Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer.

Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

Reversible intrahepatic cholestasis in metastatic prostate cancer: An uncommon paraneoplastic syndrome.

As with other genitourinary malignancies, a variety of paraneoplastic syndromes have been revealed to occur in patients with prostate cancer. Stauffer's Syndrome is a well-described clinical syndrome which manifests via intrahepatic cholestasis in patients with renal cell carcinoma. Less common is intrahepatic cholestasis occurring in association with prostate cancer. The current case report discusses a 67-year-old man presenting with liver failure secondary to intrahepatic cholestasis co-existing with metastatic prostate adenocarcinoma. The patient's liver failure completely resolved with androgen-deprivation therapy suggesting an association between these two entities. The case report evaluates existing literature on this uncommon syndrome including the clinical presentation, natural history, and potential pathophysiology.

Radiation-induced cavernous malformations of the cauda equina mimicking carcinomatous or infectious meningitis. A case report.

The authors present a case of multiple radiation-induced cavernous malformations of the cauda equina in a patient with a remote history of testicular cancer and extended field radiation therapy. Magnetic resonance imaging (MRI) demonstrated multiple nodular areas of enhancement coating the nerve roots of the cauda equina, mimicking an aggressive leptomeningeal process such as carcinomatous or infectious meningitis. Biopsy of one of these lesions revealed ectatic vascular channels devoid of intervening neuroglial tissue consistent with cavernous malformation.

Detection of a subset of CD30+ anaplastic large cell lymphoma by interphase fluorescence in situ hybridization.

T/null-cell anaplastic large cell lymphoma (ALCL) is a morphologically and clinically heterogeneous group of non-Hodgkin's lymphoma; to date several morphologic variants have been described on histologic specimens. However, the cytologic features of these variants in the fine-needle aspiration (FNA) specimens have not been well evaluated. The t(2;5)(p23;q35) has been identified in a subset of T/null-ALCL and is known to be associated with a favorable prognosis. We reviewed the cytomorphologic characteristics in 24 FNA specimens of ALCL. In all cases, the diagnosis was confirmed on histologic specimens, and immunohistochemical studies for anaplastic lymphoma kinase (ALK) protein expression were performed on the aspirates. The presence of ALK breakpoints were evaluated in nine cases, using a DNA break-apart probe on chromosome 2 covering the ALK gene by fluorescence in situ hybridization (FISH) techniques. Two hundred cells per case were examined. The results were expressed as the percentage of cells containing more than two signals of chromosome 2 to the total number of cells counted. FNA sites included lymph nodes (20), lung (2), breast (1), and soft tissue (1). The median age of the patients was 56 yr (range, 17-75 yr). Twenty cases had systemic involvement; in four cases, skin was the primary site with secondary involvement of the lymph nodes. All cases were CD30(+) by immunohistochemistry; 20 were of T-cell phenotype and 4 were null cell type. The cytologic evaluation revealed typical anaplastic morphology (common type) with many "hallmark cells" in 16 (67%) cases. Other morphologic variants identified were small cell pattern in five cases, monomorphic pattern in two cases, and lymphohistiocytic pattern in one case. FISH studies showed that six (66.7%) of nine cases had at least two signals of chromosome 2, consistent with ALK breakpoints. With careful cytomorphologic evaluation in conjunction with appropriate immunohistochemical studies, a diagnosis of ALCL can be confidently made in the FNA specimens in the cellular aspirates and its morphologic variants also can be recognized. Furthermore, the FNA specimen is suitable in detecting ALK breakpoints by FISH study, permitting rapid identification of a subset of patients with ALCL, who may have a favorable prognosis. Using a commercially available probe, detection of ALK breakpoints in the FNA specimens is simple and can be a useful diagnostic adjunct in cases where distinction from other lymphomas or lymphoid lesions is morphologically difficult.

Basal cell hyperplasia in the peripheral zone of the prostate.

Basal cell hyperplasia in the prostate is often viewed as a transition zone proliferation, related to usual, nodular glandular, and stromal hyperplasia. Basal cell hyperplasia in the prostatic peripheral zone, the most common site for development of prostatic intraepithelial neoplasia and carcinoma, has not been previously characterized. We characterized the incidence and histomorphological attributes of basal cell hyperplasia in a series of 500 consecutive sextant needle core biopsy samples and in 26 completely embedded prostate glands from radical prostatectomy specimens. Comparative proliferation indices (by MIB-1 staining) and apoptotic indices (by TUNEL labeling) were quantitated for peripheral zone versus transition zone basal cell hyperplasia versus normal basal cells. The incidence of basal cell hyperplasia in prostate needle biopsy tissue was 10.2% (51 of 500 cases). Usual basal cell hyperplasia was detected in 8.2% of the 500 cases, and basal cell hyperplasia with prominent nucleoli, in 2.0% of cases. Basal cell hyperplasia in needle biopsy tissue was typically focal and associated with inflammation, which was usually lymphocytic, in 84% of cases. Peripheral zone basal cell hyperplasia was found in 23% of whole prostate glands. Peripheral zone basal cell hyperplasia was not observed to be in direct physical continuity with intraepithelial or invasive neoplasia. Peripheral zone and transition zone basal cell hyperplasia exhibited similar mean proliferation and apoptotic indices, at 1% and 0.07%, respectively. This proliferation index was elevated, and apoptotic index was decreased, relative to normal basal cells (P = 1 x 10(-7)). Basal cell hyperplasia in the peripheral zone is present in a significant minority of prostate needle biopsy samples and whole prostate glands. The presence of prominent nucleoli in basal cell hyperplasia may cause diagnostic concern for a neoplastic proliferation. The increase in cell number in basal cell hyperplasia appears to be due to a coordinate increase in proliferation index coupled with a diminished apoptotic index. The presence of inflammation in the majority of basal cell hyperplasia foci suggests that peripheral zone basal cell hyperplasia in untreated patients may represent a stereotyped response to injury such as that sustained because of inflammation.

Prostate-specific antigen cutoff of 2.6 ng/mL for prostate cancer screening is associated with favorable pathologic tumor features.

OBJECTIVES: To evaluate the pathologic characteristics of clinical Stage T1c (nonpalpable, prostate-specific antigen [PSA]-detected) prostate cancers detected in the 2.6 to 4.0-ng/mL PSA range and compare them with Stage T1c cancers concurrently detected in the 4.1 to 10.0-ng/mL PSA range. All cancers were detected in a prostate cancer screening study. METHODS: We studied 94 patients with clinical Stage T1c prostate cancer diagnosed by four or six-sector ultrasound-guided needle biopsy who underwent radical prostatectomy between June 1995 and December 1996. We included all men whose prostatectomy specimens were processed with complete embedding of all prostatic tissue. Of these, 42 had a PSA level of 2.6 to 4.0 ng/mL and 52 a PSA level 4.1 to 10.0 ng/mL at the time of cancer detection. We determined the tumor volume by complete embedding and grid morphometry, pathologic stage, Gleason sum, and surgical margin status and compared the cancer volume and pathologic tumor stages for each group. RESULTS: Men with cancer detected at the 2.6 to 4.0 ng/mL PSA range had significantly smaller cancer volumes (1.1 +/- 1.1 cm(3) versus 1.8 +/- 1.5 cm(3), P = 0.02); however, no difference was found in the proportion (11.9% versus 11.5%, P = 0.9, and 23.8% versus 26.9%, P = 0.7, respectively) of tumors that met previously published criteria of "clinically insignificant" (organ confined, less than 0.2 cm(3) tumor volume, Gleason sum 6 or less) or "clinically unimportant" (organ confined, less than 0.5 cm(3) tumor volume, and Gleason sum 6 or less) tumors. Using the lower PSA cutoff point resulted in the detection of a significantly higher percentage of organ-confined tumors (88% versus 63%, P = 0.01). CONCLUSIONS: The use of a 2.6-ng/mL PSA threshold for screening resulted in the more frequent detection of small, organ-confined tumors without overdetecting possibly clinically insignificant ones.