A phase II trial of intrapatient dose-escalated sorafenib in patients with metastatic renal cell carcinoma.

PURPOSE: Sorafenib has been demonstrated as second-line therapy, with limited significant adverse events at a dose of 400 mg twice a day (b.i.d.) in patients with metastatic renal cell carcinoma. This study evaluated the ability of patients to dose-escalate, response rate, progression-free survival (PFS), and overall survival. METHODS: The initial dose of sorafenib was 400 mg b.i.d.. Dose escalation of sorafenib to 600 mg b.i.d. occurred from days 29-56 and increased to 800 mg b.i.d. on day 57 and beyond as tolerated. Dose modifications were performed for toxicity per the National Cancer Institute Common Toxicity Criteria version 3.0. The patients were evaluated every 2 cycles (8 weeks) by using Response Evaluation Criteria in Solid Tumors version 1.0. RESULTS: Forty-four patients were evaluable for response. Median age was 62.5 years, 39 patients had a Karnofsky Perfomance Status of 100%. Twenty-two patients received no prior therapy. Of the evaluable patients, 42 were dose escalated to 600 mg b.i.d., and 74% (31) of these were further dose escalated to 800 mg b.i.d.. Eight patients had a complete response (CR), 13 patients demonstrated a partial response (PR), and 21 patients had stable disease. Common treatment-related adverse events included hypertension, hand-foot syndrome, skin rash, diarrhea, dry skin, alopecia, and facial redness. DISCUSSION: The majority of patients were escalated to 600 mg b.i.d. or 800 mg b.i.d.. Intrapatient dose-escalated sorafenib has promising antitumor activity as demonstrated by a 48% CR-PR rate (21 patients). Antitumor activity is further suggested by a prolonged PFS ≥6 months in 64% (28) of patients. Significant antitumor activity and reversible adverse events has been demonstrated in escalated doses of sorafenib.

Clinicopathologic and immunohistochemical characteristics of adult primary cardiac angiosarcomas: analysis of 10 cases.

Primary cardiac angiosarcoma is a rare but the most common malignant neoplasm of the heart in adults. The objective of this study is to analyze the clinicopathologic characteristics of primary cardiac angiosarcoma. Ten cases of primary cardiac angiosarcoma treated in a single institution were analyzed for their clinical, pathologic, and immunohistochemical features. There were 6 men and 4 women, with a mean age of 40 years (range, 20-61 years). The patients commonly presented with dyspnea and distant metastasis. All tumors were located in the right atrium, with a mean tumor size of 6.8 cm. Tumors were hemorrhagic, with variegated tan-brown solid areas. Histologically, they exhibited high-grade morphology with mixed solid growth and anatomizing channels. Frequent mitoses and tumor necrosis were common. The tumors were strongly positive for CD31, CD34, FLI-1, and WT-1 but negative for AE1/3, D2-40, human herpesvirus 8, and epidermal growth factor receptor. The tumor cells were focally reactive to p53, with a high rate of Ki-67 expression. A complete tumor resection was not possible in any of the patients because of the size or extensive local invasion of the tumor. Overall survival ranged from 1 to 81 months (mean, 26.6 months) after initial histologic diagnosis. Primary cardiac angiosarcomas are rare tumors that commonly arise in the right atrium. The mean age is much younger than that of soft tissue angiosarcoma. Regional tumor extension and distant metastasis are extremely common at the time of diagnosis. Surgical resection with adjuvant chemotherapy is currently the preferred treatment, and survival time appears to be inversely correlated with the tumor size and degree of regional tumor extension at the time of surgery.

Adenocarcinoma in ectopic prostatic tissue at dome of bladder: a case report of a patient with urothelial carcinoma of the bladder and adenocarcinoma of the prostate.

We report a case of ectopic prostate tissue with an associated prostatic adenocarcinoma occurring in the dome of the urinary bladder. A 62-year-old man presented with a 4-month history of persistent microscopic hematuria following a urinary tract infection. Other complaints included frequent urination, but there was neither dysuria nor gross hematuria. Digital rectal examination revealed a smooth prostate of normal size. Cystoscopic examination revealed a sessile lesion of the anterior bladder neck and multiple smaller papillary lesions throughout the bladder. Following a transurethral resection of the bladder tumor with a diagnosis of muscle-invasive transitional cell carcinoma grade 3, a radical cystoprostatectomy was performed. The diagnosis of transitional cell carcinoma was confirmed, but in addition, a different lesion was also incidentally found in the dome of the bladder. This incidental lesion showed a prostatic adenocarcinoma arising from ectopic prostatic tissue within the bladder submucosa. The prostate also showed prostatic adenocarcinoma, but this was minimal, low grade, and confined to the prostate gland, and thus it was felt to be unlikely to have metastasized to the bladder dome. Adenocarcinoma arising in ectopic prostatic tissue is a rare finding and to our knowledge only 1 case has been previously described, occurring in the soft tissue adjacent to the prostate. We report the first case of adenocarcinoma arising in ectopic prostatic tissue within the bladder.

Useful immunohistochemical markers in differentiating hemangioblastoma versus metastatic renal cell carcinoma.

Hemangioblastomas (HBs) account for nearly a tenth of all posterior fossa neoplasms and can be the presenting finding in patients with von Hippel-Lindau (VHL) syndrome. HB must be differentiated from renal cell carcinoma (RCC), also seen in VHL, as the distinction between these lesions dictates the management of these patients. Currently inhibin A and RCC marker have been used in the diagnosis of HB and metastatic RCC, both with inconsistent results. Additional immunohistochemical markers including CD10, PAX-2, D2-40, and FLi-1 have been shown to have potential for the distinction of these two entities. Fifteen cerebellar HBs and 17 metastatic clear cell RCCs to the brain were selected for the study. All cases were immunostained with RCC marker, inhibin, CD10, PAX-2, D2-40, and Fli-1. The staining patterns were scored based on intensity and extent of tumor staining. In the differentiation of HB and metastatic RCC, D2-40 and RCC marker proved to be poor markers with less than 50% of HBs and RCCs, respectively, showing positive staining. PAX-2 and CD10 were superior to RCC marker in the diagnosis of metastatic RCC, with PAX-2 having better specificity. Fli-1 failed to stain tumor cells in both HBs and RCC. Inhibin A, in combination with PAX-2, showed to be the most useful markers to differentiate HB from metastatic RCC.

PAX-2 in the diagnosis of primary renal tumors: immunohistochemical comparison with renal cell carcinoma marker antigen and kidney-specific cadherin.

The diagnosis of renal cell carcinoma (RCC) remains problematic, especially in the context of metastasis or small needle biopsy specimens. The renal cell carcinoma marker (RCCM) and kidney-specific cadherin (KSC) are considered specific markers for RCC but are expressed preferentially in specific subtypes of RCC of lower grades. This study was aimed at evaluating the usefulness of PAX-2 in the diagnosis of renal tumors and comparing it with that of RCCM and KSC. Immunostaining for PAX-2, RCCM, and KSC was performed on consecutive tissue sections of 130 renal tumors. PAX-2 was successfully detected in routine tissue specimens. Although PAX-2 seems to be more sensitive than RCCM and KSC, there is significant staining overlap in relation to histologic subtypes, justifying the use of all 3 markers, which helps detect the vast majority of renal neoplasms. PAX-2 seems to have a significant role in renal neogenesis and may represent a novel therapeutic target.

Metastatic prostatic carcinoma to testis: histological features mimicking lymphoma.

We report a case of prostatic carcinoma with testicular metastasis, which mimicked malignant lymphoma of the testis. The patient was a 71 year-old man with a history of prostate adenocarcinoma of Gleason score 9 (4+5) diagnosed in 2001 for which he received hormonal therapy. Four years later, the patient developed multiple osteoblastic bone metastases. Radiotherapy of the bone metastases was given with subsequently bilateral orchiectomy for hormonal deprivation therapy in May 2005. Grossly, one of the testes had a subcapsular rubbery 0.9 cm nodule. Microscopically, the nodule was composed of malignant discohesive cells predominantly infiltrating in the interstitium with an appearance of malignant lymphoma. However, immunohistochemical stains were positive for prostate-specific antigen and prostate acid phosphatase and negative for leukocyte common antigen, which confirmed the diagnosis of metastatic prostate adenocarcinoma.

Cytologic malignancy versus benignancy: how useful are the "newer" markers in body fluid cytology?

CONTEXT: Differentiating reactive effusion, malignant mesothelioma, and metastatic adenocarcinoma in body cavity fluids can be challenging. Interpreting immunohistochemical markers in cell block preparations can be difficult because of nonspecific staining, focal staining, or poor staining quality. We selected a panel of conventional and newer markers to assess their utility in evaluating effusions. OBJECTIVE: To evaluate the efficacy of 5 immunohistochemical markers in the differential diagnosis of reactive mesothelial proliferation, malignant mesothelioma, and metastatic adenocarcinoma in body cavity fluids. DESIGN: A total of 72 formalin-fixed, paraffin-embedded cell block specimens from pleural and peritoneal effusions, including 5 mesotheliomas, 48 adenocarcinomas, and 19 benign effusions were stained with antibodies against calretinin, D2-40, XIAP, MOC-31, and WT1. RESULTS: All benign effusions and mesotheliomas demonstrated diffuse membranous staining with D2-40. All mesotheliomas displayed calretinin positivity, whereas only 58% of benign effusions stained focally with calretinin. MOC-31 was positive in all cases of adenocarcinoma, whereas all benign effusions and mesotheliomas were negative. All cases of the metastatic adenocarcinoma were negative for calretinin and D2-40. However, background reactive mesothelial cells were positive for calretinin and D2-40. Overall, D2-40 highlighted more mesothelial cells than calretinin. WT1 was positive in 50% of benign effusions, 60% of mesotheliomas, and 27% of adenocarcinomas. XIAP stained most mesotheliomas (80%), some adenocarcinomas (51%), and rare benign effusions (11%). CONCLUSIONS: MOC-31 and D2-40 were very sensitive and specific markers of epithelial and mesothelial cells, respectively. Compared with calretinin, D2-40 was a more sensitive marker of mesothelial cells. WT1 proved to be nonspecific. XIAP was not a sensitive marker for malignancy and had a limited value in cytology. We recommend using a panel to include MOC-31 and D2-40 to improve diagnostic accuracy in body cavity effusions.

Lymphoid cell proliferation in renal transplants: biologic and diagnostic implications.

It is unclear whether alloreaction develops in peripheral lymphoid organs and effector cells being recruited to the target organs, or the entire process of alloreaction can happen within the transplanted kidneys. Interstitial inflammatory cell (IIC) proliferation was evaluated by MIB-1 antigen immunostain and the rate expressed as positive cells/1000 cells. This rate was higher in acute cell-mediated rejection (ACR) (25.7, n = 14) compared with normal kidney (0.4, n = 8), acute tubular necrosis (1.2, n = 8), chronic allograft nephropathy (CAN, 2.4, n = 20), and native kidneys with diverse diseases (9.2, n = 63); but was comparable to that in CAN with significant IIC (20.6, n = 16). 10.1% and 8.3% of T lymphocytes underwent proliferation in ACR with or without CAN, whereas only rare B lymphocytes or macrophages showed this change (<1.2%), regardless of diagnostic categories. All biopsies diagnosed as ACR in conjunction with a high rate of MIB-1 + IIC and 9/12 biopsies with CAN and significant IIC in which ACR was diagnosed due to a high rate of MIB-1 + IIC, responded to anti-rejection therapy. Proliferation of IIC involves predominantly T lymphocytes. These observations provide support for the concept of in situ alloimmunization, and facilitate the diagnosis of ACR.