Faculty Publications

Birt-Hogg-Dube (BHD) syndrome is a tumor-suppressor gene disorder characterized by skin tumors, cystic lung disease and renal cell carcinoma. Very little is known about the molecular pathogenesis of BHD. Clinical similarities between BHD and tuberous sclerosis complex (TSC) suggest that the BHD and TSC proteins may function within a common pathway. The TSC proteins inhibit the activity of the mammalian target of rapamycin complex 1 (TORC1), and in Schizosaccharomyces pombe, Bhd and Tsc1/Tsc2 have opposing roles in the regulation of amino-acid homeostasis. We report here that in mammalian cells, downregulation of BHD reduces the phosphorylation of ribosomal protein S6, an indicator of TORC1 activity. To determine whether folliculin, the product of the BHD gene, regulates mammalian target of rapamycin activity in vivo, we generated a mouse with targeted inactivation of the Bhd gene. The mice developed spontaneous oncocytic cysts and tumors composed of cells that resemble the renal cell carcinomas in BHD patients. The cysts and tumors had low levels of phospho-S6. Taken together, these data indicate that folliculin regulates the activity of TORC1, and suggest a new paradigm in which both inappropriately high and inappropriately low levels of TORC1 activity can be associated with renal tumorigenesis.

PURPOSE: MDM2 regulates p53, which controls cell cycle arrest and apoptosis. Both proteins, along with Ki-67, which is an established strong determinant of metastasis, have shown promise in predicting the outcome of men treated with radiation therapy (RT) with or without short-term androgen deprivation (STAD). This report compares the utility of abnormal expression of these biomarkers in estimating progression in a cohort of men treated on RTOG 92-02. PATIENTS AND METHODS: Adequate tissue for immunohistochemistry was available for p53, Ki-67, and MDM2 analyses in 478 patient cases. The percentage of tumor nuclei staining positive (PSP) was quantified manually or by image analysis, and the per-sample mean intensity score (MIS) was quantified by image analysis. Cox regression models were used to estimate overall mortality (OM), and Fine and Gray's regressions were applied to the end points of distant metastasis (DM) and cause-specific mortality (CSM). RESULTS: In multivariate analyses that adjusted for all markers and treatment covariates, MDM2 overexpression was significantly related to DM (P = .02) and OM (P = .003), and Ki-67 overexpression was significantly related to DM (P < .0001), CSM (P = .0007), and OM (P = .01). P53 overexpression was significantly related to OM (P = .02). When considered in combination, the overexpression of both Ki-67 and MDM2 at high levels was associated with significantly increased failure rates for all end points (P < .001 for DM, CSM, and OM). CONCLUSION: Combined MDM2 and Ki-67 expression levels were independently related to distant metastasis and mortality and, if validated, could be considered for risk stratification of patients with prostate cancer in clinical trials.

BACKGROUND: Precursor B-cell lymphoblastic lymphoma (B-LBL) is an uncommon high-grade neoplasm of immature B cells. In contrast to the more common lymphoblastic lymphoma of T-cell lineage, B-LBL can be an extranodal disease, with a propensity to involve skin and bone. Most reported cases of B-LBL in the skin, a rarity in adults, are manifestations of existing systemic disease. OBSERVATIONS: We report 2 unusual cases of primary cutaneous B-LBL in adults. Fluorescence in situ hybridization studies, not previously reported in primary cutaneous B-LBL to our knowledge, demonstrated rearrangement of the MLL gene in one patient and possible hyperdiploidy in the other, both reported in precursor acute lymphoblastic leukemia. CONCLUSIONS: Review of the literature identified 13 reported cases of B-LBL occurring primarily in the skin, in addition to our 2 cases. Precursor B-cell lymphoblastic lymphoma is more common in children and in young adults, with a tropism for the head and neck region. Histologically, B-LBL must be differentiated from other high-grade lymphoid tumors and small "blue round cell" tumors. Because of the common absence of mature B-cell markers in immunohistochemical studies and the frequent expression of CD99, B-LBL may present a diagnostic challenge. Although there is a suggestion in a limited number of patients that abbreviated therapy may provide long-term disease control, the risk of relapse remains significant, particularly if a patient's condition is misdiagnosed and the patient is treated as having mature B-cell lymphoma. In the absence of prospective studies for this population, patients with B-LBL are treated currently with intensive acute lymphoblastic leukemia regimens.

OBJECTIVES: To review the collective experience evaluating pathologic concordance rates of sporadic bilateral synchronous renal tumors reported in the Surveillance, Epidemiology, and End Results (SEER) database and the published English literature and treated at Fox Chase Cancer Center; specifically, to analyze concordance rates of malignant versus benign disease, histologic type, tumor stage, and nuclear grade. METHODS: We reviewed the SEER database, the published English language literature, and our own institutional tumor registry to identify all cases of sporadic, synchronous localized (cT1-3N0M0) bilateral renal masses. Malignant and benign concordance rates were defined as agreement of any benign or malignant tumor type bilaterally. Histologic concordance was defined as bilateral histologic agreement. Tumors with mixed histologies were discordant unless all patterns were identical bilaterally. Nuclear grades were concordant if bilateral tumors were either "high" grade or "low" grade. RESULTS: The malignant concordance rate in the SEER data was 99% (273 of 274), and benign concordance was 0 (0 of 1). In the published literature and Fox Chase Cancer Center series, malignant concordance rates ranged from 84% to 95%, whereas benign concordance ranged from 39% to 67%. The SEER data revealed a histologic concordance rate of 93% (256 of 274), and nuclear grade concordance was 85% (88 of 103). CONCLUSIONS: These data demonstrate that in cases of bilateral sporadic localized synchronous renal masses, a diagnosis of ipsilateral renal cell carcinoma is associated with contralateral renal cell carcinoma in the vast majority of patients, whereas ipsilateral benign pathology is associated with contralateral benign disease at a substantially lower rate. Histologic concordance is similarly high, meaning most cases of clear cell or papillary tumors ipsilaterally are concordant in the contralateral kidney. Concordance rates of nuclear grade were slightly lower. These data are important when counseling and managing patients with bilateral synchronous sporadic renal tumors.

Plasmablastic lymphoma is a variant of diffuse large B-cell lymphoma occurring in immunocompromised individuals. Multiple organ sites may be involved; however, cutaneous involvement has been rarely reported in the medical literature. To date, there have been only 7 reports of cutaneous plasmablastic lymphoma without systemic involvement. We report a case of isolated cutaneous plasmablastic lymphoma occurring in an HIV-positive man with more than 10 years of follow-up.

Purpose: The RI-a regulatory subunit of protein kinase A type 1 (PKA) is constitutively overexpressed in human cancer cell lines and is assocd. with active cell growth and neoplastic transformation. This report examd. the assocn. between PKA expression and the endpoints of biochem. failure (BF), local failure (LF), distant metastasis (DM), cause-specific mortality (CSM), and overall mortality in men treated with radiotherapy, with or without short-term androgen deprivation in Radiation Therapy Oncol. Group trial 86-10. Methods and Materials: Pretreatment archival diagnostic tissue samples from 80 patients were stained for PKA by immunohistochem. methods from a parent cohort of 456 cases. PKA intensity was scored manually and by image anal. The Cox proportional hazards model for overall mortality and Fine and Gray's regression models for CSM, DM, LF and BF were then applied to det. the relationship of PKA expression to the endpoints. Results: The pretreatment characteristics of the missing and detd. PKA groups were not significantly different. On univariate analyses, a high PKA staining intensity was assocd. with BF (image anal., continuous variable, p = 0.022), LF (image anal., dichotomized variable, p = 0.011), CSM (manual anal., p = 0.037; image anal., continuous, p = 0.014), and DM (manual anal., p = 0.029). On multivariate analyses, the relationships to BF (image anal., continuous, p = 0.03), LF (image anal., dichotomized, p = 0.002), and DM remained significant (manual anal., p = 0.018). In terms of CSM, a trend toward an assocn. was seen (manual anal., p = 0.08; image anal., continuous, p = 0.09). Conclusion: PKA overexpression was significantly related to patient outcome and is a potentially useful biomarker for identifying high-risk prostate cancer patients who might benefit from a PKA knockdown strategy. [on SciFinder (R)]

BACKGROUND: Ductal carcinoma of the prostate is a rare variant of prostate cancer that presents most commonly with obstructive urinary symptoms or hematuria. This case series of 6 patients is the first to report the outcome of ductal carcinoma treated with external beam radiotherapy. METHODS: A retrospective review was performed of patients treated between 1980 and 2006 at Fox Chase Cancer Center, Philadelphia, Penn. Six patients were identified with ductal carcinoma. RESULTS: Five of the 6 patients were treated definitively and the sixth patient was treated at recurrence 3 years after a radical prostatectomy. Patient ages ranged from 66-80 years and the initial prostate-specific antigen (iPSA) ranged from 1.69-100.3 ng/mL. Three patients had a mixed acinar and ductal carcinoma, 2 with a Gleason score (GS) of 8 and 1 with a GS of 7. Of the patients treated definitively, 4 had clinical stage T2A-T2C and 1 had clinical stage T1B. Definitive radiotherapy was delivered to the prostate with doses between 72 Gy and 78 Gy. Pelvic lymph nodes were treated in all patients. One patient was treated postradical prostatectomy to the prostate bed to a dose of 60 Gy. Adjuvant androgen deprivation was given in 5 of the patients. Two of the patients died from metastatic disease at 1.4 and 7.1 years after treatment. The remaining 4 patients remain alive between 3.2 and 4.8 years from treatment, with 3 patients biochemically without evidence of disease. No patients have developed a local recurrence. CONCLUSIONS: Ductal carcinoma of the prostate may be treated effectively with external beam radiotherapy. Aggressive management is indicated, even with low-volume metastatic disease.

PURPOSE: Bcl-2 is antiapoptotic, and its overexpression has been associated with resistance to androgen deprivation and poor outcome in some patients treated with radiotherapy. Bax is proapoptotic, regulating Bcl-2 through heterodimer formation. In a prior study, Bcl-2 and Bax were not related to outcome in locally advanced patients treated with radiotherapy or short-term androgen deprivation + radiotherapy (STAD+RT) on another Radiation Therapy Oncology Group trial (86-10). A follow-up investigation was carried out here in more contemporary high-risk men treated on Radiation Therapy Oncology Group 92-02 with STAD+RT or long-term AD+RT (LTAD+RT). EXPERIMENTAL DESIGN: Adequate tissue was available to be analyzed immunohistochemically in 502 patients for Bcl-2 and 343 patients for Bax. Univariate and multivariate analyses by Cox proportional hazards models were applied to end points of failure. RESULTS: Bcl-2 was positive in 45.6% cases, and Bax expression altered in 53.9% cases. Abnormal Bcl-2 was not related to any of the failure end points tested. Altered Bax expression was significantly associated with any failure (P = 0.023) and marginally with biochemical failure (P = 0.085). The combination of negative Bcl-2/normal Bax expression seemed more robust, being significantly related to reduced biochemical failure (P = 0.036) and any failure (P = 0.046). The predictive value of negative Bcl-2/normal Bax was most pronounced in those who received STAD+RT, as opposed to LTAD+RT. CONCLUSIONS: Normal Bax expression was associated with significantly more favorable outcome. The combination of negative Bcl-2 and normal Bax was more consistently significant, particularly when STAD+RT was the treatment administered. These data suggest that LTAD+RT should be used when either Bcl-2 or Bax is abnormally expressed.