MPMs in premenarchal girls have an indolent biologic behavior similar to that of low-grade peritoneal serous neoplasia or well-differentiated papillary mesothelioma in adult women.

Intravascular menstrual endometrium, a rare finding in hysterectomy specimens, can pose clinically critical differential diagnostic problems. We describe a 28-year-old female with cervical dysplasia and numerous foci of menstrual endometrium in the parametrial blood vessels of her subsequent hysterectomy specimen. Histologically, the intravascular tissue consisted of small spindled stromal cells, larger cuboidal epithelial cells, or both components in close association. Immunohistochemically, the small spindled cells were vimentin positive and the larger cuboidal cells stained with epithelial markers. Distinction of intravascular menstrual endometrium from intravascular malignancies such as carcinoma, sarcoma, or lymphoma may be difficult, especially at the time of frozen-section diagnosis. Awareness of this process, attention to its cytologically bland, usually biphasic appearance, knowledge of the menstrual status, and application of appropriate immunohistochemical markers will allow distinction from neoplasia.

We present an unusual case of an extremely well-differentiated but deeply invasive squamous cell carcinoma of the penis without an obvious external lesion, arising from a chronic draining sinus tract. This case highlights how a confounding clinical history, physical examination and initial biopsies may lead to a significant delay in diagnosis. This delay may have resulted in tumour growth and the need for a more extensive partial penectomy than would have occurred had the diagnosis been made more promptly. Finally, this case demonstrates the key diagnostic utility of deep core biopsies of the penis in situations where a cutaneous lesion does not exist.

Cervical carcinoma is the most common cancer among Belizean women; however, data regarding the frequency of human papillomavirus (HPV) genotypes and their association with cervical cancer are nonexistent. We therefore included HPV genotyping as part of a week-long cervical cancer screening campaign conducted in Belize City in 2007. Conventional Papanicolaou smears with Hybrid Capture (HC) 2 HPV testing were performed on 463 women. All HC2-positive samples were genotyped using a developmental GP5+/GP6+ polymerase chain reaction-coupled Luminex assay for 2 low-risk and 18 high-risk HPV types. The prevalence of high-risk HPV was 15.6% in the total population, 10.1% in those with normal cytologic findings, and 93.3% in women with a high-grade squamous intraepithelial lesion. Of patients with HPV infections, 35% had multiple types (5.4% of the total group). Of all women and of women with normal cytologic findings, 5.2% and 2.8%, respectively, had HPV16 or 18. For all women, HPV16, 18, 56, and 52 were present in decreasing order of frequency. HPV11 was present in only one patient, and none had HPV6. HPV16 was found in 47% of high-grade squamous epithelial lesions; however, no case of HSIL had HPV18 or 45. HPV35 and HPV58 were the next most common types in high-grade squamous intraepithelial lesion, each occurring in 20% of cases of high-grade squamous intraepithelial lesion, followed by HPV31 in 13.3%. Although women younger than 25 years old were underrepresented, these data suggest that the HPV profile of this cohort of Belizean women differs somewhat from that in the region. In addition, these data are of importance with regard to the development of HPV vaccines that will be used in less developed countries, where care should be taken not to implement vaccination at the cost of basic screening and diagnostic services.

Purpose: Metastatic melanomas are generally resistant to chemotherapy and radiation, even when wild-type for p53. These tumors often grow in small nests where many of the cells have little contact with extracellular matrix (ECM). Previous work showed that M21 melanomas undergo apoptosis in response to chemotherapy when cells are adherent to ECM but not in suspension. Thus, reduced integrin-dependent adhesion to ECM could mediate therapy resistance. The goal of this study was to test whether stimulation of integrin signaling could increase chemotherapeutic efficacy. Experimental Design: Colony forming assays and survival assays were used to test the responses of melanoma lines in vitro. Severe combined immunodeficient mice with subcutaneous human melanomas received chemotherapy with or without reagents that stimulate integrin signaling; tumor volume was then monitored over time. Results: Clonal growth assays confirmed that M21 cells showed reduced sensitivity to the chemotherapeutic drug 1-β-d-arabinofuranosylcytosine (araC). When five additional primary melanoma lines were screened, 80% showed higher sensitivity when adherent compared with suspended. Subcutaneous M21 tumors in vivo showed minimal ECM between tumor cells. To evaluate the importance of integrin signaling in chemoresistance in this model, mice were treated with araC, with or without the multivalent snake venom disintegrin contortrostatin or the activating anti-β1 integrin antibody TS2/16. Although araC, TS2/16, or contortrostatin alone had little effect on M21 tumor growth, combining araC with either integrin signaling reagents strongly reduced growth (P = 0001). Conclusions: Loss of integrin-mediated adhesion is rate limiting for therapeutic response in this model. Combining chemotherapy with reagents that stimulate integrin signaling may therefore provide a new approach to therapy.

Telepathology is useful when distance is an obstacle to timely diagnosis. Performance of fine-needle aspiration (FNA) at locations distant from cytopathologists can limit timely assessment of adequacy and preliminary diagnosis. We evaluated a telepathology system for consultation between residents and faculty for assessment of FNA specimen adequacy and preliminary diagnosis using 100 consecutive cases. We compared findings with the original assessment of adequacy, preliminary interpretation, and final diagnosis. Two residents initially screened 50 cases, and images were then transmitted to cytopathologists, who communicated by telephone. We found 97% diagnostic concordance and 99% accuracy. The screening time ranged from 41 seconds to 30:19 minutes (mean, 6:35 minutes). The viewing time ranged from 10 seconds to 12:50 minutes (mean, 3:52 minutes). Our telepathology system is efficient and accurate for the initial assessment and preliminary diagnosis of FNA specimens, but we recommend its use by more senior and experienced trainees.

Intraoperative frozen section (FS) consultation is used in evaluating possible infection in cases of hip and knee revision arthroplasty, serving as an adjunct to preoperative and intraoperative studies. We examined our experience for more than 11 years to determine if FS examination had value when sections were sent nonselectively. We reviewed 244 cases, 132 with available culture results. The criterion for the presence of acute inflammation was more than 5 polymorphonuclear leukocytes per high-power field (hpf) in at least 5 separate hpfs, excluding surface inflammatory exudate and fibrin. Only 27 cases (11.1%) demonstrated positive FS or paraffin section results. In comparison with intraoperative culture, the sensitivity, specificity, positive predictive value, and negative predictive value for FS analysis alone (on review) were 29%, 95%, 40%, and 92%. As currently used, FS analysis has excellent specificity and negative predictive value but poor sensitivity and positive predictive value. We suggest that FS examination be used more selectively in conjunction with other studies, namely erythrocyte sedimentation rate and C-reactive protein.

SUMMARY Esophageal biopsy remains an important procedure for the diagnosis of RE, as well as for the identification of other causes of esophagitis. Although grasp biopsy specimens obtained by fiberoptic endoscopy are routinely performed for patients suspected of having reflux disease, they are infrequently oriented prior to their submission to the surgical pathology laboratory. Basal zone thickness and height of papillae, parameters considered by most pathologists to be useful for the diagnosis of RE, cannot be evaluated in unoriented sections. Hence, the search for intraepithelial neutrophils, and especially intraepithelial eosinophils, is critically important in grasp biopsy specimens. The finding of only a few intraesophageal eosinophils is sufficient for the diagnosis of reflux esophagitis (in the proper clinical setting) in both children and adults. In any biopsy specimen, the identification of eosinophils is easier and more reliable than the determination of basal zone thickness and height of papillae. The significance of finding only balloon cells in esophageal biopsy specimens from patients with suspected RE needs to be clarified by further study.

Residents in anatomic pathology are allowed increased diagnostic responsibility including the initial interpretation of intraoperative frozen-section consultations during their years of training. This frozen-section responsibility requires staff faculty backup for diagnostic confirmation and consultation. In this study, we tested a telepathology system using an ultra portable computer with a 4.5-in diagonal screen (scrolled image size of 2.5 x 1.75 in, width x height) and both wireless Local Area Network (LAN) final connection from a DSL and wireless Wide Area Network (WAN) telecommunications. The diagnostic agreement for a chief resident/faculty staff duo using telepathology for 100 consecutive frozen-section cases (50 with wireless LAN final connection and 50 with wireless WAN) with limited clinical information was compared with the original frozen-section diagnosis rendered by other staff pathologists. There was diagnostic agreement for 95 of the 100 cases. For the 5 that were discordant, 2 were deemed to be errors in the original frozen-section diagnosis; 1 was not clinically important; and 2 were believed to have potential clinical implications. For the 2 having potential clinical importance, the absence of knowledge of the gross findings in each case and the preoperative biopsy results for one specimen contributed to the misinterpretation of the frozen sections. The median time between transmission of image(s) from the chief resident to the faculty consultant until diagnosis by the latter was 1 minute 42 seconds for wireless WAN and 51 seconds for the wireless LAN final connection to the display device. We conclude that a telepathology system using an ultra portable computer and wireless telecommunications is useful for frozen-section consultation between an experienced resident and a faculty member in pathology.

Prostate cancer (PCa) is the second leading cause of cancer death in American men, and the cure for metastatic disease remains a significant challenge. While nearly all patients with disseminated PCa initially respond to androgen deprivation therapy (ADT), virtually every patient will relapse and develop incurable castration-resistant prostate cancer (CRPC). Androgen receptor (AR) signaling pathways continue to play a crucial role in CRPC progression. Previous studies have shown that signal transduction pathways can stimulate AR activation, suggesting that the ability of signaling cascades to influence AR function may have a significant role in CRPC progression, and that CRPC may not be effectively treated by ligand-directed therapy alone. A high-throughput RNAi screen identifying signaling pathways that regulate PCa cell growth led to our discovery that knockdown of Checkpoint Kinase 2 (CHK2) dramatically increased PCa proliferation in the presence and absence of androgen. Furthermore, CHK2 depletion hypersensitized cells to castrate androgen levels. These CHK2-mediated effects on growth were dependent on the downstream signaling proteins CDC25C and CDK1 and could be blocked by the AR antagonist MDV3100. Immunohistochemical analysis of CHK2 in patient samples demonstrated that reduced CHK2 expression significantly correlated with increased Gleason score indicating the clinical relevance of CHK2 in PCa. Moreover, CHK2 expression is lower in castration-resistant C4-2 and CWR22Rv1 cells compared to androgen-sensitive LNCaP cells consistent with loss of CHK2 expression during PCa progression. CHK2 depletion increased AR transcriptional activity on both androgen-activated and androgen-repressed genes, substantiating that CHK2 affects PCa growth through the AR. Remarkably, quantitative PCR, chromatin immunoprecipitation, and western blot analyses revealed that CHK2 is a novel AR-repressed gene, suggesting a negative feedback loop between CHK2 and the AR. Furthermore, we show that CHK2 physically associates with the AR, and that cellular stress, such as DNA damage and serum starvation, increases this association. Based on these data, we propose that CHK2 is a negative regulator of androgen sensitivity and PCa growth. Thus, alterations to CHK2 signaling may sensitize CRPC to ADT and radiation. Citation Format: Huy Q. Ta, Melissa L. Ivey, Henry F. Frierson, Mark R. Conaway, Jaroslaw Dziegielewski, James M. Larner, Daniel Gioeli. Checkpoint kinase 2 is a novel regulator of prostate cancer cell growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5049. doi:10.1158/1538-7445.AM2015-5049

Fine-needle aspiration (FNA) is used for the diagnosis and triaging of thyroid lesions. Recently, it has been shown that the pathologic interpretation of selected thyroid specimens can show a high degree of interobserver variability (IV). Because Hurthle cells may be seen in neoplastic and nonneoplastic disease, we investigated whether pathologists consistently interpret FNA specimens from these lesions. In the present study, 22 FNA specimens that showed Hurthle cells as the predominant cell type were reviewed by 7 pathologists. Cytologic features were assessed semiquantitatively. IV was calculated, and individual case diagnoses were compared with cytologic features. IV was high before diagnoses were collapsed into like diagnoses and triage recommendations (k = 0.17, 0.44, and 0.51, respectively). Overall cellularity, number of Hurthle cells, and number of lymphocytes all correlated with collapsed diagnostic agreement, and the number of air-dried rapid Romanowsky-stained slides, overall cellularity, number of Hurthle cells, and number of lymphocytes all correlated with collapsed triage recommendations.

The histologic boundaries of the extrahepatic bile ducts (EBDs) are not well defined, despite the fact that pathologic staging of carcinomas arising in these structures requires the determination of extent of tumor invasion in this area. Perhaps in part, because the smooth muscle band in the EBD wall is not well formed throughout the length of these structures, a previous definition of the outer portion of the bile duct wall included "loose, richly vascularized connective tissue, interlaced with large nerve fibers." We have experienced difficulty in the application of these criteria in staging EBD carcinomas, which requires the histologic determination of the extent of the EBD wall. To systematically study the histologic features of EBD tissue boundaries, 34 EBD specimens obtained from autopsy were analyzed with attention to the distribution of blood vessels and nerve fibers along the length of this system. The EBD specimens were divided into lower, middle, and upper portions, and the locations of blood vessels and nerve fibers were then analyzed separately at each location. We defined the fibromuscular wall as the dense concentric arrangement of collagen and smooth muscle fibers surrounding the EBD mucosa. The location of blood vessels and nerve fibers was categorized as either (1) within, (2) junctional to, or (3) outside of the fibromuscular wall. Blood vessels and nerve fibers are located predominantly outside of the fibromuscular wall and are usually surrounded by adipose tissue throughout the entire EBD, however, their distribution in this location is not consistent. Because of these histologic features, we propose that the bile duct wall is more precisely defined as occurring between the mucosa and the outermost boundary of dense fibromuscular tissue, without consideration of the presence or absence of blood vessels and nerve fibers.

Population-based cancer registries, such as those included in the Surveillance, Epidemiology, and End-Results (SEER) Program, offer tremendous research potential beyond traditional surveillance activities. We describe the expansion of SEER registries to gather formalin-fixed, paraffin-embedded tissue from cancer patients on a population basis. Population-based tissue banks have the advantage of providing an unbiased sampling frame for evaluating the public health impact of genes or protein targets that may be used for therapeutic or diagnostic purposes in defined communities. Such repositories provide a unique resource for testing new molecular classification schemes for cancer, validating new biologic markers of malignancy, prognosis and progression, assessing therapeutic targets, and measuring allele frequencies of cancer-associated genetic polymorphisms or germline mutations in representative samples. The assembly of tissue microarrays will allow for the use of rapid, large-scale protein-expression profiling of tumor samples while limiting depletion of this valuable resource. Access to biologic specimens through SEER registries will provide researchers with demographic, clinical, and risk factor information on cancer patients with assured data quality and completeness. Clinical outcome data, such as disease-free survival, can be correlated with previously validated prognostic markers. Furthermore, the anonymity of the study subject can be protected through rigorous standards of confidentiality. SEER-based tissue resources represent a step forward in true, population-based tissue repositories of tumors from US patients and may serve as a foundation for molecular epidemiology studies of cancer in this country.

Lymph node status is a critical prognostic factor for atients after radical surgery and lymphadenectomy for rostate, bladder, or kidney cancer. Yet much like our preecessors, urologists in 2004 rely on our colleagues in athology to provide us answers regarding the presence or bsence of metastases in lymph nodes. Pathologists use odern versions of methods and concepts developed long go with the description of the first usable compound miroscope by Antonj van Leeuwenhoek (1632–1723) and the ork of Rudolf Virchow (1821–1905) who was the first to ecognize that diseases arise from alterations within cells nd tissues. Yet clearly, cancer is a disease of cells having bnormal gene expression, and therefore, diagnosis and rognostication might be augmented by molecular tools. Application of such tools potentially allows more sensitive etection of cancer cells within examined lymph nodes. Alhough additional H&E-stained sections can be cut and examned, immunohistochemical and molecular assays offer enanced sensitivity for the determination of lymph node status. tudies evaluating methods other than additional routine H&Etained sections to enhance sensitivity for detecting lymph ode metastases have been carried out for prostate and bladder ancer, and will be summarized below.

We present a case of low-grade yet recurrent and invasive squamous cell carcinoma that may constitute a new biological variant of penile cancer.