High fidelity of driver chromosomal alterations among primary and metastatic renal cell carcinomas: implications for tumor clonal evolution and treatment.

Recent studies have demonstrated considerable genomic heterogeneity in both primary and metastatic renal cell carcinoma (RCC). This mutational diversity has serious implications for the development and implementation of targeted molecular therapies. We evaluated 39 cases of primary RCC tumors with their matched metastatic tumors to determine if the hallmark chromosomal anomalies of these tumors are preserved over the course of disease progression. Thirty-nine matched pairs of primary and metastatic RCCs (20 clear cell RCC, 16 papillary RCC, and 3 chromophobe RCC) were analyzed. All clear cell RCC and papillary RCC tumors were evaluated for chromosome 3p deletion, trisomy 7 and 17 using fluorescence in situ hybridization. Chromophobe RCC tumors were evaluated for genetic alterations in chromosomes 1, 2, 6, 10, and 17. Of the 20 clear cell RCC tumors, 18 primary tumors (90%) showed a deletion of chromosome 3p and were disomic for chromosomes 7 and 17. All molecular aberrations were conserved within the matched metastatic tumor. Of the 16 papillary RCC tumors, 10 primary tumors (62%) showed trisomy for both chromosomes 7 and 17 without 3p deletion. These molecular aberrations and others were conserved in the paired metastatic tumors. Of the three chromophobe RCC tumors, multiple genetic anomalies were identified in chromosomes 1, 2, 6, 10, and 17. These chromosomal aberrations were conserved in the matched metastatic tumors. Our results demonstrated genomic fidelity among the primary and metastatic lesions in RCCs. These findings may have important clinical and diagnostic implications.

Tubulocystic renal cell carcinoma is an entity that is immunohistochemically and genetically distinct from papillary renal cell carcinoma.

AIMS: Some studies have suggested that tubulocystic carcinoma may be related to papillary renal cell carcinoma. We sought to compare and contrast the molecular and immunohistochemical profiles of tubulocystic carcinoma with those of papillary renal cell carcinoma. METHODS AND RESULTS: Twelve cases of pure tubulocystic renal cell carcinoma were subjected to fluorescence in-situ hybridization assessment of chromosomal number for chromosomes 7 and 17, and for TFE3 translocation. Immunohistochemical labelling for AMACR, p63, cytokeratin 7, PAX8, cytokeratin 20 and carbonic anhydrase IX was assessed in all tumours. No tumour showed gains of chromosomes 7 or 17, or TFE3 translocation by fluorescence in-situ hybridization. Immunohistochemistry revealed all tumours to be non-reactive with antibodies against p63 and cytokeratin 20. Conversely, the antibody against AMACR gave a positive reaction in the neoplastic cells of all tumours. Four tumours showed focal labelling with antibody against carbonic anhydrase IX, and five tumours showed focally positive reactions with antibody against cytokeratin 7. Recurrence and metastatic disease were not found for the patients with available follow-up information. CONCLUSIONS: Pure tubulocystic renal cell carcinoma is an indolent tumour with a good prognosis. Our data support the distinction of this neoplasm as a separate entity.

Prevalence of endosalpingiosis and other benign gynecologic lesions.

Endosalpingiosis, traditionally regarded as an incidental pathological finding, was recently reported to have an association with gynecologic malignancies. To determine the prevalence of endosalpingiosis, we evaluated all benign appearing adnexal lesions using the Sectioning and Extensively Examining-Fimbria (SEE-Fim) protocol, and queried the pathology database for the presence of endosalpingiosis, gynecologic malignancy, endometriosis, Walthard nests, and paratubal cysts. Using the SEE-Fim protocol, the prevalence of endosalpingiosis, endometriosis, Walthard nests, and paratubal cysts were 22%, 45%, 33%, and 42% respectively, substantially higher than previously reported. All lesions were observed to increase with age except endometriosis which increased until menopause then decreased dramatically. Among specimens including ovarian tissue, the prevalence of implantation of at least one lesion type was ubiquitous in patients age 51 and older (93%). The clinical significance of endosalpingiosis should be a continued area of research with larger trials assessing prevalence, factors affecting incidence, and association with malignancy. Our findings contribute to elucidating the origin of ectopic lesions and gynecologic disease risk.

Polyglandular autoimmunity with macrophagic myofasciitis.

We report a man with chronic fatigue, multiple autoimmune disorders, and a muscle biopsy consistent with macrophagic myofasciitis. This rare and recently described muscle disorder is seen in patients exposed to vaccinations with aluminum hydroxide adjuvant. This case highlights the relationship between macrophagic myofasciitis and autoimmunity.

Thyroid-Like Follicular Carcinoma of the Kidney.

Thyroid-like follicular carcinoma of the kidney (TLFCK) is a rare but emerging renal neoplasm that morphologically mimics follicular carcinoma of the thyroid but lacks immunohistochemical expression of thyroid markers such as TTF-1 and thyroglobulin. Here, a case of an incidentally discovered TLFCK in a 27-year-old man is reported. Histologic evaluation demonstrated an encapsulated proliferation of variably sized thyroid follicle-like epithelial-lined spaces filled with colloid-like eosinophilic secretions. Immunohistochemical analysis confirmed lack of expression of the thyroid markers TTF-1 and thyroglobulin with expression of PAX8 and CD10, confirming a neoplasm of renal origin, which correlated to the clinical and radiographic absence of thyroid pathology. In this report, this case is described with an emphasis on the differential diagnosis.

Solitary fibrous tumour of the genitourinary tract: a clinicopathological study of 11 cases and their association with the NAB2-STAT6 fusion gene.

AIMS: To characterise clinicopathological features and clinical outcomes of the genitourinary tract solitary fibrous tumours, incorporating NAB2-STAT6 gene fusion status. METHODS: The presence of the molecular hallmark NAB2-STAT6 gene fusion and for the defining fusion partner product STAT6 was assessed in 11 cases of the genitourinary tract solitary fibrous tumours. NAB2-STAT6 gene fusion analysis was performed using a break-apart fluorescence in situ hybridisation (FISH) probe using a probe cocktail with Bacterial artificial chromosome (BAC) clones for STAT6 and NAB2. RESULTS: Eleven solitary fibrous tumours were diagnosed in eight male patients and three female patients with a mean age of 46 years (range: 11-64 years). Four of the tumours had malignant histological features, and three were considered moderate risk for metastasis. With a mean follow-up time of 61 months, 1 recurred locally and 2 presented at distant metastatic sites. Using a break-apart FISH probe cocktail, we found the NAB2-STAT6 gene fusion and nuclear STAT6 expression in 58% and 91% of cases, respectively. However, the NAB2-STAT6 fusion status was not correlated with STAT6 expression or useful in discriminating between malignant histological features or subsequent clinical outcomes in the genitourinary solitary fibrous tumours. CONCLUSIONS: A subset of solitary fibrous tumours of the genitourinary tract behaved aggressively. Using a break-apart FISH probe cocktail, we found the NAB2-STAT6 gene fusion in 64% of cases. However, the NAB2-STAT6 fusion status was not correlated with STAT6 expression or useful in discriminating between low-risk or high-risk tumours and subsequent clinical outcomes.

Correcting the Shrinkage Effects of Formalin Fixation and Tissue Processing for Renal Tumors: toward Standardization of Pathological Reporting of Tumor Size.

Given the importance of correctly staging renal cell carcinomas, specific guidelines should be in place for tumor size measurement. While a standard means of renal tumor measurement has not been established, intuitively, tumor size should be based on fresh measurements. We sought to assess the accuracy of postfixation and microscopic measurements of renal tumor size, as compared to fresh measurements and radiographic size. Thirty-four nephrectomy cases performed by a single surgeon were prospectively measured at different time points. The study cases included 23 clear cell renal cell carcinomas, 6 papillary renal cell carcinomas, and 5 other renal tumors. Radiologic tumors were 12.1% larger in diameter than fresh tumors (P<0.01). Furthermore, fresh specimens were 4.6% larger than formalin-fixed specimens (P<0.01), and postfixation measurements were 7.1% greater than microscopic measurements (P<0.01). The overall mean percentage of shrinkage between fresh and histological specimens was 11.4% (P<0.01). Histological processing would cause a tumor stage shift from pT1b to pT1a for two tumors in this study. The shrinkage effects of formalin fixation and histological processing may result in understaging of renal cell carcinomas. The shrinkage factor should be considered when reporting tumor size.

Basal cell carcinoma of the prostate is an aggressive tumor with frequent loss of PTEN expression and overexpression of EGFR.

Basal cell carcinoma (also referred to as adenoid cystic carcinoma) is a rare tumor of the prostate. Although largely characterized as indolent, poor outcomes have been reported in a considerable fraction of cases. As yet, optimum treatment strategies for this cancer have not been developed. This study investigates protein expression of common or potential molecular therapeutic targets and reports on the clinicopathological features of 9 new cases. We evaluated the expression of ERBB2, KIT, androgen receptor, PTEN, EGFR, ERG, and p53 via immunohistochemistry. We also examined EGFR amplification and TMPRSS2-ERG gene rearrangement by fluorescence in situ hybridization. The mean clinical follow-up was 44 months. We found that basal cell carcinoma behaved aggressively with almost one-half of the cases displaying high-risk pathologic features or local recurrence (44%). One patient died as a result of metastatic disease. The most consistent abnormalities included a loss of PTEN expression (56% of cases) and EGFR overexpression (67% of cases). EGFR overexpression occurred in the absence of gene amplification. The TMPRSS2-ERG rearrangement was not detected in any of the tumors studied, nor was ERG protein positivity identified by immunostaining. In addition, ERBB2, KIT, p53, and androgen receptor expressions were either absent or showed only weak, limited reactivity. Our results suggest that there is a high morbidity associated with this tumor, and more intense follow-up and additional treatment may be indicated. Furthermore, targeted therapies directed against the EGFR and PTEN proteins or their constitutive pathways may be promising for future clinical management.

Progressive bevacizumab-associated renal thrombotic microangiopathy.

Vascular endothelial growth factor (VEGF) is integral to the integrity of the glomerular filtration barrier. Bevacizumab is a humanized monoclonal antibody directed against VEGF with expanding clinical applications for metastatic solid tumours. We describe a case of a 61-year-old female with ovarian cancer and baseline chronic kidney disease who received three doses of bevacizumab and subsequently developed progressive renal clearance dysfunction and nephrotic range proteinuria. A renal biopsy was performed 4 months after drug discontinuation and was consistent with TMA. At baseline, prior to bevacizumab exposure, her estimated glomerular filtration rate (eGFR) was 44 mL/min/1.73 m(2) and she had no proteinuria. At the completion of therapy, eGFR was 27 mL/min/1.73 m(2) with 1+ proteinuria on urinalysis. Her renal failure and proteinuria continued to progress 5 months after discontinuation of bevacizumab therapy, at which time eGFR was 11 mL/min/1.73 m(2) and proteinuria was 5.5 g/24 h. Non-remitting TMA after bevacizumab therapy in patients with pre-existing chronic kidney disease has not been previously reported. Further studies are needed to assess the safety of this drug in patients with chronic kidney disease.