Comparison of biochemical recurrence-free survival between periprostatic and pelvic lymph node metastases of prostate cancer.

OBJECTIVE: To assess the pathologic characteristics and prognostic significance of periprostatic lymph node (LN) metastasis of prostate cancer. The latter was performed by comparing biochemical recurrence (BCR)-free survival in cases of periprostatic LN metastasis versus matched patients showing pelvic LN metastasis. METHODS AND MATERIALS: We identified 15 patients who underwent radical prostatectomy in our institution (1984-2011) showing positive periprostatic and negative pelvic LN with available follow-up information (group 1). These patients were matched 1:2 to patients with positive pelvic LN (group 2) for pertinent clinicopathologic parameters. RESULTS: Main locations of positive periprostatic LN were posterior base and mid posterolateral. Overall higher rate of positive margins, smaller LN, and metastasis size were encountered in group 1 compared with group 2. At 5 years postprostatectomy, 69% of patients in group 1 were free of BCR, whereas 26% of those in group 2 remained BCR free, suggesting that patients with periprostatic node metastasis appeared to have a lower risk of BCR. However, the difference was not statistically significant (P = .072). The same was true when adjusted for the effect of prostate-specific antigen, surgical margin status, size of LNs, size of metastasis, age, and year of surgery. CONCLUSION: Patients with periprostatic node metastasis may have a lower risk of BCR compared with those with metastasis to pelvic LN. Future analysis of larger cohorts will help establish the biologic significance of prostate cancer metastasis to periprostatic LN.

Diffuse expression of PAX2 and PAX8 in the cystic epithelium of mixed epithelial stromal tumor, angiomyolipoma with epithelial cysts, and primary renal synovial sarcoma: evidence supporting renal tubular differentiation.

Over the past decade, 3 novel, typically cystic renal neoplasms have been described: angiomyolipoma with epithelial cysts (AMLEC), mixed epithelial stromal tumor (MEST), and primary renal synovial sarcoma (SS). In all 3 neoplasms, the nature of the cystic epithelium is not clear; some have postulated that the cysts represent cystically dilated, entrapped renal tubular epithelium, whereas an alternative interpretation is that the epithelium represents epithelial differentiation by the stromal component of the neoplasm. The latter is supported by the extrarenal location of the epithelium in some cases. PAX2 and PAX8 are tissue-specific transcription factors expressed primarily in the renal and Müllerian systems and also in Wolffian duct structures (such as seminal vesicle). Their expression has not been examined in these lesions. We performed PAX2 and PAX8 immunohistochemistry on representative sections of cases of AMLEC (8 cases), MEST (8 cases), and renal SS (3 cases). The relative percentage and intensity (none, weak, moderate, and strong) of nuclear labeling were evaluated in both the benign adjacent renal tubules and the lesion's epithelial cysts. In the benign kidney, distal convoluted tubules (DCTs) labeled strongly for PAX2 and PAX8, whereas proximal convoluted tubules labeled minimally. The cystic epithelium of all 8 cases of AMLEC, including 5 that protruded beyond the renal capsule into the perirenal fat, demonstrated strong diffuse labeling for both PAX2 and PAX8. We also identified a mimic of entirely extrarenal AMLEC, angiomyolipoma with endosalpingiosis. PAX2 and PAX8 diffusely and strongly labeled the epithelial component of all 8 cases of MEST, including all architectural (phyllodes-like, large cysts, small cysts, clustered microcysts) and virtually all cytologic (hobnail, flat, cuboidal, columnar, apocrine, and clear cell) epithelial variants present. The epithelial cysts of all 3 cases of primary renal SS labeled diffusely and strongly for PAX2 and PAX8. Cyst epithelial labeling intensity was similar to that of renal DCT in all cases. The diffuse labeling for PAX2/PAX8 in the epithelial cysts of AMLEC, taken together with their consistent negativity for estrogen receptor and HMB45, supports the hypothesis that this epithelium represents entrapped, cystically dilated renal tubules that commonly herniate beyond the renal capsule. The diffuse labeling of the cyst epithelium of renal SS supports the previously proposed hypothesis that this cyst epithelium represents entrapped dilated renal tubules in a monophasic spindle cell lesion and not neoplastic epithelial differentiation. The diffuse labeling for PAX2/PAX8 in MEST epithelium, coupled with its usual estrogen receptor negativity, is consistent with the hypothesis that the epithelium of MEST demonstrates renal tubular differentiation and undergoes architectural and cytologic changes as it grows along with the stromal component. Whether this complex epithelium represents entrapped or neoplastic renal tubular epithelium remains an open question.

Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions.

Cathepsin K is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. TFE3 and TFEB are members of the same transcription factor subfamily as MITF and all three have overlapping transcriptional targets. We have shown that all t(6;11) renal cell carcinomas, which harbor an Alpha-TFEB gene fusion, as well as a subset of the Xp11 translocation renal carcinomas, which harbor various TFE3 gene fusions, express cathepsin K, while no other common renal carcinoma does. We have hypothesized that overexpression of TFEB or certain TFE3 fusion proteins function like MITF in these neoplasms, and thus activate cathepsin K expression. However, the expression of cathepsin K in specific genetic subtypes of Xp11 translocation carcinomas, as well as alveolar soft part sarcoma, which harbors the same ASPSCR1-TFE3 gene fusion as some Xp11 translocation carcinomas, has not been addressed. We performed immunohistochemistry for cathepsin K on 14 genetically confirmed t(X;1)(p11;q21) carcinomas, harboring the PRCC-TFE3 gene fusion; eight genetically confirmed t(X;17)(p11;q25) carcinomas, harboring the ASPSCR1-TFE3 gene fusion; and 18 alveolar soft part sarcomas (12 genetically confirmed), harboring the identical ASPSCR1-TFE3 gene fusion. All 18 alveolar soft part sarcomas expressed cathepsin K. In contrast, all eight ASPSCR1-TFE3 carcinomas were completely negative for cathepsin K. However, 12 of 14 PRCC-TFE3 carcinomas expressed cathepsin K. Expression of cathepsin K distinguishes alveolar soft part sarcoma from the ASPSCR1-TFE3 carcinoma, harboring the same gene fusion. The latter can be useful diagnostically, especially when alveolar soft part sarcoma presents in an unusual site (such as bone) or with clear cell morphology, which raises the differential diagnosis of metastatic ASPSCR1-TFE3 renal cell carcinoma. The difference in expression of cathepsin K between the PRCC-TFE3 and ASPSCR1-TFE3 carcinomas, together with the observed clinical differences between these subtypes of Xp11 translocation carcinomas, suggests the possibility of functional differences between these two related fusion proteins.

Hepatocyte nuclear factor-1ß expression in clear cell adenocarcinomas of the bladder and urethra: diagnostic utility and implications for histogenesis.

The histogenesis of clear cell adenocarcinoma of the bladder/urethra is uncertain. Hepatocyte nuclear factor-1ß is a homeodomain protein that has been reported to be frequently overexpressed in ovarian clear cell adenocarcinoma in comparison with rare or no expression in other types of epithelial ovarian tumors. We assessed the expression of hepatocyte nuclear factor-1ß in a series of 18 clear cell adenocarcinomas of the bladder and urethra and compared it with that of invasive high-grade transitional/urothelial carcinoma (n = 35); adenocarcinomas of the bladder, urethra, and paraurethral glands (n = 21); as well as nephrogenic adenomas of the bladder (n = 8). Staining intensity and extent were evaluated using a 4-tiered grading system (0-3). A case was considered positive for hepatocyte nuclear factor-1ß if 10% or more of tumor cells showed at least weak nuclear staining or if any moderate or strong nuclear staining was observed. All 18 clear cell adenocarcinomas exhibited nuclear staining in at least 50% of tumor cells (16 strong, 1 moderate, and 1 weak with focal strong nuclear staining) in comparison with positive nuclear staining (moderate) in 1 of 21 bladder adenocarcinoma, 1 of 35 invasive high-grade transitional/urothelial carcinoma (weak to moderate staining), and 2 of 8 nephrogenic adenomas (1 weak and 1 moderate to strong staining). We concluded that hepatocyte nuclear factor-1ß is a useful marker in differentiating clear cell adenocarcinomas of the bladder/urethra from invasive high-grade transitional/urothelial carcinoma and other types of bladder adenocarcinomas and to a lesser extent from nephrogenic adenomas. Hepatocyte nuclear factor-1ß is of no diagnostic utility in discriminating primary bladder/urethral clear cell adenocarcinomas from metastatic clear cell adenocarcinomas of the female genital tract to the bladder/urethra. From a histogenesis standpoint, although the expression of hepatocyte nuclear factor-1ß in both gynecologic and urologic tract clear cell adenocarcinomas may point to a Müllerian derivation/differentiation, this immunohistochemical evidence is insufficient to completely exclude an urothelial association.

Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors.

Alterations in methylation of CpG dinucleotides at the 5 position of deoxycytidine residues (5(m)C) are a hallmark of cancer cells, including testicular germ cell tumors. Virtually all testicular germ cell tumors are believed to be derived from intratubular germ cell neoplasia unclassified (IGCNU), which is thought to arise from primordial germ cells. Prior studies revealed that seminomas contain reduced levels of global DNA methylation as compared with nonseminomatous germ cell tumors. Smiraglia et al have proposed a model whereby seminomas arise from IGCNU cells derived from primordial germ cells that have undergone 5(m)C erasure, and nonseminomas arise from IGCNU cells derived from primordial germ cells that have already undergone de novo methylation after the original erasure of methylation and contain normal 5(m)C levels. Yet the methylation status of IGCNU has not been determined previously. We used immunohistochemical staining against 5(m)C to evaluate global methylation in IGCNU and associated invasive testicular germ cell tumors. Strikingly, staining for 5(m)C was undetectable (or markedly reduced) in the majority of IGCNU and seminomas, yet there was robust staining in nonseminomatous germ cell tumors. The lack of staining for 5(m)C in IGCNU and seminomas was also found in mixed germ cell tumors containing both seminomatous and nonseminomatous components. Lack of 5(m)C staining was not related to a lack of the maintenance methyltransferase (DNA methyltransferase 1) protein. We conclude that testicular germ cell tumors are derived in most cases from IGCNU cells that have undergone developmentally programmed 5(m)C erasure and that the degree of subsequent de novo methylation is most closely related to the differentiation state of the neoplastic cells. That is, IGCNU cells and seminoma cells remain unmethylated, whereas all other histological types appear to arise after de novo methylation.

Predictors for nonsentinel node involvement in breast cancer patients with micrometastases in the sentinel lymph node.

Sentinel lymph node (SLN) biopsy in breast cancer allows for a more thorough pathologic assessment with serial sectioning and cytokeratin staining. This has resulted in increased detection of micrometastatic disease (tumor size < 2 mm) in the SLN. Unfortunately, the value of completion axillary dissection after finding micrometastatic disease in the SLN remains poorly defined. Over a 2-year period, a prospective database of 305 patients who underwent SLN biopsy for breast cancer at Baylor University Medical Center was reviewed. Eighty-four (27.5%) of the patients had evidence of metastatic disease in the SLN. Twenty-four of the 41 patients identified as having micrometastatic disease in the SLN underwent completion axillary lymph node dissection. In these patients, all nonsentinel nodes were further studied by serial sectioning and immunohistochemistry. The median age of these 24 patients was 52 years (range, 34-83). Their primary tumor stages were T1a and T1b (n = 5), T1c (n = 15), and T2 (n = 4). A total of 328 nonsentinel lymph nodes were examined, including 225 from patients with infiltrating ductal carcinoma (n = 17) and 103 from patients with infiltrating lobular carcinoma (n = 7). In the patients with infiltrating ductal carcinoma, no additional nodal metastases were identified, while in those with infiltrating lobular carcinoma, additional nodal disease was found in 5 lymph nodes (2 of 12 patients, 17%). Primary tumor characteristics were not predictive of additional nodal disease. These data suggest that patients with micro-metastasis in the SLN from infiltrating lobular carcinoma have a significant risk of harboring additional nodal disease and should undergo completion axillary dissection. However, those with micrometastatic disease from infiltrating ductal carcinoma have a very low incidence of additional metastasis and may not need completion axillary dissection.