Experts and performance in histopathology--a study in breast pathology.

This study was undertaken to determine if it was possible to identify expertise within Histopathologists (trainees, district general pathologists and pathologists with a special interest in breast disease) using an objective measure of performance. The method of assessment of performance is based on the CWS (Cochran-Weiss-Shanteau) ratio formed by the individual's ability to discriminate between a spectrum of disease categories and their level of inconsistency when assessed at intervals. The slides circulated represented the spectrum of breast disease seen in routine practice. The results demonstrated the average CWS ratio to be lowest in trainees and highest in pathologists with a special interest in breast pathology although there was no statistical difference in the CWS scores obtained between the district general pathologists and pathologists with a special interest. Differences in inconsistency rather than discriminatory ability mainly accounted for the difference in the CWS ratio observed between the groups studied. The study shows that the CWS ratio is potentially a very useful tool in the assessment of pathologists with regard to assessing their progress through training.

External quality assessment slide schemes: pathologists' experiences and perceptions.

BACKGROUND: External quality assessment schemes (EQAS) in pathology have been established in the United Kingdom for several years with the aim of raising standards. OBJECTIVE: To determine the experiences and perceptions of pathologists undertaking EQAS. METHODS: A questionnaire was distributed to histo/cytopathologists in the south and west of England. RESULTS: A large proportion of pathologists responding felt that the EQAS was educational, and 69% said participation had encouraged them to undertake additional educational activities. Some reservations were expressed about marking schemes. Asked if EQAS using digital images (CD-ROM or web based) rather that glass slides were valid alternatives two thirds responded no, despite 75% claiming to have appropriate IT skills. CONCLUSIONS: EQAS play a valuable role in helping to maintain standards in histopathology and cytopathology. Some reservations were expressed about the marking schemes and further work is needed to establish a robust marking method. Significant barriers need to be overcome if digital EQAS are to be successfully implemented.

The NHS breast screening programme (pathology) EQA: experience in recent years relating to issues involved in individual performance appraisal.

BACKGROUND: The original role of the National Health Service breast screening programme (pathology) external quality assessment (EQA) scheme was educational; it aimed to raise standards, reinforce use of common terminology, and assess the consistency of pathology reporting of breast disease in the UK. AIMS/METHODS: To examine the performance (scores) of pathologists participating in the scheme in recent years. The scheme has evolved to help identify poor performers, reliant upon setting an acceptable cutpoint. Therefore, the effects of different cutpoint strategies were evaluated and implications discussed. RESULTS/CONCLUSIONS: Pathologists who joined the scheme improved over time, particularly those who did less well initially. There was no obvious association between performance and the number of breast cancer cases reported each year. This is not unexpected because the EQA does not measure expertise, but was established to demonstrate a common level of performance (conformity to consensus) for routine cases, rather than the ability to diagnose unusual/difficult cases. A new method of establishing cutpoints using interquartile ranges is proposed. The findings also suggest that EQA can alter a pathologist's practice: those who leave the scheme (for whatever reason) have, on average, marginally lower scores. Consequently, with the cutpoint methodology currently used (which is common to several EQA schemes) there is the potential for the cutpoint to drift upwards. In future, individuals previously deemed competent could subsequently be erroneously labelled as poor performers. Due consideration should be given to this issue with future development of schemes.

Impact of a national external quality assessment scheme for breast pathology in the UK.

BACKGROUND: This article presents the results and observed effects of the UK National Health Service Breast Screening Programme (NHSBSP) external quality assurance scheme in breast histopathology. AIMS/METHODS: The major objectives were to monitor and improve the consistency of diagnoses made by pathologists and the quality of prognostic information in pathology reports. The scheme is based on a twice yearly circulation of 12 cases to over 600 registered participants. The level of agreement was generally measured using kappa statistics. RESULTS: Four main situations were encountered with respect to diagnostic consistency, namely: (1) where consistency is naturally very high-this included diagnosing in situ and invasive carcinomas (and certain distinctive subtypes) and uncomplicated benign lesions; (2) where the level of consistency was low but could be improved by making guidelines more detailed and explicit-this included histological grading; (3) where consistency could be improved but only by changing the system of classification-this included classification of ductal carcinoma in situ; and (4) where no improvement in consistency could be achieved-this included diagnosing atypical hyperplasia and reporting vascular invasion. Size measurements were more consistent for invasive than in situ carcinomas. Even in cases where there is a high level of agreement on tumour size, a few widely outlying measurements were encountered, for which no explanation is readily forthcoming. CONCLUSIONS: These results broadly confirm the robustness of the systems of breast disease diagnosis and classification adopted by the NHSBSP, and also identify areas where improvement or new approaches are required.

Are external quality assurance (EQA) slide schemes a valid tool for the performance assessment of histopathologists?

Quality assurance plays a vital role in the healthcare profession and histopathologists play a central role in the diagnosis and treatment of disease. In the past these specialists have worked in isolation and quality assurance of their work has been difficult. In recent years this has changed with the introduction of External Quality Assurance slide schemes. This paper discusses how these schemes have evolved, the problems of standard setting and their validity as a measure of pathologists performance.

Age is an independent prognostic factor in rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: Although age <1 year at diagnosis has been associated with a worse prognosis in rhabdomyosarcoma (RMS), the relationship of age at diagnosis to clinical presentation and outcome has not been evaluated carefully. We reviewed data from recent Intergroup Rhabdomyosarcoma Study Committee (later called Group, IRSG) trials to examine this relationship in order to estimate prognosis more accurately and further refine treatment. PROCEDURE: We used data from IRS-III, -IV Pilot, and -IV (1983-97, N=2,343) to study the relationship of patient age with clinical features and prognosis in a large cohort of patients treated with contemporary therapy. RESULTS: We showed that, after adjusting for important prognostic factors, age was an independent risk factor for treatment failure and patients could be classified into three failure-risk categories based on age (i.e., <1 year; 1-9 years; >10 years). Infants and adolescents were more likely to have unfavorable features, including alveolar or undifferentiated tumors and advanced Group and Stage, and also had significantly poorer failure-free survival (FFS) than did children aged 1-9 (53 and 51% vs. 72%, P<0.001). Although there was a difference in FFS among age categories, there was no evidence that age influences outcome within the three categories. CONCLUSIONS: Since age relates independently to outcome after adjustment for known risk factors, it is likely that other factors, including perhaps patients' tolerance of protocol-specified therapy, explain this relationship.

Rhabdomyosarcoma of the parotid region occurring in childhood and adolescence. A report from the Intergroup Rhabdomyosarcoma Study Group.

BACKGROUND: Rhabdomyosarcoma (RMS) of the parotid region is rare and to the authors' knowledge little information is available regarding the site of tumor origin, clinical presentation, and outcome in these patients. Therefore, the authors reviewed the files of all patients with RMS of the parotid region who were registered on the Intergroup Rhabdomyosarcoma Studies (IRS) I-IV. METHODS: Patient charts and the Intergroup Rhabdomyosarcoma Study Group (IRSG) database were reviewed. RESULTS: Sixty-two patients presenting with a mass in the parotid region were identified. None of the tumors was localized exclusively to the parotid gland, so the primary site was referred to as the "parotid region." The tumor invaded a parameningeal site in 30 patients. These cases have been designated as parameningeal-parotid tumors to distinguish them from 32 cases that did not invade a parameningeal site and were designated as nonparameningeal-parotid tumors. The majority of patients had Group III tumors in both the nonparameningeal-parotid and parameningeal-parotid subgroups. However, although there were 16 patients with Group I or II tumors in the nonparameningeal-parotid subgroup, no patients with Group I or II tumors were found in the parameningeal-parotid subgroup (P = 0.001). Fifty-six of 62 patients (90%) received radiotherapy. The parameningeal primary site designation resulted in intensification of both chemotherapy and radiotherapy for patients with parameningeal-parotid RMS. The 5-year failure-free survival rate was 81% and the 5-year survival rate was 84%. There were no deaths reported among patients with Group I or II tumors. The 5-year failure-free survival did not appear to differ when comparing patients with parameningeal-parotid tumors with patients with nonparameningeal-parotid tumors (P = 0.21). CONCLUSIONS: Treatment as defined by the IRS protocols has been reported to be highly effective for patients with RMS of the parotid region. Outcome for the more aggressively treated patients with parameningeal-parotid RMS appears similar to that for patients with nonparameningeal-parotid RMS.

Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group.

BACKGROUND: The cure rate for children/adolescents with localized rhabdomyosarcoma (RMS) has tripled over the past 25 years, but patients with metastatic disease at presentation have not benefited similarly, and urgently need new therapy. We evaluated a new drug pair, ifosfamide + doxorubicin, for such patients. PROCEDURE: We estimated the complete and partial response rates (i.e., CR and PR) of 152 previously untreated children/adolescents with metastatic RMS entered on the IRS-IV pilot from July 1988 to October 1991 who received an "up-front window" of ifosfamide (1.8 gm/m(2)/day for 5 days) and doxorubicin (30 mg/m(2)/day for 2 days) given every 3 weeks for 12 weeks. This was followed by combination chemotherapy with vincristine, actinomycin D, and cyclophosphamide (VAC), given every 3 weeks for an additional 36 weeks. RESULTS: Of 115 patients evaluable for early response at 12 weeks, 28 (20%) had CR and 66 (43%) had PR. The ultimate CR rate was 52%. Overall, about one-third of patients survived. Prognostic factor analysis revealed that patients < 10 years old (P < 0.001), those with embryonal tumors (P = 0.002), or a GU primary site (P = 0.010), and those who lacked nodal disease (P = 0.041), and those who lacked bone or bone marrow metastasis (P < 0.001) fared better than did others. CONCLUSIONS: The 63% CR + PR rate achieved at 12 weeks and overall 5-year FFS seen with this drug pair is similar to that achieved with previously evaluated drug combinations. We conclude that ifosfamide/doxorubicin is highly active in advanced RMS, and should be considered for inclusion in frontline therapy for children with intermediate or high-risk RMS.

Factors associated with delays in accessing HIV primary care in rural Arkansas.

While debate continues at what stage of human immunodeficiency virus (HIV) disease to begin combination antiretroviral therapy, a number of clinical and public health benefits are linked to early entry into primary care soon after first testing HIV positive. However, HIV-infected patients continue to test late and delay entry into care. We used routinely collected demographic and clinical information to examine which factors are associated with delays in seeking care in a predominantly rural, economically poor area of Arkansas. The study population is 75% African American and male and 70% lack health insurance; nearly one fourth were referred from prison. At diagnosis, two thirds of the population had CD4 counts below 500 cells per microliter. Days from initial HIV diagnosis to entry into care declined from a median of 178 in 1994 to 24 in 1998. In 1998, 75% of the population entered into primary care within 2 months of diagnosis. However, CD4 counts at HIV diagnosis also declined in this period, from a median of 427 in 1995 to 208 cells per microliter in 1998. More recent year of diagnosis was associated with a shorter delay in seeking care; males, and individuals lacking health insurance took significantly longer to enter into care than females and those with insurance, respectively. Our univariate finding of extensive delays in seeking care in the prison population did not hold in the multivariate analysis. We found significant delays in time to initial HIV diagnosis, and further considerable delays in males and those lacking health insurance in the time taken to enter into primary care.

Pathologic classification of rhabdomyosarcomas and correlations with molecular studies.

Rhabdomyosarcoma, the most common soft-tissue malignancy of childhood and adolescence, comprises a group of differing pathobiologic entities linked by their common propensity for formation of neoplastic skeletal muscle, a feature that results from biological forces related to aberrant transcription signals and the resultant production of myogenic proteins. At a molecular level, however, rhabdomyosarcomas form a heterogeneous group that can be subdivided into distinct clinicopathologic entities based on morphologic appearance and genetic makeup. These differing morphologic features were recognized in the mid-1900s by Horn and Enterline with their division of rhabdomyosarcomas into embryonal, alveolar, botryoid, and pleomorphic subtypes. More recent histologic and biologic studies have resulted in description of additional entities, such as spindle cell and anaplastic rhabdomyosarcoma, and refinements in recognition of the original entities, such as solid-alveolar rhabdomyosarcoma. Familiarity with newer classifications and their relationship to molecular aberrations is key to stratifying patients on current therapeutic protocols and proposed innovative genetic therapies.

The frozen section yesterday and today: pediatric solid tumors--crucial issues.

This article is the offshoot of a Pediatric Oncology Group (POG) seminar presented at the Adams Mark Hotel, Denver, Colorado, Friday, May 21, 1999, titled "The Frozen Section in Pediatric Solid Tumors--Crucial Issues." There were eight presenters who spoke on a wide range of topics that included historical perspectives of the frozen section and discussion of the following systems: brain, renal, germ cell, bone, soft tissue, and lymph nodes. To complement these presentations, a pediatric surgeon explained his concern and philosophy regarding the use of frozen sections, and a lawyer tackled the issues and risks in rendering a frozen section diagnosis. We think that this review covers all the important aspects of the frozen section in our current practice of pediatric pathology.

Thallium bone imaging as an indicator of response and outcome in nonmetastatic primary extremity osteosarcoma.

PURPOSE: We investigated one 201Tl bone scintigraphy method as a predictor of histologic response and event-free survival (EFS) of nonmetastatic extremity osteosarcoma. MATERIALS AND METHODS: We evaluated images of the primary tumor to determine whether they exhibited a donut of avidity for 40 patients enrolled on a single institutional protocol. Participants underwent three serial 201Tl bone scintigraphy studies during preoperative neoadjuvant chemotherapy. Intra- and interobserver variability of the method was assessed, and the presence of the donut of avidity was examined as a predictor of EFS and histologic response. RESULTS: Fifty-three percent of patients were female and 75% were Caucasian; the median age at diagnosis was 13.5 years. Intraobserver agreement was moderate to very good, ranging from 0.595 to 0.865. Interobserver agreement was moderate to good for all time points, ranging from 0.576 to 0.708. There was a significant difference in EFS among patients with and without the donut-shape at any of the three time points (P = 0.049); patients whose tumors displayed a donutshape had inferior EFS. CONCLUSION: The pattern of donut avidity in extremity OS is a predictor of lower EFS, but does not correlate with histologic response to therapy.

Primary malignant neuroepithelial tumors of the kidney: a clinicopathologic analysis of 146 adult and pediatric cases from the National Wilms' Tumor Study Group Pathology Center.

Primary malignant neuroepithelial tumors of the kidney (NETKs) comprise a group of primitive, highly malignant neoplasms that histologically and clinically are not well characterized. A large cohort of 146 of these tumors, occurring in adults and children, has been collected at a single depository site, the National Wilms' Tumor Study Group (NWTSG) Pathology Center. The authors undertook a systematic retrospective review of the histologic, ultrastructural, and clinical features of these tumors, based on materials collected by the NWTSG and the consultation files of one of the authors (J.B.B.). Histologic features were generally those of primitive neural tumors with varying amounts of rosettes and neuropil; however, a large proportion of cases displayed unusual features such as spindle cells, ganglion cells, clear cell sarcoma-like foci, rhabdoid cells, epithelioid cells, and organoid foci. CD99 staining had been performed on 69 cases and showed membranous staining in 65. The NETKs were present in patients with a wide age spectrum, ranging from 1 month to 72 years (median, 18 years). EWS/FLI1 fusion analysis using reverse transcriptase-polymerase chain reaction and immunohistochemical stains for cytokeratin, chromogranin, and epithelial membrane antigen were performed successfully on a subset of 45 cases with available paraffin blocks. Only 13 of the 45 were fusion-positive, and there was no correlation between fusion status and histology, presence of rosettes, ultrastructural features, or cytokeratin positivity. CD99-negative cases were usually fusion-negative (six of seven cases), and all three chromogranin-positive cases were fusion-negative. Tumor staging, performed on 72 clearly defined and quantifiable cases by using NWTSG criteria, indicated that these are aggressive tumors, because only six were Stage 1, compared with 16 Stage 2, 31 Stage 3, and 19 Stage 4 lesions. The authors conclude that NETKs are a somewhat diverse group of generally aggressive, high-grade lesions that may present in a wide age range and are difficult to characterize without immunohistochemistry and cytogenetics/molecular biology.

Comparison of immunohistochemistry and silver stain for the diagnosis of pediatric Helicobacter pylori infection in urease-negative gastric biopsies.

We compared immunohistochemical and silver stains of pediatric gastric biopsy sections for the identification of Helicobacter pylori infection with chronic inflammation and a negative urease screening test. Thirty-seven patients (age range 10 months to 21 years) whose gastric antral biopsies were negative for the rapid urease test (CLO(R)) but positive for lymphocytic infiltration were selected for a retrospective study. Specimens had been subjected to a rapid urease test (CLO(R)) and hematoxylin and eosin staining, and Dieterle silver staining and immunohistochemical staining specific for H. pylori were also performed. Twelve additional patients with urease-positive biopsies were used as controls. With Dieterle staining, 8/37 (22%) urease-negative biopsies contained organisms morphologically compatible with H. pylori, 21/37 (56%) contained organisms not compatible with H. pylori, and 8/37 (22%) were negative for organisms. Immunostaining confirmed 6/8 (75%) Dieterle-positive cases as being H. pylori, was negative in 2/8 (25%) Dieterle-positive cases, and was positive in 2/8 (25%) Dieterle-negative cases. Biopsies from 8/12 (67%) urease-positive specimens contained organisms seen with both Dieterle and immunohistochemical stains, and 4/12 (33%) were negative with both stains. Although both stains yielded comparable results with H. pylori-positive biopsies, Dieterle staining was potentially confusing because of nonspecific staining of other organisms. A significant proportion of (CLO(R))-negative biopsies was positive for H. pylori with special stains. We therefore recommend the use of immunohistochemical staining rather than silver staining in the evaluation of urease-negative gastric biopsies demonstrating chronic inflammation in children.

Carboplatin/ifosfamide window therapy for osteosarcoma: results of the St Jude Children's Research Hospital OS-91 trial.

PURPOSE: To determine the activity of carboplatin/ifosfamide in patients with previously untreated osteosarcoma and to estimate patient outcomes after a multiagent chemotherapy protocol that eliminated cisplatin. PATIENTS AND METHODS: Sixty-nine patients with newly diagnosed, previously untreated osteosarcoma received three cycles of carboplatin (560 mg/m(2) x 1) and ifosfamide (2.65 g/m(2)/d x 3). Assessment of response was evaluated after two (week 6) and three (week 9) chemotherapy cycles. At week 9, histologic response was assessed. Adjuvant therapy comprised two additional carboplatin/ifosfamide cycles, doxorubicin, and high-dose methotrexate. Patients were stratified at enrollment: stratum A, resectable primary tumor without metastases; stratum B, unresectable primary tumor; and stratum C, metastatic disease at diagnosis. Week 6 response was compared with that of a historic group that received only ifosfamide during the initial window evaluation. RESULTS: The clinical and radiographic response rate to three cycles of carboplatin/ifosfamide was 67.7% (95% confidence interval, 55.0% to 78.8%). Compared with the historic population who received only ifosfamide, the combination of carboplatin and ifosfamide reduced the progressive disease rate at week 6 (31.9% v 9%, P: = .003). For patients in stratum A, the 3-year event-free survival and survival were 72.3% +/- 6.7% and 76.4% +/- 6.4%, respectively. Patients who received carboplatin-based therapy had less long-term renal toxicity and ototoxicity. CONCLUSION: This pilot trial suggests that carboplatin/ifosfamide combination chemotherapy has substantial antitumor activity. In the context of a multiagent chemotherapy protocol comprising high-dose methotrexate and doxorubicin, we found that the addition of carboplatin/ifosfamide resulted in patient outcomes comparable to trials using cisplatin-based therapy with less long-term toxicity.

Axillary lymph node scarring and the association with tumour response following neoadjuvant chemoendocrine therapy for breast cancer.

We observed that the axillary lymph nodes of some of our breast cancer patients who received neoadjuvant chemoendocrine therapy (NCT) showed evidence of scarring. The purpose of this study is to determine whether such scarring exists and, if so, whether it is confined to neoadjuvant patients and may be related to response to therapy of the primary tumour. We examined the axillary lymph nodes of a consecutive series of 255 breast cancer patients, all of whom had undergone radical axillary dissection. Fifty-three had received NCT; the remainder formed the control group. A scar was defined as an area of cellular fibrous tissue >0.25 mm in diameter and for each patient scar count, median size and score were recorded. Nodes with scars were stained immunohistochemically (IHC) with 2 epithelial markers for the presence of occult micrometastases. The nodes of 20.7% of patients who had received NCT contained scars compared with 13.4% of controls. The median scar size was significantly greater in neoadjuvant patients (P<0.001) and within this group scar count and score were significantly higher (P=0.026 and 0.020) in those with no or minimal evidence of residual primary tumour. Scars which were IHC-positive for micrometastases were almost exclusively confined to neoadjuvant patients. Our results suggest that axillary lymph node scarring does exist, but is not a common phenomenon. It is more significant in neoadjuvant patients and within this group is most marked in those with the greatest primary tumour response to therapy. We believe that scarring is likely to represent downstaging of axillary disease. A prospective study involving a larger group of patients receiving NCT is indicated, to confirm these preliminary findings and establish whether scarring has prognostic or predictive potential.

Fibroadenoma with atypical giant cells occurring in Li Fraumeni Syndrome.

This report describes a patient with Li Fraumeni Syndrome who first presented with an unusual fibroadenoma containing atypical multinucleated giant cells. These cells are thought to be fibrohistiocytic in nature and are rarely seen in fibroepithelial lesions of the breast. Previously these cells were considered incidental in nature. The possibility of Li Fraumeni Syndrome needs to be considered when such features are encountered in future.