p16INK4a expression in actinic keratosis and Bowen's disease.

BACKGROUND: Progression of cutaneous squamous neoplasms from actinic keratosis (AK) to Bowen's disease (BD; squamous cell carcinoma in situ) has important implications for clinical management and treatment, thus requiring accurate diagnosis. p16INK4a is a cell cycle regulatory tumour suppressor protein that negatively regulates D-type cyclins in the G1 cell cycle phase via intimate interplay with the retinoblastoma gene. Expression of a paraffin-reactive p16INK4a marker has recently been shown to increase in cervical squamous neoplasms as lesions progress from low-grade dysplasia to squamous cell carcinoma in situ. p16INK4a expression in the progression of squamous cutaneous neoplasia, however, has not been evaluated. OBJECTIVES: To evaluate p16INK4a expression in the progression of squamous cutaneous neoplasia. METHODS: Biopsies of 203 squamous cutaneous neoplasms with unequivocal features of AK (n = 87) and BD (n = 116) as well as a benign squamous control group (verruca vulgaris: n = 10; seborrhoeic keratosis: n = 11; scar tissue: n = 8) obtained between January and December 2001 at Henry Ford Hospital (Detroit, MI, U.S.A.) were immunostained for p16INK4a (Dako; clone E6H4; dilution 1 : 50) using large core (1.5 mm) tissue microarray analysis. Nuclear/cytoplasmic immunoreactivity in > 10% of neoplastic cells was considered positive. RESULTS: Of 203 cases, 166 (81.8%) were interpretable (AK 59; BD 107). Mean patient age was 71.0 years (range 33-93); 57% were male. Sites of involvement were: head and extremities 75.9%, trunk/buttocks 21.7%, genital region 2.4%. p16INK4a immunostaining was positive in 90 of 107 (84.1%) BD cases, four of 59 (6.8%) AK cases and none of 29 benign squamous controls. The sensitivity and specificity of p16INK4a for a diagnosis of BD (vs. benign squamous controls/AK) was 84.1% and 95.5%, respectively (P < 0.0001, Fisher's exact test, two-sided). CONCLUSIONS: p16INK4a is a sensitive and specific marker for distinguishing BD from AK/benign squamous cutaneous lesions and may be helpful as an adjunct to histomorphology in the diagnosis and appropriate clinical management of these lesions.

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

Renal angiomyolipoma: further immunophenotypic characterization of an expanding morphologic spectrum.

BACKGROUND: Renal angiomyolipoma is a benign tumor histologically characterized by proliferation of spindle cells, epithelioid cells, and adipocytic cells in concert with many thick-walled blood vessels. To add further diagnostic confusion, an epithelioid cell-predominant variant of renal angiomyolipoma has recently been described. HMB-45 immunoreactivity correlates with ultrastructural striated organelles that closely resemble premelanosomes, although no evidence of melanogenesis has been documented in this tumor. OBJECTIVE: To further characterize the immunophenotypic and ultrastructural profile of renal angiomyolipoma based on phenotypic cell type (epithelioid, spindle, and adipocytic cell). DESIGN: Formalin-fixed, paraffin-embedded tissues from 27 renal angiomyolipomas and 8 renal cell carcinomas were immunostained with monoclonal antibodies to the melanoma-associated antigens HMB-45, HMB-50, NKI/C3 (CD63), and tyrosinase; the smooth muscle-related antigens calponin and muscle-specific actin (HHF-35); S100; and cytokeratin (CK). All renal angiomyolipomas were also immunostained with a polyclonal antibody to renin. Ultrastructural examination was performed on 9 selected cases. RESULTS: All renal angiomyolipomas stained positive for HMB-45, HMB-50, NKI/C3, muscle-specific actin (HHF-35), and calponin. Overall, HMB-45, HMB-50, and NKI/C3 preferentially stained the epithelioid cells. Tyrosinase staining was present in 50% of the renal angiomyolipomas with adequate tissue for staining (12 of 24 cases); positive staining and intensity paralleled HMB-45, HMB-50, and NKI/C3. Muscle-specific actin (HHF-35) and calponin preferentially stained the spindle cells. The adipocytic cells stained positive for both melanoma-associated antigens and smooth muscle antigens. Epithelioid cells, spindle cells, and adipocytic cells were CK, S100, and renin negative. Ultrastructural findings paralleled immunohistochemical staining patterns. Premelanosome-like organelles and electron dense granules were more readily detected in the epithelioid cells within the tumor, whereas ultrastructural characteristics of smooth muscle cells were more easily found in the spindle cells. All renal cell carcinomas stained positive for CK, NKI/C3 staining was variable, and all were negative for HMB-45, HMB-50, smooth muscle actin (HHF-35), and calponin. CONCLUSION: In renal angiomyolipoma, the epithelioid and spindle cells have preferential staining patterns for melanoma-associated antigens versus smooth muscle antigens, respectively. Positivity in renal angiomyolipoma for HMB-50, NKI/C3, and tyrosinase, in addition to HMB-45, provides evidence for the presence of different melanoma-associated gene products. Immunophenotypic overlap of the 3 histologically distinct renal angiomyolipoma cell populations suggests a common cell line, supporting a unitarian concept for renal angiomyolipoma. Ultrastructural characteristics of the 3 renal angiomyolipoma cell phenotypes parallel the immunophenotype, giving further support to a common cell line. Our study lends further credence to the perivascular epithelioid cell concept as proposed by Bonetti and colleagues.

Surgical pathology-based outcomes assessment of breast cancer early diagnosis: a College of American Pathologists Q-Probes study in 199 institutions.

OBJECTIVE: To develop breast cancer outcomes data relating pathologic tumor variables at diagnosis with clinical method of detection. DESIGN: Anatomic pathologists assessed 30 consecutive breast cancers at each institution, resulting in an aggregate database of 4232 breast cancers. SETTING: Hospital-based laboratories from the United States (98%), Canada, Australia, and Belgium. PARTICIPANTS: One hundred ninety-nine laboratories in the 1999 College of American Pathologists Q-Probes voluntary quality improvement program. MAIN OUTCOME MEASURES: Pathologic variables indicative of favorable outcomes included percentage of carcinomas detected at the in situ stage, tumors < or = 1 cm in diameter, and invasive cancers with lymph nodes negative for metastases. RESULTS: All outcomes measures, including percent in situ carcinomas (26.9% vs 13.8%), tumor size < or = 1 cm (57.8% vs 36.5%), and lymph node-negative status (77.8% vs 64%), were more favorable when tumors were detected by screening mammography (P <.001) compared to all other detection methods. CONCLUSIONS: This study demonstrates an opportunity for pathologists to develop outcomes information of interest to health care organizations, providers, patients, and payers by integrating routine oncologic surgical pathology and clinical breast cancer detection data. Such readily obtained interim outcomes data trended and benchmarked over time can demonstrate the relative clinical efficacy of preventive breast care provided by health care systems long before mortality data are available.

Two-color, cytokeratin-labeled dna flow cytometric analysis of 332 breast cancers: lack of prognostic value with 12-year follow-up.

CONTEXT: DNA flow cytometry of breast cancer is a proposed tumor marker of prognostic significance that is of controversial clinical utility because of lack of standardization and confirmatory studies. OBJECTIVE: To evaluate the prognostic significance of the more informative technique of multiparametric 2-color DNA flow cytometry as recommended by the 1992 DNA Cytometry Consensus Conference. DESIGN: Three hundred thirty-two breast carcinomas with 7 to 12 years of follow-up were prospectively analyzed as fresh tumors that were mechanically dissociated into whole cell suspensions. These suspensions were dual fluorescence-labeled with propidium iodide (DNA) and antibodies to cytokeratin (epithelium) and leukocyte common antigen (internal leukocyte control) for gated analysis of subpopulations. Multicycle software with histogram-dependent algorithms employing background, aggregate, and debris correction were used in DNA and cell-cycle quantitation. Data were analyzed according to the DNA Flow Cytometry Consensus Conference recommendations. RESULTS: DNA ploidy and proliferation stratified into 3 categories were not predictive of overall or disease-free survival. Sixty-five percent of tumors were nondiploid, and 35.4% were diploid. Two hundred six tumors were able to be evaluated for synthesis-phase fraction (SPF) analysis, with 74 of 206 cases in the low range (<13.4%), 36.4% in the intermediate range (>13.5 to <25.4%), and 27.6% in the high SPF (>25.5%) category. Aneuploid tumors tended to have a higher SPF. Univariate survival analysis showed prognostic significance of the following: tumor size, stage, TNM components, vascular invasion, nuclear grade, and histologic grade. Only T classification, presence of positive axillary lymph nodes, and distant metastases were significant independent predictors of survival in multivariate Cox regression models. Age and hormone receptor status showed no prognostic significance. Synthesis-phase fraction was significantly correlated with tumor size, stage, T classification, nuclear and histologic grade, presence of estrogen or progesterone receptors, and axillary lymph node status. None of the histologic parameters showed any significant association with DNA aneuploidy, except for high nuclear and histologic grade and the absence of estrogen receptors. CONCLUSIONS: Despite the use of state-of-the-art processing and flow cytometry analytic techniques, DNA ploidy and proliferation measurements were not predictive of survival in any stage of breast cancer. However, select histopathologic parameters and TNM stage were significant predictors of survival in univariate and multivariate analyses. We conclude that DNA ploidy and proliferation measurements do not provide significant prognostic information for clinicians to integrate into therapeutic decision making for patients with breast cancer.

Molecular approaches to identification of tissue contamination in surgical pathology sections.

The finding of possibly contaminant tissues or cells in surgical or cytology case material can be a challenging problem in diagnostic anatomical pathology samples. The reported rates of occurrence have ranged from 0 to 8.8% (including prospective and retrospective cases). A diagnostically dissimilar tissue fragment, whether contiguous with other tissue or among other fragments within a paraffin section, and which is not incompatible with the case tissue, often requires a rigorous investigation to confirm or deny its relevance to the case. Fluorescence in situ hybridization using dual red and green DNA probes to regions of the X and Y chromosomes, respectively, were used in one case where the potential contaminant was suspected to have originated from a male patient. The putative contaminant tissue fragment was confirmed as male, with cells having one X and one Y chromosome, unlike the other tissue fragments on the slide with two X chromosomes. In a second case, DNA polymorphisms were used to compare allelic patterns that were informative not only in proving the extraneous tissue as a contaminant, but in addition, could be used to trace the latter to its original tissue source. The molecular tools of fluorescence in situ hybridization in sex-mismatched cases and of DNA microsatellite probes that are applicable to paraffin sections can provide definitive identifiers of tissues and individual cells. They are important adjuncts to histology for the anatomical pathologist when faced with the diagnostic problems of tissue contamination encountered in routine practice.

Cytokeratin immunostaining patterns of benign, reactive lymph nodes: applications for the evaluation of sentinel lymph node specimen.

The use and interpretation of cytokeratin (CK) immunostains of sentinel lymph node specimens for breast carcinoma remain controversial. Variable immunoreactivity with anti-CK antibodies and CK-positive interstitial reticulum cells may complicate interpretation. The authors examined a series of reactive lymph nodes selected from patients without a history of malignancy. To demonstrate potential diagnostic pitfalls, three different CK antibody combinations were studied to characterize the immunostaining patterns. Formalin-fixed sections of lymph nodes were immunostained with a labeled streptavidin-biotin method using a DAKO autostainer. The anti-CK antibody preparations evaluated were AE1/AE3, CAM 5.2, and an in-house-prepared CK cocktail composed of 7 antibodies. The authors observed that up to 10% of cells in benign, reactive lymph nodes may be immunoreactive with anti-CK antibodies. AE1/AE3 stained 2 of 20 cases with rare immunoreactive reticulum cells, whereas CAM 5.2 and the CK cocktail immunostained cells in 85% of cases with reticulum cells in sinuses and the paracortex. Rare positive to 2+ cells were present in a similar distribution with these two antibodies. Careful interpretation of CK immunostaining of sentinel lymph node biopsies is essential, as is awareness of the presence of CK-positive native reticulum cells, to avoid confusion with single cells of metastatic carcinoma.

The association of HER-2/neu amplification with breast cancer recurrence.

HYPOTHESIS: Amplification of the HER-2/neu oncogene in 25% of breast cancers is associated with a shortened disease-free survival. DESIGN: Retrospective analysis of a patient population referred to a tertiary care facility for HER-2/neu testing. The mean follow-up was 56 months. SETTING: Large, urban, tertiary care hospital. PATIENTS: From 1995 to 1999, a consecutive sample of 190 patients with breast cancer had tissue samples tested for overexpression of the cell surface oncoprotein by immunostaining (IM) or amplification of the HER-2/neu oncogene by fluorescence in situ hybridization or both. Forty-nine subjects were excluded because they had tissue samples tested at our institution but received their treatment elsewhere. All patients tested for HER-2/neu after diagnosis with breast cancer in 1999 (n = 47) were excluded from analysis because of short follow-up time. One patient was excluded who had in situ ductal carcinoma. The remaining 93 patients were analyzed. RESULTS: Of 93 patients, 40 (43%) had gene amplification. Overall, patients with oncogene amplification had a shorter median disease-free interval (22 months) compared with controls (40 months) (P =.003). Analysis by the Cox regression model showed that the HER-2/neu status remained significantly associated with time to relapse even after adjusting for age and tumor grade (P =.002; adjusted relative risk, 2.4; 95% confidence interval, 1.4-4.4). No association was found between gene amplification and tumor grade (P =.98), estrogen/progesterone receptor status (P = .29 and P = .43, respectively), or lymph node status (P = .98). Seventy-two patients (77%) eventually had disease recurrence, with 18 (25%) of these recurring locally. CONCLUSIONS: The HER-2/neu oncogene is an independent prognostic indicator of a subset of breast cancers that are at high risk of early recurrence, regardless of tumor grade, estrogen/progesterone receptor status, and lymph node status. Patients amplifying the HER-2/neu oncogene have a shorter disease-free survival than patients without the oncogene.

Ultrastructural observations on mitochondria and microvesicles in renal oncocytoma, chromophobe renal cell carcinoma, and eosinophilic variant of conventional (clear cell) renal cell carcinoma.

On light microscopic examination, the morphologically overlapping features of granular eosinophilic cytoplasm in renal oncocytoma and the eosinophilic variants of chromophobe renal cell carcinoma and conventional (clear cell) renal cell carcinoma may pose difficulties in diagnosis. We investigated the ultrastructure of 5 renal oncocytomas, 7 eosinophilic variants of chromophobe renal cell carcinoma, and 5 eosinophilic variants of conventional (clear cell) renal cell carcinoma. Special attention was paid to mitochondria and microvesicles and interrelations thereof. The electron microscopic features were correlated with the light microscopic findings. All of the tumors had abundant mitochondria. Although abundant microvesicles were present in all of the chromophobe renal cell carcinomas, scant numbers of microvesicles were also sometimes present in renal oncocytomas (2 of 5) and in the eosinophilic variant of conventional (clear cell) renal cell carcinoma (1 of 5). The mitochondria in all three types of renal neoplasms studied differed in morphology, being predominantly uniform and round with predominantly lamellar cristae in renal oncocytoma, variable in shape and size with predominantly tubulocystic cristae in chromophobe renal cell carcinoma, and swollen and pleomorphic with rarefied matrix and attenuated cristae in the eosinophilic variant of conventional (clear cell) renal cell carcinoma. Variable numbers of mitochondria in all of the chromophobe renal cell carcinomas had outpouchings of the outer membranes, some of which carried parts of inner membrane within them. These outpouchings closely resembled the nearby cytoplasmic microvesicles, as did the tubulocystic cristae of the mitochondria. Some microvesicles contained homogeneous, electron-dense, finely granular matrix, similar to that seen in mitochondria. In one of seven chromophobe renal cell carcinomas, microvesicles were present in rough endoplasmic reticulum, and in two others, mitochondria were present within some vesicles. These features strongly suggest a close relationship between the microvesicles and mitochondria. Based on the role of vesicle formation in normal mitochondriogenesis, and some of our observations, we propose that defective mitochondriogenesis may be the source of microvesicles in chromophobe renal cell carcinomas.

The oncologic pathology report. Quality by design.

OBJECTIVE: To review tenets of basic quality assurance and identify opportunities for quality improvement in the laboratory assessment of prognostic factors. DESIGN: College of American Pathologists Q-Probes data obtained from hundreds of American laboratories throughout the 1990s are used to illustrate laboratory performance and practice opportunities in the preanalytic, analytic, and postanalytic phases of the total testing process. RESULTS: A wide range of performance deficiencies are documented, most in the preanalytic and postanalytic phases, and contributed by individuals outside and not under the control of the laboratory. In the analytic phase, the effectiveness of checklists on the content and completeness of reported diagnostic and prognostic data for breast and colon cancers is proven. CONCLUSIONS: In the preanalytic phase, marked enhancements in quality would result from improvements in (1) patient and specimen identification, (2) adherence to patient-sampling and specimen-handling requirements, and (3) communication to the laboratory of the pertinent clinical context of the individual test. Once basic analytic quality control and laboratory quality assurance issues are resolved, a focus on standardization and enhancement of preanalytic and postanalytic communications and satisfaction of clinical expectations becomes the source of improved laboratory performance.

Microvessels that predict axillary lymph node metastases in patients with breast cancer.

HYPOTHESIS: The density of vasoactive endothelial growth factor receptor 3-immunostained microvessels in primary breast cancers correlates with the incidence of axillary lymph node metastasis. DESIGN: Breast cancer microvessel clusters ("hot spots") were sequentially immunostained for factor VIII, type IV collagen, and vasoactive endothelial growth factor receptor 3. Microvessels were counted under light microscopy at a magnification of x 200. Axillary lymph nodes were evaluated for metastases by light microscopy. SETTING: A multidisciplinary breast cancer clinic and laboratory. PATIENTS: Sixty patients with T2 breast cancers treated by lumpectomy (or mastectomy) and axillary lymphadenectomy. MAIN OUTCOME MEASURES: Putative lymphatic microvessel density compared with axillary metastases. RESULTS: There were 16% (SE, 1.4%) vs 4% (SE, 0.8%) vasoactive endothelial growth factor receptor 3-immunostained microvessels (P<.001), 38% (SE, 3.9%) vs 65% (SE, 3.1%) type IV collagen-immunostained microvessels (P<.001), and 46% (SE, 4.1%) vs 31% (SE, 3.2%) unstained microvessels (P = .004) in node-positive vs node-negative patients, respectively. A fitted logistic model based on the relative percentage of putative lymphatic microvessels to blood microvessels correctly predicted that 23 (96%) of 24 patients would have a low risk and that 26 (96%) of 27 patients would have a high risk of lymph node metastases. Six (67%) of 9 patients predicted to have an intermediate risk had lymph node metastases. CONCLUSION: The odds of a patient with breast cancer having axillary lymph node metastasis increased substantially as the proportion of putative lymphatic microvessels increased and the relative proportion of blood microvessels in angiogenic hot spots decreased (log likelihood = 14.6; chi2 = 53.4; P<.001; area under the receiver operation characteristic curve = 0.97).

Salivary gland basal cell and canalicular adenomas: immunohistochemical demonstration of myoepithelial cell participation and morphogenetic considerations.

OBJECTIVE: To evaluate cellular composition of salivary gland adenomas using 3 monoclonal antibodies that recognize a smooth muscle phenotype confirmed to be sensitive for myoepithelial differentiation. DESIGN: Immunohistochemical evaluation of 25 salivary gland basal cell and canalicular adenomas. SETTING: Archival pathology material from the files of Henry Ford Hospital, Detroit, Mich, and the University of California at San Francisco. RESULTS: All basal cell adenoma variants exhibit some degree of myoepithelial cell participation with periductal, epithelioid, and spindled (stromal-like) morphologic structures. Only the canalicular adenomas, even if mixed with trabecular and solid patterns, are devoid of staining with these 3 antibodies, suggesting an adenoma composed exclusively of ductal luminal cells. CONCLUSIONS: There is an overlapping histomorphologic and common cellular composition of the basal cell adenoma variants with other recognized adenomas, such as pleomorphic adenoma and myoepithelioma. Relative differentiation toward 3 cell phenotypes (ductal luminal, basal, and myoepithelial) and the character of extracellular matrix production in varying proportions by the neoplastic myoepithelial cells distinguishes the spectrum of salivary gland adenomas identified in current classification schemes.

Monitoring anatomic pathology practice through quality assurance measures.

This article describes the art and science of continuous performance measurement and applications for quality improvement in anatomic pathology. Numerous novel benchmarks derived from multi-institutional data acquired from the College of American Pathologists Q-Probes quality improvement program are illustrated as they relate to specific disciplines in anatomic pathology and aspects of the total testing cycle. Comparative data quantifying performance deficiencies and opportunities for practice improvement are also identified.

Chromosomal aberrations identified in culture of squamous carcinomas are confirmed by fluorescence in situ hybridisation.

AIMS: Chromosomal aberrations in tumour cells are often not discernable by direct analysis. Although cell culture allows qualitative analysis of the karyotype, potential selection and evolution during growth in vitro may yield misleading data. To determine whether aberrations observed in vitro are representative of the original lesion, chromosomal aberrations found after prolonged growth in vitro of two squamous cell carcinomas of the head and neck (SSCHN) were evaluated with fluorescence in situ hybridisation (FISH) on the original tumour nuclei. METHODS: Specific karyotypic aberrations identified in cultures of two squamous cell carcinomas were targets for FISH analysis on tumour sections. Chromosome painting mixtures were selected based on in vitro karyotypic data. FISH was performed on cultured interphase and metaphase cells, and on histological sections from the original tumours. RESULTS: The 9cen and 17cen probes yielded FISH signals consistent with the aneusomies predicted for the respective chromosomes from the culture karyotypes. Whole chromosome 9 paint confirmed the prior existence in the tumours of i(9p) and i(9q), although only the latter hybridised with the 9cen probe. FISH data also supported in vivo representation of the diploid and tetraploid tumour subclones observed in cultures. In tumour HFH-SCC-8a, FISH results were generally concordant between cultured interphase and metaphase cells and the histological sections, and improved the interpretation of marker chromosomes identified in culture. CONCLUSION: The karyotypes obtained in these cases after prolonged passage in culture were consistent with the genetic alterations in the original tumours.

The myoepithelial immunophenotype in 135 benign and malignant salivary gland tumors other than pleomorphic adenoma.

BACKGROUND: We have previously studied the immunoreactivity of 3 novel smooth muscle-specific proteins, alpha-smooth muscle actin, smooth muscle myosin heavy chains, and calponin, to assess myoepithelial differentiation in pleomorphic adenomas. OBJECTIVE: To further expand our knowledge of myoepithelial differentiation in other benign and malignant salivary gland tumors. DESIGN: Formalin-fixed paraffin sections of 135 salivary gland tumors with associated normal glands were stained with monoclonal antibodies using the avidin-biotin complex immunoperoxidase method and enzymatic and microwave heat-induced epitope retrieval. RESULTS: In adenoid cystic carcinomas and epithelial-myoepithelial carcinomas, all 3 markers exclusively highlighted the myoepithelial cell components and the epithelial cells were entirely negative. No immunostaining was detected in canalicular adenomas, oncocytomas, Warthin tumors, acinic cell carcinomas, mucoepidermoid carcinomas, squamous cell carcinomas, and polymorphous low-grade adenocarcinomas. Salivary duct carcinomas and adenocarcinomas, not otherwise specified had a distinctive pattern of uniform periductal staining of reactive myofibroblastic cells, and in salivary duct carcinomas some ducts retained a peripheral immunoreactive myoepithelial cell layer. CONCLUSION: Immunoreactivity for these 3 smooth muscle-specific proteins confirms the known neoplastic myoepithelial component of adenoid cystic carcinomas and epithelial-myoepithelial carcinomas. The consistently positive staining pattern in adenoid cystic carcinomas may be diagnostically useful in discriminating histologically similar but consistently negative polymorphous low-grade adenocarcinomas. Periductal linear staining in adenocarcinoma, not otherwise specified and salivary duct carcinomas is distinctive and appears to represent a tight cuff of myofibroblasts associated with the infiltrating glands.

Diagnostic uncertainty expressed in prostate needle biopsies. A College of American Pathologists Q-probes Study of 15,753 prostate needle biopsies in 332 institutions.

OBJECTIVE: To determine the rate of diagnostic uncertainty in rendering diagnoses on prostate needle biopsies and to examine pathology practice variables that influence that rate. DESIGN: Anatomic pathology departments participating in the College of American Pathologists Q-Probes laboratory quality improvement program retrospectively reviewed their last 50 consecutive prostate needle biopsy diagnoses. For each diagnosis, participants provided information concerning patients' prostate-specific antigen levels; number, locations, and laterality of biopsy specimens; number of tissue levels examined; performance of high-molecular-weight cytokeratin immunoperoxidase staining; and acquisition of consultations from general pathologists or experts in prostate pathology. Characteristics of pathology practices included yearly surgical and prostate needle biopsy caseloads, number of pathologists rendering biopsy diagnoses, use of standard descriptive checklists, access to patients' prostate-specific antigen and digital rectal examination results, percentages of prostate needle biopsies routinely submitted for internal consultations, and presence of departmental experts in prostate pathology. SETTING AND PARTICIPANTS: Three hundred thirty-two public and private institutions located in the United States (n = 318), Canada (n = 6), Australia (n = 5), United Kingdom (n = 2), and Guam (n = 1). MAIN OUTCOME MEASURE: The rate of diagnostic uncertainty in prostate needle biopsy diagnoses. RESULTS: Participants submitted diagnoses on a total of 15 753 prostate needle biopsy cases, of which 33.4% were adenocarcinoma; 55.5% were benign; 3.9% were carcinoma in situ, prostatic intraepithelial neoplasia, or both; and 7.1% were diagnostically uncertain. The median rate of diagnostic uncertainty was 6%, ranging from 0 at the 10th percentile to 14% at the 90th percentile of all participating laboratories. Performing high-molecular-weight cytokeratin immunoperoxidase staining resolved diagnostic uncertainty in 68% of cases in which it was performed, and obtaining intradepartmental and extradepartmental consultations resolved diagnostic uncertainty in 70% to 87% of cases for which they were obtained. Knowledge of patients' prostate-specific antigen results and examining multiple biopsy cores had marginal effects on the rate of uncertainty. Thoroughness of prostate gland sampling and examination of multiple tissue block levels were not associated with the aggregate rate of diagnostic uncertainty. We found no particular pathology departmental practices or institutional demographic characteristics associated with institutional rates of diagnostic uncertainty. CONCLUSIONS: Use of high-molecular-weight cytokeratin immunoperoxidase staining and obtaining intradepartmental and extradepartmental consultations may be effective in reducing diagnostic uncertainty in prostate biopsies.

Necessity of clinical information in surgical pathology.

OBJECTIVES: To examine the frequency and nature of problems caused by inadequate clinical data provided on surgical pathology requisition forms. DESIGN: Participants in the 1996 Q-Probes voluntary quality improvement program of the College of American Pathologists were asked to document prospectively all surgical pathology cases with inadequate information. Inadequate clinical information was defined as the pathologist's need for additional clinical information before a diagnosis could be rendered, regardless of the amount of information already present on the requisition slip. Cases that had no clinical information on a requisition slip were not counted if the lack of history did not hinder diagnosis. The study concluded when 3 months had elapsed or 40 surgical pathology cases were documented. The following data were recorded for each case: anatomic site, type of procedure, nature of disease, method of obtaining additional information, importance of obtained information, and the length of delay in the final diagnosis. PARTICIPANTS: Three hundred forty-one laboratories, 322 of which were from the United States. RESULTS: A total of 5594 cases (0.73%) required additional clinical information for diagnosis (10th through 90th percentile range, 3.01% to 0.08%). Institutions with greater average occupied bedsize, a greater number of cases accessioned per year, and a greater number of pathologists had a lower percentage of cases with inadequate clinical data (P <.05). Sixty-eight percent of these cases had no delay in completion of a case, 16.2% had a delay of 1 day or less, and 15.1% of cases were delayed more than 1 day. In 59.4% of cases, the additional clinical information obtained confirmed the initial diagnostic impression. In 25.1%, the information was not relevant to the pathologic diagnosis. In 6.1% there was a substantial change in the diagnosis or a revised report was issued, and in 2.2% no additional information could be obtained. Specific anatomic sites that correlated with a higher rate of changed diagnoses or revised reports in cases with inadequate information included the small bowel, the bronchus/lung, and the ovary. Resection specimens were also significantly associated with a higher rate of changed diagnoses or revised reports when additional information was obtained, as were malignant neoplasms and therapy-induced changes. CONCLUSIONS: This study establishes an aggregate rate of cases with inadequate clinical information for diagnosis (0.73%) and documents the extent of problems caused by inadequate clinical information. The criticality of appropriate clinical information provided to the pathologist is identified for specific anatomic sites and disease processes and is reflected in changed diagnoses or revised reports.

Immunohistochemical profile of myogenin and MyoD1 does not support skeletal muscle lineage in alveolar soft part sarcoma.

BACKGROUND: The histogenesis of alveolar soft part sarcoma remains elusive. Myogenic origin is favored, although conflicting data on immunohistochemical demonstration of muscle-associated markers exist. Myogenin and MyoD1, transcription factors of the myogenic determination family, have crucial roles in commitment and differentiation of mesenchymal progenitor cells to myogenic lineage and in maintenance of skeletal muscle phenotype. Their immunohistochemical detection is specific in characterization of rhabdomyosarcoma. METHODS: Antibodies for myogenin, MyoD1, desmin, and muscle-specific actin were employed on a large series of cases (n = 19) of formalin-fixed, paraffin-embedded alveolar soft part sarcoma. RESULTS: Minimal scattered nuclear staining was seen with myogenin. All cases had pronounced, nonspecific granular cytoplasmic immunostaining with MyoD1; nuclei were negative. All tumors were negative for desmin and muscle-specific actin. Ultrastructural study in 10 cases failed to reveal features of skeletal muscle differentiation. CONCLUSIONS: Cytoplasmic staining with MyoD1 in alveolar soft part sarcoma may correspond to cross-reactivity with an undetermined cytoplasmic antigen. The lack of immunostaining with myogenin, MyoD1, desmin, and muscle-specific actin provides evidence against a myogenic origin for alveolar soft part sarcoma.