Diagnosing Osteomyelitis: A Histology Guide for Pathologists.

Histopathologic examination of bone specimens coupled with bone culture is considered the gold standard for the diagnosis of osteomyelitis (OM). Despite this, studies have demonstrated interpathologist agreement in the diagnosis of OM as low as 30%, largely stemming from a lack of specific definitions and diagnostic criteria. Review of the literature has provided insight into the lifecycle of OM, illustrating the histologic progression of OM phases from acute to chronic, and provides support for defining subcategories of OM. Using an algorithmic histopathologic tool consisting of 15 criteria, each with an associated score, we defined 5 categories of OM: (1) acute OM, (2) acute and chronic OM, (3) chronic OM, (4) chronic active OM, and (5) chronic inactive OM. We reviewed 462 microscopic slides from 263 patients with suspected OM, and for each slide, we determined an algorithm-derived diagnosis, which was then used to calculate a total histopathologic load score (Jupiter score). Algorithm-derived diagnoses recapitulated original clinical diagnoses and diagnosed cases as OM that had not been originally diagnoses. These novel cases were more likely to have subsequent clinical complications. Finally, pathologic load scores were assessed for association with the category of OM.

A pilot study in intraparenchymal therapy delivery in the prostate: a comparison of delivery with a porous needle vs standard needle.

BACKGROUND: New biologic therapies directly injected into the prostate are in clinical trials for prostatic diseases. There is a need to understand distribution of injected therapies as a function of prostatic anatomy, physiology, and device design. METHODS: A needle with a porous length of customizable-length was tested and its performance compared with a standard needle. Injections of magnetic resonance contrast reagent were placed into ex-vivo human prostates after surgical excision in standard of care therapy for invasive bladder cancer patients. Magnetic resonance images were acquired using sequences to quantify volume delivered, distributed, and backflow. RESULTS: Magnetic resonance images analysis revealed heterogeneity distribution with injection into the specimens. There was low resistance to flow along ductal pathways and high resistance to flow into glandular nodules and smooth muscle/fibrous parenchyma. Data confirm previous studies showing injection loss via urethra backflow, urethra, and prostatic ducts. Tissue fraction of dose was significantly higher with porous needle compared with standard needle (p = .03). We found that a greater volume of distribution divided by the amount infused (Vd/Vi) increased by 80% with the porous needle, though no statistically significant association due to small sample size. CONCLUSIONS: This study demonstrated that prostatic tissue is anatomically heterogenic and limits distribution of needle injection. There is greater distribution in the ex-vivo prostate using a porous needle. The complexity of intra prostatic flow pathways suggests preoperative imaging and pre-treatment planning will enhance therapy.

Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study.

BACKGROUND: Optimum management of clinically localised prostate cancer presents unique challenges because of the highly variable and often indolent natural history of the disease. To predict disease aggressiveness, clinicians combine clinical variables to create prognostic models, but the models have limited accuracy. We assessed the prognostic value of a predefined cell cycle progression (CCP) score in two cohorts of patients with prostate cancer. METHODS: We measured the expression of 31 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumour samples, and created a predefined score and assessed its usefulness in the prediction of disease outcome. The signature was assessed retrospectively in a cohort of patients from the USA who had undergone radical prostatectomy, and in a cohort of randomly selected men with clinically localised prostate cancer diagnosed by use of a transurethral resection of the prostate (TURP) in the UK who were managed conservatively. The primary endpoint was time to biochemical recurrence for the cohort of patients who had radical prostatectomy, and time to death from prostate cancer for the TURP cohort. FINDINGS: After prostatectomy, the CCP score was useful for predicting biochemical recurrence in the univariate analysis (hazard ratio for a 1-unit change [doubling] in CCP 1·89; 95% CI 1·54-2·31; p=5·6×10(-9)) and the best multivariate analysis (1·77, 1·40-2·22; p=4·3×10(-6)). In the best predictive model (final multivariate analysis), the CCP score and prostate-specific antigen (PSA) concentration were the most important variables and were more significant than any other clinical variable. In the TURP cohort, the CCP score was the most important variable for prediction of time to death from prostate cancer in both univariate analysis (2·92, 2·38-3·57, p=6·1×10(-22)) and the final multivariate analysis (2·57, 1·93-3·43; p=8·2×10(-11)), and was stronger than all other prognostic factors, although PSA concentration also added useful information. Heterogeneity in the hazard ratio for the CCP score was not noted in any case for any clinical variables. INTERPRETATION: The results of this study provide strong evidence that the CCP score is a robust prognostic marker, which, after additional validation, could have an essential role in determining the appropriate treatment for patients with prostate cancer. FUNDING: Cancer Research UK, Queen Mary University of London, Orchid Appeal, US National Institutes of Health, and Koch Foundation.

Do mixed histological features affect survival benefit from neoadjuvant platinum-based combination chemotherapy in patients with locally advanced bladder cancer? A secondary analysis of Southwest Oncology Group-Directed Intergroup Study (S8710).

OBJECTIVE: • To determine whether the effect of neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) on the survival of patients with locally advanced urothelial carcinoma (UC) of the bladder treated with radical cystectomy varies with the presence of non-urothelial components in the tumour. PATIENTS AND METHODS: • This is a secondary analysis of the Southwest Oncology Group-directed intergroup randomized trial S8710 of neoadjuvant MVAC followed by cystectomy versus cystectomy alone for treatment of locally advanced UC of the bladder. • For the purpose of these analyses, tumours were classified based on the presence of non-urothelial components as either pure UC (n= 236) or mixed tumours (n= 59). Non-urothelial components included squamous and glandular differentiation. • Cox regression models were used to estimate the effect of neoadjuvant MVAC on all-cause mortality for patients with pure UC and for patients with mixed tumours, with adjustment for age and clinical stage. RESULTS: • There was evidence of a survival benefit from chemotherapy in patients with mixed tumours (hazard ratio 0.46; 95% CI 0.25-0.87; P= 0.02). Patients with pure UC had improved survival on the chemotherapy arm but the survival benefit was not statistically significant (hazard ratio 0.90; 95% CI 0.67-1.21; P= 0.48). • There was marginal evidence that the survival benefit of chemotherapy in patients with mixed tumours was greater than it was for patients with pure UC (interaction P= 0.09). CONCLUSION: • Presence of squamous or glandular differentiation in locally advanced UC of the bladder does not confer resistance to MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy.

Gleason Score Evolution and the Effect on Prostate Cancer Outcomes.

OBJECTIVES: We evaluated how the changes in Gleason grading affected the long-term outcomes of a large prostatectomy cohort. METHODS: We obtained long-term follow-up (16.7 years) in 581 patients having undergone radical retropubic prostatectomy between 1985 and 1995. We excluded those with seminal vesicle and/or lymphatic involvement. We regraded the specimens according to contemporary guidelines and compared how this affected outcomes compared with their original (pre-1995) Gleason scoring. In total, 499 patients were evaluable. RESULTS: A Gleason score of 6 or less declined from 73% to 29%, and the number increased from 25% to 63% for a Gleason score of 7 and from 5% to 8% for a Gleason score of 8 to 9. As a result, for a Gleason score less than 7, biochemical failure decreased from 28% to 23%, metastatic disease 5% to 2%, and prostate cancer death from 5% to 3%. The same results were 50% to 37%, 11% to 7%, and 10% to 6% for a Gleason score of 7 and 86% to 71%, 43% to 32%, and 29% to 26% for a Gleason score more than 7, respectively. With the most recent grade grouping, for groups 1 to 5, biochemical failure occurred in 23%, 32%, 45%, 69%, and 78%, respectively. Metastatic disease occurred in 2%, 4%, 12%, 24%, and 56%, respectively. Prostate cancer-related death occurred in 2%, 4%, 9%, 21%, and 44%, respectively. CONCLUSIONS: The revised Gleason scores improved the outcomes in all risk groups. Based on Gleason score, patients with prostate cancer will appear to have better outcomes than they did before 2005, making any comparison tenable. The current grading system shows a consistent increased risk in biochemical failure, metastatic disease, and prostate cancer-related death with each successive grade.

Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms.

Endometriosis is a debilitating disease characterized by the presence of functional endometrial glandular epithelium and stroma outside the uterine cavity that affects up to 20% of women of child-bearing age. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandin E(2) (PGE(2)), is highly expressed in endometriotic tissues and results in increased concentrations of peritoneal PGE(2) in women. In this study, we determined the expression of COX-2 protein in ectopic and eutopic endometria in humans and the role of COX-2 in endometriotic cell survival, migration, and invasion in humans. Our results indicate that COX-2 protein is abundantly expressed in ectopic endometria compared with eutopic endometria. Comparatively, expression of COX-2 protein is higher in eutopic endometria from women with endometriosis compared with women without endometriosis. Inhibition of COX-2 decreases survival, migration, and invasion of endometriotic cells that are associated with decreased production of PGE(2). Cell growth inhibitory effects of COX-2 inhibition/silencing are mediated through nuclear poly (ADP-ribose) polymerase-mediated apoptosis. Cell motility and invasion inhibitory effects of COX-2 inhibition/silencing are mediated through matrix metalloproteinase-2 and -9 activities. Interestingly, effects of COX-2 inhibition is more profound in endometriotic epithelial than in stromal cells. Furthermore, inhibition of COX-2 affects invasion rather than migration of endometriotic epithelial and stromal cells. It is the first evidence showing that inhibition of COX-2 decreases endometriotic epithelial and stromal cell survival, migration, and invasion in humans. Our results support the emerging concept that COX-2/PGE(2) promotes the pathophysiology and pathogenesis of endometriosis in humans.

Benign breast disease.

Benign breast disease includes all nonmalignant conditions of the breast, including benign tumors, trauma, mastalgia, mastitis, and nipple discharge. Benign tumors include pathologic changes that do not increase a patient's risk for developing cancer, lesions that confer a slightly increase risk, and lesions that are associated with an up to 50% risk of developing breast cancer. Both benign and malignant breast disorders can present with a palpable mass; skin dimpling, thickening, or erythema; pain; nipple discharge and inversion or distortion; or an abnormal screening mammogram with no clinical findings. Tools available to investigate breast problems include clinical breast examination, mammogram, and ultrasound. This article discusses the gynecologist's role in maintaining breast health, the clinical evaluation of breast problems, and management of benign breast disease.

Failure of Ploidy and Proliferative Fraction to Predict Long-Term Outcome After Prostatectomy.

BACKGROUND: Historically, ploidy and S phase percentage appeared to be promising predictors for prostate cancer recurrence. Lack of uniformity and consistency hampered their development. We evaluated ploidy and S phase for prostate cancer death in a cohort of patients with long-term follow-up. METHODS: We identified 127 patients that had ploidy and S phase determined at the time of their radical prostatectomy for prostate cancer. With 15 years of follow-up, we determined the risk of biochemical failure and risk of death from prostate cancer. We correlated the S phase and ploidy findings with standard pathology findings. RESULTS: A total of 107 (84%) had diploid and 20 (16%) had non-diploid cancers. The median S phase was 6.6%. There was no correlation of ploidy (P = 0.472) or S phase with preoperative PSA or Gleason score. On univariate analysis, EPE, margin positivity, seminal vesicle involvement, lymph node involvement, high Gleason score and PSA > 10 ng/mL were all predictive of biochemical failure. Ploidy and S phase were not. For prostate cancer death, only Gleason score was predictive. CONCLUSIONS: With long-term follow-up in our cohort, Gleason score was predictive of prostate cancer death. Ploidy and S phase were not predictive for biochemical failure or prostate cancer mortality.

Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer.

BACKGROUND: Despite aggressive local therapy, patients with locally advanced bladder cancer are at significant risk for metastases. We evaluated the ability of neoadjuvant chemotherapy to improve the outcome in patients with locally advanced bladder cancer who were treated with radical cystectomy. METHODS: Patients were enrolled if they had muscle-invasive bladder cancer (stage T2 to T4a) and were to be treated with radical cystectomy. They were stratified according to age (less than 65 years vs. 65 years or older) and stage (superficial muscle invasion vs. more extensive disease) and were randomly assigned to radical cystectomy alone or three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy. RESULTS: We enrolled 317 patients over an 11-year period, 10 of whom were found to be ineligible; thus, 154 were assigned to receive surgery alone and 153 to receive combination therapy. According to an intention-to-treat analysis, the median survival among patients assigned to surgery alone was 46 months, as compared with 77 months among patients assigned to combination therapy (P=0.06 by a two-sided stratified log-rank test). In both groups, improved survival was associated with the absence of residual cancer in the cystectomy specimen. Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group (38 percent vs. 15 percent, P<0.001). CONCLUSIONS: As compared with radical cystectomy alone, the use of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy increases the likelihood of eliminating residual cancer in the cystectomy specimen and is associated with improved survival among patients with locally advanced bladder cancer.

Global hypomethylation is common in prostate cancer cells: a quantitative predictor for clinical outcome?

This study was designed to determine if cytological detection of 5-methylcytosine (5MC) was feasible on prostate tumor sections and to determine if levels of 5MC differed in malignant compared to normal prostate tissue. We further sought to see if 5MC levels correlated with any clinical outcome data. Thirty prostate tumor sections were obtained from patients who underwent radical prostatectomies from 1988 to 1995; these represented a mix of low to high grade tumors. Clinical data were maintained for each of these patients with a minimum of 7 years of follow up. Sections were stained with a commercially available antibody to 5MC and immunocytochemistry levels were subsequently quantified using a computer-assisted true-color imaging system. Tumor and benign regions of the same archived sections were compared, in addition to a series of 12 normal prostate samples. Prostate cancer cells exhibited a pronounced global decrease in methylation compared with benign and normal tissue. This was observed in 29 of 30 patients (96.7%) studied and densitometric scanning of methylation staining indicated that this value was quantifiable. Overall, higher methylation values were detected in men who had positive surgical margins and recurrent disease. These data suggest that loss of methylation is a feature of prostate cancer, and partial gain of methylation (presumably at promoters of specific genes) is associated with clinical outcome and is measurable using whole-cell assays.

The histogenesis of clear cell adenocarcinoma of the lower urinary tract. Case series and review of the literature.

Clear cell adenocarcinoma of the lower urinary tract is a rare neoplasm whose histogenesis has not been thoroughly investigated. We have examined six specimens of clear cell adenocarcinomas collected from three institutions using histological, histochemical, and immunohistochemical techniques. Results indicate that almost all clear cell adenocarcinomas of this region express morphological and antigenic features, suggesting müllerian differentiation, and that müllerian differentiation is not a feature of either nonclear cell adenocarcinomas or normal female paraurethral glands. Including the authors' six specimens, 46 specimens have been reported in the available English literature. The accumulated experience confirms the initial impression that these tumors develop predominantly in the urethras of women and occur over a wide age range. Despite high stage at diagnosis, most patients have been alive with no evidence of disease when reported, a prognosis that seems to apply regardless of length of follow-up.

Assessment of serum gamma glutamyl transpeptidase levels in low stage renal cell carcinoma.

In the past, serum levels of various enzymes have been studied to aid in the evaluation of neoplastic diseases. Gamma glutamyl transpeptidase (GGTP) is present in highest amounts in the proximal convoluted tubules of the kidney, which are considered to be the site of origin for renal cell carcinomas. A retrospective study of 63 patients who had serum GGTP levels tested within 10 days before the resection of a renal cell carcinoma was performed to determine whether serum GGTP was elevated in low stage (stages I and II) renal cell carcinomas. Only 5 of the 63 patients had elevated GGTP levels (two of which were only slightly elevated). The authors conclude that serum GGTP levels as routinely measured in clinical laboratories are not reliably elevated in low stage renal cell carcinomas.

Serum prostate-specific antigen levels in stage A1 prostatic cancer.

Quantitation of serum prostate-specific antigen (PSA) has recently come into widespread use. Controversy exists regarding its usage in screening for carcinoma of the prostate (CAP), based partly on concern that it may detect small foci of CAP that will not cause any significant morbidity or mortality. This study was conducted to evaluate serum PSA levels in stage A1 CAP. The authors identified 143 consecutive men who had PSA levels drawn within 8 weeks of transurethral resection performed for presumed benign prostatic hyperplasia. One hundred twenty-four of these (86.7%) had no cancer, 11 (7.7%) were found to have stage A1 CAP, and eight (5.6%) were found to have CAP beyond stage A1. The mean PSA level in patients with stage A1 CAP was 2.3 ng/mL, and the benign (no cancer) group had a mean PSA level of 3.8 ng/mL. Ten of the 11 patients in the stage A1 group had PSA values less than 4.0 ng/mL. Therefore, it was found that most patients with stage A1 CAP did not have elevated PSA levels. In the authors' experience, elevation of PSA levels caused by CAP is indicative of a tumor burden greater than that found in stage A1 CAP.

Variation in reference cells for DNA analysis of paraffin-embedded tissue.

Selection of the diploid reference cells used in flow cytometric DNA analysis of paraffin-embedded tissue is inconsistent in the literature. To determine which types of cells were most suitable for use as reference cells, benign paraffin-embedded tissue was evaluated from nine randomly selected autopsies. Benign kidney, lymph node, gastrointestinal mucosa, laryngeal mucosa, bronchial mucosa, bladder mucosa, pancreas, and, when available, prostate tissue were studied. Ten paraffin-embedded surgical specimens also were studied. In the autopsy specimens, great variability in the mean peak channels was noted on intrapatient evaluation and even more variability was present when comparing similar organs (especially lymph nodes) from different patients. Similar results were obtained using lymph nodes from surgical specimens. It is concluded that the most suitable diploid reference cells for DNA analysis of paraffin-embedded tissue are the benign cells present in the paraffin tumor block that have been processed in the same way as the tumor cells.

Atypical hyperplasia in prostates of 20 to 40 year old men.

One hundred prostates from 20 to 40 year old men obtained at necropsy were completely sectioned and studied microscopically. Atypical hyperplasia was found in 10 (20%) of 20-29 year old men and in 12 (24%) of 30-40 year old men. The prostates with atypical hyperplasia had similar weights as those without, and the atypical hyperplasia was most common in the lateral lobes of the prostate and near the apex. The atypical hyperplasias were (i) usually mild in degree rather than moderate or severe; (ii) almost equally divided between circumscribed and "infiltrating" lesions; (iii) usually occurred as multiple foci within the same prostate rather than as a single focus of atypical hyperplasia; and (iv) were not associated with inflammation. The finding that atypical hyperplasia is common in men between the ages of 20 and 40 years may be helpful in increasing the understanding of the histopathology of the prostate.

Mesenchymal chondrosarcoma. A cytogenetic, immunohistochemical and ultrastructural study.

A case of mesenchymal chondrosarcoma was studied. The tumor was near-tetraploid and the clonal structural chromosomal abnormalities included add(7)(p13), add(22)(q13), markers, and double minutes. The ultrastructural and immunohistochemical findings were consistent with the diagnosis. Strong immunoreactivity for desmin was an unusual, not previously reported, feature of the neoplasm.

Evaluation of age-specific normal ranges for prostate-specific antigen.

OBJECTIVES: To compare the traditional normal range (TNR) of 0.0 to 4.0 ng/mL for serum prostate-specific antigen (PSA) to age-specific normal ranges (ASNRs). METHODS: An autopsy series of completely sectioned, clinically benign prostates from 171 consecutive Caucasian men over the age of 40 years was selected. These patients were divided into those having no prostate cancer at autopsy, prostate cancer less than 1 cc in volume, and prostate cancer at least 1 cc in volume. The PSA values of each group were compared using both the TNR and the ASNR. RESULTS: Twenty-three of 105 (21.9%) patients with no cancer had elevated PSA values by the TNR, whereas only 18 (17.1%) were elevated using the ASNR. Nine of 54 (16.7%) with cancer less than 1 cc were elevated using the TNR, and 7 of 54 (13.0%) using the ASNR. Of 12 patients with cancer at least 1 cc, all had elevated PSA levels using the TNR and 11 (91.7%) were elevated using the ASNR. All discrepancies between the TNR and ASNR occurred in the 60- to 79-year age range. CONCLUSIONS: Use of ASNRs appears helpful in increasing the specificity of PSA by eliminating some elevated values in patients in their 60s and 70s.

Characteristics of prostatic infarcts and their effect on serum prostate-specific antigen and prostatic acid phosphatase.

OBJECTIVES: To determine how prostatic infarcts affect serum prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) levels. METHODS: Two hundred eighteen clinically benign, whole prostates were obtained at autopsy, completely sectioned, and examined histologically. PSA and PAP levels were determined from premortem serum. RESULTS: Six of the 218 (2.8%) prostates had infarcts. The infarcts were usually multiple and usually located in the central and/or middle concentric zones of the middle third of the prostate without a preference for a particular lobe. Serum PSA by immunoradiometric assay were elevated in all 6 cases. Serum PAP by both enzymatic assay (ACA), and immunoradiometric assay were available for 5 cases and were elevated by both methods in 2 cases, approached elevated levels by both methods in 1 case, and were normal by both methods in 2 cases. The PSA and PAP levels appeared to be affected more by the age than by the size of the infarct. CONCLUSIONS: Prostatic infarcts elevate PSA levels more frequently than PAP levels, and prostatic infarcts may be responsible for some unexplained elevations of serum PSA and PAP levels.

Unusual case of stridor and wheeze in an infant: tracheal bronchogenic cyst.

Bronchogenic cysts are congenital anomalies that represent aberrant development of the foregut. Bronchogenic cysts in the mediastinum have been documented in both children and adults, but only one case of tracheal bronchogenic cyst in an infant was found in the literature. We report on a case of an infant with wheeze, stridor, and retractions, caused by a midtracheal bronchogenic cyst. This entity, with its unusual location, should be considered in the differential diagnosis of respiratory distress, cyanotic spells, wheezing, and stridor in infants.

Combined Fontana-Masson-mucin staining of Cryptococcus neoformans.

Cryptococci react positively with various histochemical stains, including the Fontana-Masson (FM), which stains the cell wall, and mucin stains, such as alcian blue and mucicarmine, which stain the capsule. Combinations of the FM stain with both the alcian blue and mucicarmine stains were performed on paraffin-embedded tissue specimens that were obtained from 15 patients who had culture-proved cryptococcosis. Combined FM-mucicarmine and FM-alcian blue stains were compared with other individual fungal stains. The FM stain, followed by either the mucicarmine or alcian blue stain, distinctively demonstrated both the cell wall and capsule of most organisms. More organisms were recognized in the combined stains than with either stain done individually. No interference between the stains was noted. Combining the FM stain with either of these two mucin stains appears to be helpful for identifying cryptococci.