Wnt/ß-catenin activation promotes prostate tumor progression in a mouse model.

Our previous studies have found that activation of Wnt/ß-catenin signaling resulted in mouse prostatic intraepithelial neoplasia (mPIN). In the large probasin promoter directed SV40-large T-antigen (LPB-Tag) expressing mouse prostate, mPIN forms with rare areas of adenocarcinoma. Combining expression of both Wnt-signaling and Tag expression in the mouse prostate, we have studied the role of Wnt/ß-catenin signaling in the progression from mPIN to adenocarcinoma. Our results show that the prostates of mice expressing Tag alone or nuclear ß-catenin alone developed mPIN, whereas the activation of both Tag and the Wnt/ß-catenin pathway resulted in invasive prostate adenocarcinoma. Furthermore, Foxa2, a forkhead transcription factor, was induced by active Wnt/ß-catenin signaling, and the expression of Foxa2 was associated with the invasive phenotype in the primary prostate cancer. In the LPB-Tag/dominant active (DA) ß-catenin prostates, MMP7, a Wnt/ß-catenin target gene, was upregulated. Furthermore, we also assessed AR and AR signaling pathway in these LPB-Tag/DA ß-catenin mice. Although ß-catenin is a well-known AR co-activator in vitro, our study provides strong in vivo evidences indicating that both AR protein and the AR pathway were downregulated in the prostate of LPB-Tag/DA ß-catenin mice. Histological analysis shows that prostate sections derived from the LPB-Tag/DA ß-catenin mice display neuroendocrine differentiation (NED), but NE cancer does not develop. Together, our findings indicate that Wnt/ß-catenin signaling has an important role in the progression of mPIN to prostate adenocarcinoma.

Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma.

The oncogenic PIM1 kinase has been implicated as a cofactor for c-MYC in prostate carcinogenesis. In this study, we show that in human prostate tumors, coexpression of c-MYC and PIM1 is associated with higher Gleason grades. Using a tissue recombination model coupled with lentiviral-mediated gene transfer we find that Pim1 is weakly oncogenic in naive adult mouse prostatic epithelium. However, it cooperates dramatically with c-MYC to induce prostate cancer within 6-weeks. Importantly, c-MYC/Pim1 synergy is critically dependent on Pim1 kinase activity. c-MYC/Pim1 tumors showed increased levels of the active serine-62 (S62) phosphorylated form of c-MYC. Grafts expressing a phosphomimetic c-MYCS62D mutant had higher rates of proliferation than grafts expressing wild type c-MYC but did not form tumors like c-MYC/Pim1 grafts, indicating that Pim1 cooperativity with c-MYC in vivo involves additional mechanisms other than enhancement of c-MYC activity by S62 phosphorylation. c-MYC/Pim1-induced prostate carcinomas show evidence of neuroendocrine (NE) differentiation. Additional studies, including the identification of tumor cells coexpressing androgen receptor and NE cell markers synaptophysin and Ascl1 suggested that NE tumors arose from adenocarcinoma cells through transdifferentiation. These results directly show functional cooperativity between c-MYC and PIM1 in prostate tumorigenesis in vivo and support efforts for targeting PIM1 in prostate cancer.

The association between body size, prostate volume and prostate-specific antigen.

Increasing prostate volume contributes to urinary tract symptoms and may obscure prostate cancer detection. We investigated the association between obesity and prostate volume, prostate-specific antigen (PSA) and PSA density among 753 men referred for prostate biopsy. Among men with a negative biopsy, prostate volume significantly increased approximately 25% from the lowest to highest body mass index (BMI), waist or hip circumference or height categories. PSA was 0.7 ng/ml lower with a high waist-to-hip ratio. These associations were less consistent among subjects diagnosed with high-grade prostatic intraepithelial neoplasia or cancer. Our data suggest that obesity and height are independently associated with prostate volume..

Kearns-Sayre syndrome with features of Pearson's marrow-pancreas syndrome and a novel 2905-base pair mitochondrial DNA deletion.

Kearns-Sayre syndrome (KSS) and Pearson's marrow-pancreas syndrome (PMPS) are rare disorders caused by the same molecular defect, one of several deletion mutations in mitochondrial DNA (mtDNA). KSS is an encephalomyopathy with ophthalmoplegia, retinal degeneration, ataxia, and endocrine abnormalities. PMPS is a disorder of childhood characterized by refractory anemia, vacuolization of bone marrow cells, and exocrine pancreas dysfunction. Children with PMPS that have a mild phenotype, or are supported through bone marrow failure, often develop the encephalomyopathic features of KSS. The subject of numerous reports in the neuromuscular, genetic, and pediatric literature in recent years, very few cases of either disorder have ever been studied at autopsy. We report the results of our studies of a patient with clinically documented KSS who presented with renal dysfunction and was found to have a novel mtDNA deletion and degenerative changes in the central nervous system, retina, skeletal muscle, and pancreas.

How often are diagnostic features missed with less extensive histologic sampling of prostate needle biopsy specimens?

The authors determined whether clinically relevant diagnostic information would be lost by examination of <3 levels per tissue core in prostate needle biopsy specimens. They evaluated 439 consecutive sextant biopsy specimens for the following three histopathologic features: presence of adenocarcinoma involving one core, Gleason pattern 4 in cases of grade 3 + 4 = 7 adenocarcinoma, and perineural invasion (PNI) by carcinoma. For all cases, 3 levels from each involved core were reviewed for the presence or absence of these three features. In 50 cases with adenocarcinoma involving only 1 core, diagnostic carcinoma was present on all 3 levels in 43 cores (86%). Carcinoma was present on only 2 levels in 3 cores (6%), present only on 1 level in 3 cores (6%), and present only on additional cut-downs, not on the original 3 levels in 1 core (2%). Among 32 cases, 51 cores were identified that contained Gleason grade 3 + 4 = 7 adenocarcinoma. In 41 cores (80%), pattern 4 was identified in all 3 levels. In 5 cores (10%), pattern 4 was identified on only 2 levels, and in another 5 cores (10%), pattern 4 was present on only 1 level. Among 36 cases, 69 tissue cores were identified that contained perineural invasion (PNI). In 54 cores (78%), PNI was present on all 3 levels. In 7 cores (10%), PNI was present on only 2 of 3 levels, while in 7 other cores (10%), PNI was present on only 1 of 3 levels. In 1 core (1.5%), PNI was noted only on additional cutdowns, not on the original 3 levels. We estimated that reducing the number of levels to 1 per core could result in the misdiagnosis of PNI, grading, or carcinoma in approximately 8-11% of cores with these features and could have changed the case diagnosis in 9 of 439 cases. If only 2 levels were reviewed, we predict misdiagnosis in 5% to 6% of cores with these features and a change in the case diagnosis in 5 of 439 cases. Misdiagnosis of clinically relevant features on prostate biopsy specimens can be minimized with histologic review of 3 levels per tissue core.

Ability of sextant biopsies to predict radical prostatectomy stage.

OBJECTIVES: There are few studies evaluating multiple variables on sextant biopsies with the intent to predict stage in radical prostatectomy specimens. METHODS: We studied 113 sextant biopsies with corresponding totally submitted radical prostatectomy specimens. Variables evaluated on sextant biopsies included total length and percent of cancer; maximum length and percent of cancer on one core; location (apex, mid, base); bilaterality; Gleason grade; number of cores involved; serum prostate-specific antigen (PSA) level; and serum PSA density (PSAD). Radical prostatectomy stage was classified as organ versus non-organ confined. RESULTS: The following variables individually correlated with radical prostatectomy stage: total cancer measured in millimeters (P <0.0001) or percent (P <0.0005); biopsy Gleason score (P <0.0001); number of involved cores (P <0.0001); maximum cancer on one core measured in millimeters (P = 0.0001); maximum percent of cancer on one core (P = 0.01); bilaterality (P = 0.01); PSA level (P = 0.03), and PSAD (P = 0.001). The most predictive sets of two variables that correlated with stage included high Gleason score (P <0.0001) combined with numbers of cores involved (P = 0.002). When biopsies had Gleason scores of 6 or less, two or fewer positive cores, and serum PSA of 0 to 4 ng/mL, 89% were organ confined. When biopsies had Gleason scores of 6 or less with two unilaterally positive cores, 87% were organ confined. In biopsies with Gleason scores of 7 or more and more than one positive core, only 10% were organ confined. CONCLUSIONS: The most important predictors of stage by sextant needle biopsy evaluation are numbers of cores involved with carcinoma and high Gleason score. Bilaterality and serum PSA values improved prediction in two small subgroups. In 37% of our population we were able to predict with a greater than 87% probability the organ-confined versus non-organ-confined status.

Partial atrophy in prostate needle cores: another diagnostic pitfall for the surgical pathologist.

We have seen in consultation a variant of atrophy, which is frequently confused with well-differentiated adenocarcinoma of the prostate. We have designated this entity as partial atrophy to distinguish it from its more common counterpart of fully developed atrophy. Partial atrophy is defined as benign prostate glands with relatively scant cytoplasm, yet the glands are not fully atrophic in that they do not appear basophilic at low magnification. Fifty-one cases of partial atrophy were identified (4 from Johns Hopkins Hospital, 47 from consultation). Within the partial atrophy focus, irregular (crinkled) nuclei were frequent in 23.5% and occasionally present in 33.3% of cases. Visible nucleoli were frequent in 25.4% of cases. Basal cells were not identifiable in 27.4% of cases or were hard to identify in 35.3% of cases. No intraluminal crystalloids or blue-tinged mucinous secretion was identified in partial atrophy. Adenocarcinoma or glands suspicious for cancer were present in other cores in 15.6% of cases. More fully developed atrophy was present in simultaneously obtained needle cores in 35.3% of cases. In the cases in which regular atrophy was the only coexisting condition, it was present within one 10x field from the partial atrophy in 22.2%, farther than one 10x field from the partial atrophy in 11.1%, and present in the same gland as the partial atrophy in 66.7%. Partial atrophy may be confused with low-grade adenocarcinoma because of the focus of crowded glands, irregular nuclei, and visible nucleoli. Clues for recognizing partial atrophy include relatively scant cytoplasm, distinct crinkled nuclei, pale cytoplasm similar to adjacent, more recognizably benign glands, and association with more fully developed benign atrophy.

Inflammatory (pseudosarcomatous) myofibroblastic tumor of the bladder.

We present a case of inflammatory (pseudosarcomatous) myofibroblastic tumor of the bladder in a child, along with a review of the literature. The benign nature of this rare disorder needs to be recognized so that superfluous radical therapy can be avoided. The clinical features and microscopic, ultrastructural, and immunohistochemical characteristics that help to identify this entity are described. To date, 72 such cases involving the bladder have been reported in the literature including the present one.

Incidence of high-grade prostatic intraepithelial neoplasia in sextant needle biopsy specimens.

OBJECTIVES: There is scant literature on the frequency of high-grade prostatic intraepithelial neoplasia (PIN) in needle biopsy specimens. These data have implications as to how often pathologists should be expected to diagnose these lesions on needle biopsy and impact on the feasibility of cancer chemoprevention trials for prostate cancer. METHODS: We reviewed 439 consecutive 18-gauge sextant needle biopsy specimens from the Johns Hopkins Hospital. RESULTS: Based on the pathology reports, high-grade PIN was recorded in 12 (2.7%) of the cases and was confirmed upon review. Following review of the slides, unequivocal high-grade PIN was found in an additional 6 cases. There were 6 other cases where the findings were borderline between high- and low-grade PIN, but which were believed to be more consistent with high-grade PIN. Considering these latter cases in conjunction with the unequivocal cases of high-grade PIN, the incidence of high-grade PIN was 5.5% (24 of 439). CONCLUSIONS: Recognizing that approximately 50% of men with high-grade PIN on needle biopsy will be found to have carcinoma on repeat biopsy, the management of high-grade PIN on biopsy will only apply to 50% of the men initially discovered with this finding. If only 2.75% of men who are biopsied eventually need therapy for high-grade PIN on needle biopsy, the number of cases needed to study the decrease of high-grade PIN following chemoprevention might be prohibitively high. If the incidence of high-grade PIN on needle biopsy requiring therapy is only 2.75%, it may also not be worthwhile developing large trials to investigate various treatment regimens for high-grade PIN found on biopsy.

Potentiation of hyperthermia in a murine tumour by metabolic inhibitors rhodamine 123 and 2-deoxy-D-glucose or 5-thio-D-glucose.

Rhodamine 123 injected into mice on 3 days consecutively before a single hyperthermia treatment (45 degrees C for 15 min) potentiated hyperthermia as evidenced by an increased mean tumour growth delay of a transplantable murine mammary adenocarcinoma (MTG-B). Addition of three daily injections of either 2-deoxy-D-glucose, or 5-thio-D-glucose, coordinated with the rhodamine 123, and administered before hyperthermia, resulted in an additional tumour growth delay, but not large enough to suggest an additional significant interaction between the two drugs and heat. This effect was obtained using doses of the glucose analogues which did not potentiate therapeutically when combined with heat without rhodamine 123. On the third day of treatments, rhodamine 123 or 5-thio-D-glucose, or the two drugs together, 60 min before heating, produced a longer growth delay compared with each combination treatment with drugs administered 15 min before heating. However, this effect was not significant. Results of these experiments suggest that in this murine tumour thermopotentiation can be attained by combining these two classes of metabolic inhibitors with hyperthermia.