The chromosomal numerical aberration pattern in mucinous tubular and spindle renal cell carcinoma (MTSRCC) is referred to as variable with frequent gains and losses. The objectives of this study are to map the spectrum of chromosomal aberrations (extent and location) in a large cohort of the cases and relate these findings to the morphologic variants of MTSRCC. Fifty-four MTSRCCs with uniform morphologic pattern were selected (of 133 MTSRCCs available in our registry) and divided into 3 groups: classic low-grade MTSRCC (Fuhrman nucleolar International Society of Urological Pathology grade 2), high-grade MTSRCC (grade 3), and overlapping MTSRCC with papillary renal cell carcinoma (RCC) morphology. Array comparative genomic hybridization analysis was applied to 16 cases in which DNA was well preserved. Four analyzable classic low-grade MTSRCCs showed multiple losses affecting chromosomes 1, 4, 8, 9, 14, 15, and 22. No chromosomal gains were found. Four analyzable cases of MTSRCC showing overlapping morphology with PRCC displayed a more variable pattern including normal chromosomal status; losses of chromosomes 1, 6, 8, 9, 14, 15, and 22; and gains of 3, 7, 16, and 17. The group of 4 high-grade MTSRCCs exhibited a more uniform chromosomal aberration pattern with losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22 and without any gains detected. (1) MTSRCC, both low-grade and high-grade, shows chromosomal losses (including 1, 4, 6, 8, 9, 13, 14, 15, and 22) in all analyzable cases; this seems to be the most frequent chromosomal numerical aberration in this type of RCC. (2) Cases with overlapping morphologic features (MTSRCC and PRCC) showed a more variable pattern with multiple losses and gains, including gains of chromosomes 7 and 17 (2 cases). This result is in line with previously published morphologic and immunohistochemical studies that describe the broad morphologic spectrum of MTSRCC, with changes resembling papillary RCC. (3) The diagnosis of MTSRCC in tumors with overlapping morphology (MTSRCC and PRCC) showing gains of both chromosomes 7 and 17 remains questionable. Based on our findings, we recommend that such tumors should not be classified as MTSRCC but rather as PRCC.

The histiocytoses are rare tumors characterized by the primary accumulation and tissue infiltration of histiocytes and dendritic cells. Identification of the activating BRAFV600E mutation in Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) cases provided the basis for the treatment with BRAF and/or MEK inhibitors, but additional treatment options are needed. Twenty-four cases of neoplastic histiocytic diseases [11 extrapulmonary LCH, 4 ECD, 4 extranodal Rosai-Dorfman disease (RDD), 3 follicular dendritic cell sarcoma (FDCS), 1 histiocytic sarcoma (HS) and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN)] were analyzed using immunohistochemical and mutational analysis in search of biomarkers for targeted therapy. BRAF V600E mutations were detected in 4/11 LCH and 4/4 ECD cases. A pathogenic PTEN gene mutation and loss of PTEN protein expression were identified in the case of HS. Increased expression of PD-L1 (≥2+/≥5%) was seen in 3/4 ECD, 7/8 LCH, 3/3 FDCS and 1/1 HS, with overall 81% concordance between 2 antibodies used in the study (SP142 vs. MAB1561 clone). These results show for the first time significant expression of the PD-L1 immune checkpoint protein in these disorders, which may provide rationale for addition of immune check-point inhibitors in treatment of disseminated and/or refractory histiocytoses.

Secondary angiosarcoma of the breast is a rare, but well-described complication of radiation therapy for primary breast carcinoma. Currently, it appears refractory to most systemic chemotherapy though rare responses to taxanes exist (1,2). Overall, patient prognosis is poor (3). A 78-year-old female underwent left breast conservation and axillary node dissection in 1999 for invasive ductal carcinoma followed by whole breast radiation therapy. Eleven years later, she noted multiple small nodules in the medial aspect of the left breast. Biopsy of the nodules revealed angiosarcoma of the breast. A metastatic follow-up showed no evidence of distant disease and a modified radical mastectomy performed. Histopathology confirmed the presence of angiosarcoma with all margins negative. The patient completed a course of postmastectomy irradiation with dose limitation by previous radiation for her original breast conserving procedure. This was administered concurrently with adjuvant chemotherapy (Taxol and Adriamycin). The patient did not tolerate the chemotherapy but finished the course of radiation therapy. Ten months later, angiosarcoma nodules recurred along the mastectomy scar. Chemotherapy with single agent carboplatinum was ineffective. Six months later, she underwent a wide resection of the skin and soft tissue of the left chest wall with multiple cutaneous nodules and positive deep margin (the pectoral muscle/ribs) was noted. In the interim, she underwent a split thickness skin graft to cover the large defect. Within 6 months, recurrent disease appeared in the graft and surrounding soft tissue. With no documented distant metastases, the patient again underwent a resection of recurrent tumors, chest wall and two ribs requiring TRAM flap coverage. A Caris profile was requested. She remained free of local recurrence for only 4 months, when multiple and rapidly growing subcutaneous nodules became evident about the chest wall and flap (Fig. 1A). The Caris gene expression assay performed earlier demonstrated a potential therapeutic benefit of sunitinib due to the upregulation of VEGFR2. Sunitinib was then

BACKGROUND Infiltrating UC represents the second most common genitourinary malignancy. Advanced UC has a poor prognosis and new treatments are needed. Molecular profiling of UC might identify biomarkers associated with targeted therapies or chemotherapeutics, providing physicians with new treatment options. MATERIALS AND METHODS Five hundred thirty-seven cases of locally advanced or metastatic UC of the bladder, 74 nonbladder, and 55 nonurothelial bladder cancers were profiled using mutation analysis, in situ hybridization, and immunohistochemistry assays for biomarkers predictive of therapy response. RESULTS Molecular profiling of UC showed high overexpression of topoisomerase 2α, common phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha and/or phosophatase and tensin homolog (PTEN) alterations in nonbladder (27%) and bladder UC (21%), and rare gene mutations across subtypes. Compared with nonbladder, bladder UC consistently exhibited more frequent abnormal protein expression, including HER2 (10% vs. 3%; P = .04), tyrosine protein c-Kit receptor kinases (11% vs. 5%), c-Met proto-oncogene, receptor tyrosine kinases (25% vs. 8%), androgen receptor (16% vs. 6%), O(6)-methylguanine-methyltransferase (63% vs. 43%), ribonucleotide reductase M1 (32% vs. 11%), Serum protein acidic and rich in cysteine (SPARC) (69% vs. 33%), and topoisomerase 1 (63% vs. 39%). Bladder UC also exhibited increased amplification of HER2 (12% vs. 2%; P = .06). CONCLUSION Comprehensive molecular profiling of UC identified a large number of biomarkers aberrations that might direct treatment in conventional chemotherapies and targeted therapies, not currently recommended in this population. As a group, bladder UC exhibited higher levels of actionable biomarkers, suggesting that UC from different primary sites and non-UC are driven by different molecular pathways. These differences could have clinical implications resulting in different treatment regimens depending on the site of origin of UC.

Epigenetic mechanisms play a crucial role in cellular proliferation, migration and differentiation in both normal and neoplastic development. One of the key signaling pathways whose components are altered through the epigenetic mechanisms is the Wnt signaling pathway. In this review, we briefly discuss the key concepts of epigenetics and focus on the recent advances in the Wnt signaling pathway research and its potential diagnostic and therapeutic implications.

Background Cancer of unknown primary (CUP) accounts for approximately 3% of all malignancies. Despite extensive laboratory and imaging efforts, the primary site usually cannot be unequivocally confirmed, and the treatment for the most part remains empirical. Recently, identification of common cancer pathway alterations in diverse cancer lineages has offered an opportunity to provide targeted therapies for patients with CUP, irrespective of the primary site. Patients and Methods 1806 cancers of unknown primary were identified among more than 63,000 cases profiled at Caris Life Sciences. Multiplatform profiling of the tumor samples included immunohistochemistry, gene sequencing and in situ hybridization methods in an effort to identify changes in biomarkers that are predictive of drug responses. Results Biomarkers associated with a potential drug benefit were identified in 96% of cases. Biomarkers identified included those associated with potential benefit in nearly all classes of approved cancer drugs (cytotoxic, hormonal, targeted biological drugs). Additionally, biomarkers associated with a potential lack of benefit were identified in numerous cases, which could further refine the management of patients with CUP. Conclusion Comprehensive biomarker profiling of CUP may provide additional choices in treatment of patients with these difficult to treat malignancies.

We report two new cases of cystic fibroepithelioma of Pinkus together with immunohistochemical features and analyze the presence of cystic changes in a series of 16 classical fibroepitheliomas of Pinkus. Our findings show that the formation of cystic spaces is most probably caused by ischemic degeneration of stromal fenestrations, rather than by central tumor cell necrosis. This finding is supported by lack of CD34 positive blood vessels in edematous and hyalinized stromal fenestrations undergoing transformation into cystic spaces, as opposed to the uninvolved stromal fenestrations. Therefore, it is probably more accurate to refer to this process as pseudocystic stromal degeneration rather than true cyst formation. Also, two out of 16 classical Pinkus fibroepitheliomas exhibited focal pseudocystic changes in 50% and 10% of the tumor, respectively, demonstrating that this degenerative process can be found, rarely and focally, in classical cases as well.