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Context.--Previous investigations on sentinel lymphnode biopsies have demonstrated their importance in nodal staging of patients with breast cancer. However, sentinel node biopsy in breast cancer is currently a controversial procedure and continues to provoke debate. Objectives.--We designed our study to determine the usefulness of a standard protocol for evaluating sentinel lymph node metastases and to assess the value of sentinel node biopsy as the only procedure in nodal staging in breast cancer patients. Materials and Methods.--A retrospective analysis of 84 breast cancer patients with sentinel node biopsies, who also underwent axillary dissection, was conducted using a standard protocol (3 levels of immunohistochemical stains for keratin and 2 levels of hematoxylin-eosin (HE) stains on the first 3 negative lymph nodes). Results.--Hematoxylin-eosin staining identified 20 patients (23.8%) with sentinel node metastases. The remaining 64 negative patients (76.1%) were tumor free on sentinel lymph nodes at level 1 HE. Additional immunohisto-chemical stains for keratin and HE stains on specimens from these 64 patients showed an additional 5 patients (7.8%) to be positive for lymph node micrometastases (<2 mm). The total percentage of cases with sentinel lymph node metastases detected by HE staining and immunohis-tochemistry was 29.7%. Of the remaining 59 cases that were negative on HE and immunohistochemistry, axillary dissection revealed 3 cases that had metastases in the axillary lymph nodes. The false-negative rate was 10.7%. The concordance rate between sentinel lymph nodes and axillary lymph nodes was 96.4%. The sensitivity was 89% and specificity was 100%. Conclusion.--Immunohistochemistry and multiple-level sectioning increased detection of metastases by 7.8% in sentinel lymph nodes. Caution should be used in accepting sentinel node biopsy alone as the only procedure for staging due to a high false-negative rate (10.7%). A predictive value of... [ABSTRACT FROM AUTHOR]

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.

Context: Results of prior pathology workforce surveys have varied between a state of equilibrium and predictions of shortage., Objective: To assess the current and future supply of pathologists, and apply a dynamic modeling tool for assessing the effects of changing market forces and emerging technologies on the supply of pathologists' services through 2030., Design: Data came from various sources, including the literature, College of American Pathologists' internal data, and primary research through custom-developed surveys for the membership and for pathology practice managers, Results: Through 2010, there were approximately 18 000 actively practicing pathologists in the United States (5.7 per 100 000 population), approximately 93% of whom were board certified. Our model projects that the absolute and per capita numbers of practicing pathologists will decrease to approximately 14 000 full-time equivalent (FTE) pathologists or 3.7 per 100 000 in the coming 2 decades. This projection reflects that beginning in 2015, the numbers of pathologists retiring will increase precipitously, and is anticipated to peak by 2021. Including all types of separation, the net pathologist strength will begin falling by year 2015. Unless workforce entry or exit rates change, this trend will continue at least through 2030. These changes reflect the closure of many training programs 2 to 4 decades ago and the substantially decreased number of graduating residents., Conclusions: This comprehensive analysis predicts that pathologist numbers will decline steadily beginning in 2015. Anticipated population growth in general and increases in disease incidence owing to the aging population, to be presented in a companion article on demand, will lead to a net deficit in excess of more than 5700 FTE pathologists. To reach the projected need in pathologist numbers of nearly 20 000 FTE by 2030 will require an increase from today of approximately 8.1% more residency positions. We believe a pathologist shortage will negatively impact both patient access to laboratory services and health care providers' abilities to deliver more effective health care to their patient populations.

Endometriosis is a benign chronic gynecological disease of reproductive-age women characterized by the presence of functional endometrial tissues outside the uterine cavity. It is an estrogen-dependent disease. Current treatment modalities to inhibit biosynthesis and actions of estrogen compromise menstruation, pregnancy, and the reproductive health of women and fail to prevent reoccurrence of disease. There is a critical need to identify new specific signaling modules for non-estrogen-targeted therapies for endometriosis. In our previous study, we reported that selective inhibition of cyclooxygenase-2 prevented survival, migration, and invasion of human endometriotic epithelial and stromal cells, which was due to decreased prostaglandin E(2) (PGE(2)) production. In this study, we determined mechanisms through which PGE(2) promoted survival of human endometriotic cells. Results of the present study indicate that 1) PGE(2) promotes survival of human endometriotic cells through EP2 and EP4 receptors by activating ERK1/2, AKT, nuclear factor-kappaB, and beta-catenin signaling pathways; 2) selective inhibition of EP2 and EP4 suppresses these cell survival pathways and augments interactions between proapoptotic proteins (Bax and Bad) and antiapoptotic proteins (Bcl-2/Bcl-XL), facilitates the release of cytochrome c, and thus activates caspase-3/poly (ADP-ribose) polymerase-mediated intrinsic apoptotic pathways; and 3) these PGE(2) signaling components are more abundantly expressed in ectopic endometriosis tissues compared with eutopic endometrial tissues during the menstrual cycle in women. These novel findings may provide an important molecular framework for further evaluation of selective inhibition of EP2 and EP4 as potential therapy, including nonestrogen target, to expand the spectrum of currently available treatment options for endometriosis in women.

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.

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.

Background: The traditional normal range for prostate-specific antigen has been 0.0 to 4.0 ng/mL. Two different age-specific normal ranges have been proposed, one by Oesterling et al and the other generated by the Prostate Cancer Awareness Week experience., Methods: We studied 213 consecutive cases of biopsy-proven prostate adenocarcinoma to evaluate age-specific normal ranges for prostate-specific antigen. We examined each patient's age, stage of disease, and serum concentration of prostate-specific antigen at the time of diagnosis. The three normal ranges were applied to each case., Results: The patients ranged in age from 45 to 87 years. At all stages of disease, more patients had elevated serum prostate-specific antigen values using the traditional normal range as opposed to either age-specific normal range. These discrepancies were most obvious for stage II disease, in which 93 of 119 cases (78%) were elevated according to the traditional normal range versus 78 of 119 cases (66%) according to the Oesterling et al range and 80 of 119 cases (67%) according to the range defined during Prostate Cancer Awareness Week. For patients aged 40 to 59 years, all three normal ranges provided identical results (18 of 22 [82%] cancers detected)., Conclusions: Use of either age-specific normal range would have missed more than 10% of stage II prostate adenocarcinomas in patients over the age of 60 years. This indicates that caution should be exercised when applying age-adjusted normal ranges for serum concentrations of prostate-specific antigen in patients of that age group.

Background: Fine-needle aspiration biopsy (FNAB) has been shown to be rapid and cost effective in the evaluation of thyroid nodules. The significance of nondiagnostic (unsatisfactory) FNAB is uncertain, however., Methods: We reviewed 345 consecutive thyroid FNABs and identified 59 patients with initially unsatisfactory specimens. These patients had follow-up to determine whether their thyroid nodules proved to be malignant., Results: Three patients (5.1%) were found to have organ-confined papillary carcinoma of the thyroid, the largest tumor mass measuring 1.2 cm. Six patients (10.2%) had benign adenomas., Conclusions: In most cases of initially nondiagnostic FNAB of a thyroid nodule, neoplasia is not found subsequently. A minority of cases may still harbor malignancy. None of our patients in whom repeated FNA was either nondiagnostic or suggestive of benign disease were ultimately found to have a malignancy.

Objective: To determine whether the quantification of certain neuroendocrine and proliferative markers would help in the prognostic evaluation of prostatic adenocarcinomas obtained during transurethral resection of the prostate (TURP)., Materials and Methods: Samples from two groups of patients with prostate cancer were examined. One group comprised 23 patients, of whom 12 were stage IV and 11 stage III, all with Gleason scores of > or = 7; this group was designated as high-grade, high-stage (HGHS). The second group comprised 10 consecutive patients with stage T1a adenocarcinoma of the prostate with Gleason scores of < or = 6, designated as low-grade, low-stage (LGLS) tumours. Tumour tissue from each TURP was stained with MIB-1 (an indicator of cell proliferation), neuron-specific enolase (NSE), chromogranin A (ChA) and synaptophysin (Syn), and 1000 cells counted to determine the percentages of positive cells in both benign and malignant tissue. The percentage of MIB-1-positive cells was designated as the proliferative index (PI). Patients were clinically followed to evaluate tumour progression, documented by rising prostate-specific antigen (PSA) levels, X-ray evidence of recurrent or metastatic carcinoma, or tissue biopsy showing malignancy., Results: The mean number of neuroendocrine cells (NEC) for each marker and the mean PI were greater in the HGHS tumours than in the LGLS tumours or surrounding benign tissue of either group (P < 0.01). The LGLS tumours were remarkable for a having mean PI of about twice that of the benign tissue (2.9 and 1.3, respectively, P < 0.01); the NEC in these cases were more frequent in the benign than in the malignant tissue. There was no significant difference between the mean PIs and the mean percentages of NEC in the 14 HGHS tumours that progressed and the nine HGHS tumours that did not (P values 0.37-0.96)., Conclusions: Although the PI assessed by MIB-1 and the number of NEC-positive cells were much higher in HGHS than LGLS tumours, this finding did not appear to have independent prognostic significance. The significance of the higher PI in LGLS tumours than in corresponding benign tissue is uncertain; LGLS tumours had fewer NEC than the surrounding benign tissue. The quantification of any of these four markers (MIB-1, NSE, ChA, Syn) was not prognostically helpful in these groups of cancers present in TURP specimens.

Objective: To evaluate serum prostate-specific antigen (PSA) levels in patients with granulomatous prostatitis, an inflammatory condition that can clinically mimic malignancy., Patients and Methods: The study comprised 10 consecutive patients (age range 53-80 years) with histologically-documented granulomatous prostatitis and who had serum PSA levels recorded before and after diagnosis., Results: PSA levels in six of the patients were normal (< 4.0 ng/mL) at diagnosis. The other four had slightly elevated PSA levels, with three being between 4.0 and 6.0 ng/mL and the other 10.1 ng/mL. In six of the patients, there was a dramatic decrease (> 40%) in PSA level within 6-12 months after the histological documentation of granulomatous prostatitis. At the final follow-up, all 10 patients had normal PSA levels., Conclusion: Granulomatous prostatitis may cause a relatively mild and transient increase in serum PSA level which resolves when the inflammation subsides.

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.

Primary lymphoma of the liver is rare. In the 50 previously reported cases in the literature, computed tomography usually showed a solitary, bulky hypodense area in the liver. We report a case of primary lymphoma of the liver presenting multiple lesions in the liver and clinical and biochemical evidence suggestive of metastatic adenocarcinoma of the liver.

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.

Background: Neuroendocrine differentiation has been demonstrated by immunohistochemical preparations in many cases of acinar type prostatic adenocarcinoma (CAP). Some studies have suggested that this differentiation may indicate an adverse prognosis., Methods: Tissue samples from 38 consecutive patients with clinical Stage II (AJCC) CAP who underwent radical retropubic prostatectomy (RRP) were studied after preparations were made with antichromogranin (ChA) and neuron-specific enolase (NSE). All patients were followed for at least 4 years post-RRP or until disease progression was documented by rising serum prostate specific antigen concentration, X-ray evidence of recurrence, or a positive tissue biopsy., Results: Nine of the 38 RRP specimens (24%) were positive for NSE, and 11 (29%) were positive for ChA. Neither of these neuroendocrine markers showed a significant correlation with tumor progression. Neuroendocrine differentiation in needle biopsy specimens from these same patients (when available) did not correlate with tumor progression either. Of the patients with tumor progression, 9 of 11 (82%) had pathologic Stage III disease after RRP; of those with no progression of CAP, only 7 of 27 (26%) had pathologic Stage III disease., Conclusions: Neuroendocrine differentiation, as demonstrated by NSE and ChA preparations, was not helpful in predicting tumor progression of CAP.

Breast biopsies have traditionally been one of the most common specimens submitted for frozen section. However, many breast biopsies now consist of fibrofatty tissue with no areas grossly suspicious for malignancy. Because some physicians have criticized the routine use of frozen sections in such specimens, the usefulness of frozen sections performed on grossly benign breast biopsies was evaluated. Four hundred thirty-two consecutive breast biopsies having frozen sections were studied. Of these, 167 (38.7%) showed a mass by gross examination. The remaining 265 contained no areas grossly suspicious for neoplasia. Frozen-section diagnosis was deferred in seven of these cases, with the other 258 reported as benign. Ten of these 258 (3.9%) had small areas of in situ or invasive carcinoma diagnosed on permanent sections; seven of these lesions were not present on the frozen section slide. Twelve (4.7%) had areas of atypical hyperplasia (10 ductal, two lobular) identified only on permanent sections. This study indicates that frozen sections done on breast biopsies that are grossly benign do not add to the gross impression, and may be misleading mostly because of the false-negative rate.

Three combinations of histochemical stains were used to study 69 routinely processed tissues containing various "yeast-like" fungal organisms (Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Candida albicans). Fontana-Masson stain combined either with mucicarmine or Alcian blue produced distinctive staining of C. neoformans (Fontana-Masson-positive wall and mucin-positive capsule) that was not identified in other fungi. The Alcian blue stain combined with periodic acid-Schiff reaction also was useful for fungal classification, because the Alcian blue component reacted with only C. neoformans (capsule) and B. dermatitidis (wall) and the periodic acid-Schiff reaction reacted with the cell wall and body of each fungus. We concluded that the combined histochemical stains used in conjunction with morphologic study of hematoxylin and eosin- and Gomori methenamine silver-stained sections are helpful in the differential diagnosis of yeast-like fungal organisms.

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.

Some deaths during the first year of life are classified as sudden infant death syndrome (SIDS), the diagnosis of which requires a complete autopsy without adequate explanation for the death. We report a 1-month-old infant whose clinical history was fairly typical for SIDS. Postmortem examination was remarkable in revealing clinically unsuspected central nervous system (CNS) abnormalities, including lobar holoprosencephaly, absence of the olfactory tracts and grooves (arhinencephaly), subependymal gray matter heterotopias, and delayed myelination. Although the CNS findings do not adequately explain the patient's sudden death, this case illustrates the need for a complete autopsy to include careful CNS evaluation, especially in any presumed SIDS death.

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.