Prevalence of androgen receptor gene mutations in latent prostatic carcinomas from Japanese men.

The incidence rate of clinically apparent prostatic carcinoma is 8-fold higher in the United States than in Japan, while the prevalence of latent prostatic carcinoma, a presumed precursor to clinical carcinoma, is similar in the two countries. The purpose of this study was to investigate the hypothesis that this profound difference in incidence rates of clinical carcinoma reflects distinct profiles of molecular genetic alterations in the latent precursor lesions that occur in the two countries. A significant fraction of latent carcinomas from Japanese men were found to contain inactivating mutations of the androgen receptor gene, while no such mutations were found in latent carcinomas from American men. No mutations were found in clinical carcinomas from either country. These data offer a potential molecular genetic explanation that may partially account for the distinct prostatic carcinoma incidence rates in these two populations.

Histochemistry of the prostate.

Histochemistry, including immunohistochemistry, is helpful to the practicing pathologist in the diagnosis of prostatic carcinoma. Of equal importance, histochemistry is being increasingly used to study the pathobiology of the prostate. This article reviews these histochemical techniques and their applications.

Hair granuloma of the prostate.

We report the second case of so-called hair granuloma of the prostate in a transurethral resection specimen. We hypothesize that the hair was most likely embedded in bladder/neck/prostate tissue by an earlier perineal prostate needle biopsy.

Interobserver reproducibility of Gleason grading of prostatic carcinoma: general pathologist.

Only a few large studies of interobserver reproducibility of Gleason grading of prostatic carcinoma exist. Thirty-eight biopsies containing prostate cancer were distributed for Gleason grading to 41 general pathologists in Georgia. These cases had "consensus" Gleason grade groups (2-4, 5-6, 7, and 8-10) that were agreed on by at least 7 of 10 urologic pathologists. The overall kappa (kappa) coefficient for interobserver agreement for these 38 cases was 0.435, barely moderate agreement, with a kappa range from 0.00 to 0.88. There was consistent undergrading of Gleason scores 5-6 (47%), 7 (47%) and, to a lesser extent, 8-10 (25%). In cases with consensus primary patterns, there was consistent undergrading of patterns 2 (32%), 3 (39%), and 5 (30%). Pattern 2 was often (17%) mistaken for pattern 3. Pattern 4 was often undergraded (21%) and also mistaken for pattern 5 (17%). The most significant (P < .005) demographic factor associated with better interobserver agreement was having learned Gleason grading at a meeting or course. We believe that Gleason grading can be learned to a satisfactory level of interobserver reproducibility and have undertaken additional studies that support this belief.

Interobserver reproducibility of Gleason grading of prostatic carcinoma: urologic pathologists.

Gleason grading is now the most widely used grading system for prostatic carcinoma in the United States. However, there are only a few studies of the interobserver reproducibility of this system, and no extensive study of interobserver reproducibility among a large number of experienced urologic pathologists exists. Forty-six needle biopsies containing prostatic carcinoma were assigned Gleason scores by 10 urologic pathologists. The overall weighted kappa coefficient kappa(w) for Gleason score for each of the urologic pathologists compared with each of the remaining urologic pathologists ranged from 0.56 to 0.70, all but one being at least 0.60 (substantial agreement). The overall kappa coefficient kappa for each pathologist compared with the others for Gleason score groups 2-4, 5-6, 7, and 8-10 ranged from 0.47 to 0.64 (moderate-substantial agreement), only one less than 0.50. At least 70% of the urologic pathologists agreed on the Gleason grade group (2-4, 5-6, 7, 8-10) in 38 ("consensus" cases) of the 46 cases. The 8 "nonconsensus" cases included low-grade tumors, tumors with small cribriform proliferations, and tumors whose histology was on the border between Gleason patterns. Interobserver reproducibility of Gleason grading among urologic pathologists is in an acceptable range.

Pathology residents' use of a Web-based tutorial to improve Gleason grading of prostate carcinoma on needle biopsies.

Little is known about pathology residents' ability to Gleason grade or their ability to learn surgical pathology using Internet-based technology. A free Web-based program (available at www.pathology. jhu.edu/prostate) was developed that consisted of 20 pretutorial images for grading, 24 tutorial images, and the same 20 posttutorial images for Gleason grading. The grading images were selected from cases that had a consensus Gleason grade from 10 uropathology experts. In 2.5 months, 255 residents visited the website, and 151 (59%) completed it. Of those who completed the website, their year in training was known in 85 (56%): 1st year, 25.8%; 2nd year, 20%; 3rd year, 22.3%; 4th year, 14.1%; 5th year, 15.3%; and 6th year, 2.4%. Eighty percent learned Gleason grading in residency versus being self-taught, and 66% were male. In a multivariate analysis, higher pretutorial scores were associated with both their year in training (P = .001) and their hospital size (P = .003). Improvements in grading posttutorial were not related to the residents' year in training. Overall, the website significantly improved grading in 11 of 20 images and had no effect in 9 of 20 images. Improvements were noted in 1 of 1 Gleason score 4; 2 of 7 Gleason score 5 to 6; 2 of 6 Gleason score 7; and 6 of 6 Gleason score above 7 tumors. In summary, a Web-based tutorial improved Gleason grading accuracy by pathology residents to an equal extent regardless of their year in training. It is more difficult to teach residents to grade Gleason scores 5 to 7 tumors, and additional training should be concentrated in this area.

Ganglioglioma, a malignant tumor? Correlation with flow deoxyribonucleic acid cytometric analysis.

This study describes the flow cytometric deoxyribonucleic acid (DNA) analysis of a resected ganglioglioma. The initial histopathological analysis revealed a benign tumor characterized by a predominance of mature ganglion cells. The flow cytometric DNA analysis of the necrotic areas, however, demonstrated an aneuploid population of cells. Further examination by histological analysis of the tumor revealed both benign and atypical foci. The retrospective DNA analysis performed from paraffin sections of tissue with benign-histological findings demonstrated euploid populations of cells consistent with a benign, slow-growing lesion. In contrast, DNA analysis performed from tissue with atypical histological findings revealed aneuploid populations of cells consistent with a malignant phenotype. Our analysis provides additional data supporting the existence of tumor progression in some gangliogliomas. Results support the concept of tumor cell heterogeneity and the importance of adequate tumor sampling. The finding of aneuploid populations with unfavorable histology further supports the use of flow cytometry as an adjunct method in assessing tumor biology.

Multiple congenital hemangiopericytomas of the head and neck.

Hemangiopericytoma is a vascular tumor arising from contractile cells, the pericyte of Zimmermann. The neoplasms most frequently involve deep musculature; however, 16% occur in the head and neck region. The case presented here represents the rare occurrence of multiple congenital hemangiopericytoma of the head and neck. In older patients, these rather poorly differentiated tumors recur locally after excision in 50%-80% of cases depending on the organ site involved. Distant metastasis to lung or bone may follow. Congenital hemangiopericytomas appear to follow a more benign clinical course, possibly due to a more superficial location and a tendency to transform into hemangioendotheliomas. Recommended treatment is wide local excision and long-term follow-up.

Flow cytometry shows recurrent aneuploid clone after remission in megakaryocytic leukemia.

Flow cytometry using a DNA label can quantitate aneuploid clones in malignant tissue. We illustrated the clinical value of this technique in a 71-year-old woman with acute megakaryocytic leukemia, which was diagnosed by staining of the blasts with factor VIII antigen and their morphologic resemblance to megakaryoblasts. Marrow cells were removed from needle biopsies by vortexing in RPMI medium, centrifuged in Ficoll-Hypaque, stained with a propidium-iodide/NP-40 mixture, and analyzed at 488 nm using an argon laser. During 3 weeks of low-dose cytosine arabinoside (ara-c) infusion therapy, hyperdiploid peak A dropped from 35% (day 0) to 2.3% (day 14) to 0% (day 21), with development of marrow hypoplasia. Similarly, hyperdiploid peak B, went from 7.6% to 9.1% to 3.5%. Subsequently, her marrow recovered normal morphology and lost the aneuploid peaks. Her blood counts recovered to near normal. Four months later, she relapsed and had a return of the day-21, incompletely eradicated peak B. There was no evidence of peak A. Repeated treatment with ara-c resulted in temporary suppression of the disease, but she died 3 months later with progressive hepatosplenomegaly. Analysis of cells from her enlarged liver, heavily infiltrated with blasts, showed a large hyperdiploid peak B. In this patient, ara-c therapy induced a remission with permanent eradication of one clone, but incomplete eradication of a second clone, which ultimately led to her relapse and death.

Liposarcoma of the larynx.

To our knowledge, only seven cases of laryngeal liposarcoma have been reported in the English language literature. We add an eighth case and review the other seven cases. Our patient presented with a pedunculated mass arising from the left aryepiglottic fold and obstructing both the larynx and pharynx. The lesion has recurred locally three times in a period of four years. We discuss pathologic findings and management of this patient.

Estradiol and progesterone receptors in a case of fibromatosis of the breast.

A case of fibromatosis of the breast with positive cytosol assays for estradiol and progesterone receptors is described. Estrogen and progesterone receptors in fibromatosis have been only rarely reported in the English literature, and never, to our knowledge, in fibromatosis of the breast. We discuss the implications of these findings and review the literature.

Needle biopsies of the prostate: what constitutes adequate histologic sampling?

OBJECTIVE: The automated biopsy gun and increased screening for adenocarcinoma of the prostate have led to increased numbers of biopsies with only tiny foci of prostatic carcinoma. Consequently, the risk of failing to sample a small focus of carcinoma histologically has increased as well. Most pathologists routinely sample prostatic needle biopsies at more than 1 level. An expert panel has recently suggested that prostatic needle biopsies be sampled at at least 2 levels. However, there have been no studies measuring the amount of additional tissue sampled by multiple levels versus 1 level. METHODS: Forty-two prostatic needle biopsies were serially sectioned at 4-microm levels. Hematoxylin-eosin-stained slides were prepared from every fifth section. The total length of each biopsy was compared with the length sampled by 1 level (50% through the block) and 3 levels (25%, 50%, and 75% through the block). RESULTS: Sampling the tissue at 1 level missed an average of 23.4% of the total biopsy length. Sampling the tissue at 3 levels significantly improved this average to 7% (P = .0001). CONCLUSIONS: This study shows that a single histologic section of a prostatic needle biopsy often fails to sample a significant portion of available tissue. This could occasionally result in failure to sample a small focus of prostatic carcinoma. The authors recommend that prostatic needle biopsies be routinely sampled at 3 levels (approximately 25%, 50%, and 75% through the block).

Embryonal rhabdomyosarcoma in ascitic fluid. Immunocytochemical and DNA flow cytometric study.

We report the case of an 18-year-old woman who had a small-cell malignant neoplasm of the left paranasal sinuses and who, 18 months later, developed malignant ascites. Immunoperoxidase stains of the ascitic fluid cells and, subsequently, the original tumor, identified it as embryonal rhabdomyosarcoma. Flow cytometric DNA analysis of the ascitic fluid demonstrated an aneuploid cell population that was also present in the paraffin-embedded tissue on which the original diagnosis had been made.

Flow cytometric analysis of prostatic carcinoma with and without bone marrow metastasis.

We have analyzed 68 prostates obtained at autopsy, for DNA ploidy by means of flow cytometry from patients who had clinical prostatic carcinoma with (29 cases) and without (39 cases) bone marrow metastasis. Flow cytometric analysis revealed 42 diploid cases and 26 aneuploid cases in a total of 68 cases. Among the 26 cases of aneuploidy, 4 cases were tetraploid aneuploid and 22 cases were not tetraploid aneuploid. The highest incidence for the aneuploidy was found in stage D2 disease (19/29, 65.5%), while the highest incidence for diploid was seen in stage B disease (23/25, 92.0%). The correlation between ploidy and bone marrow metastasis was significant (P < 0.01). We thus reconfirm that flow cytometric analysis of paraffin embedded tissue is useful for prognostic evaluation of prostatic carcinoma.

Cytologic detection of urothelial cancer and other abnormalities in a cohort of workers exposed to aromatic amines.

A total of 541 members of a cohort at increased risk for occupational bladder cancer underwent a 33-month program of screening with urine cytology. Selected workers received further urologic study with cystoscopy and bladder biopsies. Eight workers had positive or suspicious cytologic findings. Only one of the eight had a prior history of bladder cancer. Biopsies showed invasive carcinoma and/or nonpapillary carcinoma in situ in five workers in this group, severe atypia in one, and no significant abnormality in two. Of 56 workers who had atypical cytologic findings, 16 had bladder biopsies, which showed atypia of flat urothelium in 11, nonpapillary carcinoma in situ in one, noninfiltrating papillary carcinoma in one, and no significant abnormality in three. The cytologic detection of urothelial abnormalities often required more than a single specimen. Since the cohort in this study may develop more bladder cancers with the passage of time, continued follow-up is indicated.

Flow cytometric DNA analysis.

Flow cytometric DNA analysis, including principles, techniques, and applications, is reviewed. Flow cytometry, a relatively recently developed technology, is being increasingly used in the diagnosis and treatment of a wide variety of benign and malignant diseases. Current major applications include phenotypic analysis of cells, cell sorting, and DNA analysis. DNA analysis by flow cytometry is rapid, reliable, and reproducible. Flow cytometric DNA analysis offers a quick, reliable method of analyzing cellular DNA content capable of identifying cell populations with abnormalities in total DNA content.

Acute megakaryocytic leukemia. Flow cytometric analysis of DNA content at diagnosis and during the course of therapy.

Flow cytometry (FCM) for the determination of DNA content and cell cycle analysis was performed on multiple bone marrows from a case of acute megakaryocytic leukemia in a 71-year-old woman. Two aneuploid (multiploid) peaks were present at diagnosis. This multiploidy was a stable characteristic when studied temporally. The disappearance of the peaks in the bone marrow specimens directly correlated with complete remission morphologically. These findings further support the concept of FCM as an adjunct to morphologic study in identifying residual tumor burden.

Down's syndrome and acute myelofibrosis. Time study of DNA content during the progression to leukemia.

Flow cytometry (FCM) for the determination of cellular DNA content was performed on multiple bone marrow biopsy specimens from a 3-year-old boy with Down's syndrome and myelofibrosis. A rapidly fatal acute nonlymphocytic leukemia developed within 3 months after initial bone marrow evaluation. The clinical and morphologic changes corresponded to the development of aneuploidy as determined by FCM and cytogenetic analysis. These findings support the clinical observations of the premalignant potential of myelofibrosis in Down's syndrome.

A web-based tutorial improves practicing pathologists' Gleason grading of images of prostate carcinoma specimens obtained by needle biopsy: validation of a new medical education paradigm.

BACKGROUND: The Internet, although it is in widespread use in medicine, to the authors' knowledge has not been tested rigorously as an educational tool. The authors investigated, as a model to validate web-based education for physicians, the Gleason grading of images of prostate carcinoma tissue specimens that were obtained by needle biopsy, which provides critical information for patient management. METHODS: A free, web-based program (available at www. pathology.jhu.edu/prostate) was developed. It consisted of 20 pretutorial quiz images of prostate carcinoma specimens that were obtained by needle biopsy for grading, followed by 24 tutorial images with text describing the Gleason grading system. Subsequently, pathologists took a posttutorial quiz, which consisted of the same 20 images that were used in the pretutorial quiz. RESULTS: In 16 months, there were 2021 visits with 916 participants completing the entire web site; 643 participants (70.2%) were practicing pathologists and formed the basis of the current study. Only the location of practice within the United States compared with outside the United States (P < 0.0001) and < 5 years in practice (P = 0.003) were correlated independently with a higher pretutorial quiz score. Overall, the web-based tutorial significantly improved grading in 15 of 20 images. Of these, on average, there was an 11.9% increase (range, 6-25.3%) in assigning the correct Gleason score. Improvements were noted in images of tumors with the following grades: Gleason score, 2-4 (0 of 1 images); Gleason score, 5-6 (5 of 7 images); Gleason score, 7 (4 of 6 images); and Gleason score, 8-10 (6 of 6 images). Greater improvement after taking the tutorial was correlated with lower pretutorial scores (P < 0.0001). CONCLUSIONS: A web-based tutorial improves the accuracy of Gleason grading of practicing pathologists. To the authors' knowledge the current study is the first large scale, international study that has evaluated and validated the use of a web-based program to educate a population of widely dispersed physicians.