Sahussapont Joseph Sirintrapun

Coordinate Loss of MAP3K7 and CHD1 Promotes Aggressive Prostate Cancer

Prostate cancer subtypes are poorly defined and functional validation of drivers of ETS rearrangement-negative prostate cancer has not been conducted. Here, we identified an ETS(-) subtype of aggressive prostate cancer (ERG(-)MAP3K7(del)CHD1(del)) and used a novel developmental model and a cell line xenograft model to show that cosuppression of MAP3K7 and CHD1 expression promotes aggressive disease. Analyses of publicly available prostate cancer datasets revealed that MAP3K7 and CHD1 were significantly codeleted in 10% to 20% of localized tumors and combined loss correlated with poor disease-free survival. To evaluate the functional impact of dual MAP3K7-CHD1 loss, we suppressed Map3k7 and/or Chd1 expression in mouse prostate epithelial progenitor/stem cells (PrP/SC) and performed tissue recombination experiments in vivo. Dual shMap3k7-shChd1 PrP/SC recombinants displayed massive glandular atypia with regions of prostatic intraepithelial neoplasia and carcinoma apparent. Combined Map3k7-Chd1 suppression greatly disrupted normal prostatic lineage differentiation; dual recombinants displayed significant androgen receptor loss, increased neuroendocrine differentiation, and increased neural differentiation. Clinical samples with dual MAP3K7-CHD1 loss also displayed neuroendocrine and neural characteristics. In addition, dual Map3k7-Chd1 suppression promoted E-cadherin loss and mucin production in recombinants. MAP3K7 and CHD1 protein loss also correlated with Gleason grade and E-cadherin loss in clinical samples. To further validate the phenotype observed in the PrP/SC model, we suppressed MAP3K7 and/or CHD1 expression in LNCaP prostate cancer cells. Dual shMAP3K7-shCHD1 LNCaP xenografts displayed increased tumor growth and decreased survival compared with shControl, shMAP3K7, and shCHD1 xenografts. Collectively, these data identify coordinate loss of MAP3K7 and CHD1 as a unique driver of aggressive prostate cancer development.

Urachal carcinomas of the nonglandular type: salient features and considerations in pathologic diagnosis.

The vast majority of malignant urachal epithelial tumors have a glandular morphology (ie, adenocarcinoma), to which our principal understanding of urachal carcinoma and its prevailing set of diagnostic criteria are largely ascribed. The 2004 World Health Organization classification of genitourinary tumors recognizes other rarer histologic types of urachal carcinomas such as urothelial, squamous cell, and other carcinomas. However, the clinicopathologic data for these nonglandular groups of urachal carcinomas are very limited, being detailed only in sporadic case reports. Some of the criteria recommended for pathologic confirmation of urachal carcinomas were formulated almost exclusively for urachal adenocarcinoma and may not be relevant or applicable for nonglandular tumors. Here, we present 7 examples of pure (5) and mixed predominant (2) nonglandular urachal carcinomas. Patients were 45 to 85 years of age (mean, 64.1) with a male predominance (male-to-female ratio=6:1). Six tumors were related to the bladder [dome (3) or dome/supravesical (3)] and 1 was entirely supravesical. Histologically, 5 were urothelial carcinomas, of pure or mixed histology, all were high grade and invasive, and 2 were small cell carcinomas. Two urothelial carcinomas had focal (<5%) glandular differentiation and signet ring cell change, and 1 had admixed focal malignant squamous cells and high-grade dedifferentiated components. Four of 5 urachal urothelial carcinomas exhibited solid and partly cavitary or luminal growth with papillary structures and a variable amount of necrosis within the cavity. The 2 small cell carcinomas were pure, had classic undifferentiated neuroendocrine histology, were situated at the bladder dome, and were partly cavitary filled with necrotic debris. Urachal remnant was identified in 6 tumors mainly with dysplastic transitional cells in the urachal canal or rudimentary nests and tubules. All 6 bladder-related urachal tumors exhibited reverse invasive front from the surface, including 2 tumors that ulcerated the bladder mucosa. One tumor had concomitant in situ and noninvasive high-grade papillary urothelial carcinomas in the main bladder lumen. Sheldon stages at presentation were IIIA (2), IVA (3), and IVB (2). Follow-up in all 7 cases (<1 to 60 mo; median, 12.5 mo) showed that 6 patients had died of disease, including the 2 patients with small cell carcinoma. In conclusion, nonglandular urachal carcinoma may occur with pure histology or admixed with high-grade dedifferentiated morphologies and a minor adenocarcinoma component. These tumors may arise as deep-seated bladder-related or completely supravesical tumors along the urachal tract and may exhibit reverse invasive spread toward the bladder surface. Cavitary or luminal growth may occur that could be attributed to the intraurachal neoplastic proliferation. Urachal urothelial carcinomas in particular may contain papillary structures within the tumor and urachal cavity. Concomitant primary urothelial carcinoma outside of the urachus and tumor extension to bladder mucosa may occur, which should not negate diagnosis of an urachal primary. Behavior appears poor, as most tumors present with higher stage.

Benefits of a combined approach to sampling of renal neoplasms as demonstrated in a series of 351 cases.

Percutaneous radiofrequency ablation is increasingly used for curative treatment of primary cancers of the kidney. We reviewed our experience of percutaneous sampling performed under computed tomographic guidance with fine needle aspiration biopsy (FNAB) and core biopsy (CB), and we report on the complementary roles of these 2 techniques in a series of 351 consecutive patients undergoing radiofrequency ablation for renal neoplasms. Both FNAB and CB were obtained in 290 cases, of which 156 patients (54%) were positive for neoplasm in both specimens, and 27 (9%) were negative for tumor in both specimens. In 58 (20%) patients, the FNABs were positive, but the CBs were negative, and the reverse occurred in 11 patients (4%). When suspicious interpretations by FNAB and CB are included as positives in the calculations, both their complementary nature and the relative higher diagnostic yield of FNAB persisted. In 25 cases with FNABs positive for neoplasm, the CB allowed a more specific tumor classification. The 19 cases of FNAB which were read as negative/benign had corresponding CBs that were also negative/benign in 13 cases; yet, 6 were diagnostic of renal cell carcinoma not otherwise specified (1 case), renal cell carcinoma clear cell/conventional (4 cases), and non-Hodgkin lymphoma (1 case). These and additional findings illustrate the complementary value of the combination of the 2 biopsy methods for a reliable pretherapy morphologic confirmation of specific renal neoplasms. FNAB has relatively greater sensitivity and utility for onsite evaluation, whereas CB provides an additional sample for more specific subclassification and additional studies.

A Histomorphologic Grading System That Predicts Overall Survival in Diffuse Malignant Peritoneal Mesothelioma With Epithelioid Subtype.

Diffuse malignant peritoneal mesothelioma (MPeM) is rare and arises from peritoneal serosal surfaces. Although it shares similar histomorphology with its counterpart, malignant pleural mesothelioma, etiologies, clinical courses, and therapies differ. Nuclear grading and level of mitoses have been correlated with prognosis in malignant pleural mesothelioma with epithelioid subtype. Whether nuclear grading and level of mitoses correlate with prognosis in MPeM is still unknown. Our study utilizes a 2 tier system incorporating nuclear features and level of the mitoses to stratify cases of MPeM with epithelioid subtype. Fifty-one cases of MPeM with clinical follow-up underwent retrospective microscopic review. From that subset, 46 cases were of epithelioid subtype, which were then stratified into a low-grade or high-grade tier. Survival times were calculated on the basis of Kaplan-Meier analysis. The low-grade tier had higher overall survival with a median of 11.9 years and 57% at 5 years when compared with the high-grade tier with a median of 3.3 years and 21% at 5 years (P=0.002). Although not statistically significant, the low-grade tier had higher progression-free survival with a median of 4.7 years and 65% at 5 years when compared with the high-grade tier with a median of 1.9 years and 35% at 5 years (P=0.089). Our study is first to specifically evaluate and correlate nuclear features and level of mitoses with overall survival in MPeM with epithelioid subtype.

The different morphologies of urachal adenocarcinoma do not discriminate genomically by micro-RNA expression profiling

Urachal adenocarcinoma has several morphologic presentations that include mucinous, enteric, signet ring cell, and not otherwise specified. Mixtures of these morphologies can occur, and percentage cut-offs are used for classification. The clinical significance of these morphologic types is currently unknown, and genetic analysis that could elucidate possible intertumoral differences has not been performed. In this study, we analyzed the micro-RNA expression profiles of 12 urachal adenocarcinomas classified using strict morphologic criteria (3 pure enteric, 3 pure mucinous, 2 signet ring cell [both 90% signet ring cell], 2 pure not otherwise specified, and 2 mixed cell types). Of 598 unique human micro-RNAs, 333 were expressed in more than 50% of the samples. Hierarchal clustering showed no distinct patterns in the genetic profiles of the morphologic types. However, there were individual micro-RNA differences when the different types were compared individually or grouped together, either by intracellular mucin production or by grouping enteric and signet ring cell together. In the later group, 13 messenger RNA species were differentially expressed (adjusted P value of ≤.05). However, these micro-RNA differences were small, suggesting more biologic similarity than differences among these entities. Thus, this study suggests that the different morphological subtypes may represent patterns of differentiation or a continuum of a single biological tumor type rather than several distinct types that arose from the urachal remnant epithelium. This finding, if further validated in larger studies, may have implications in future clinical therapeutic trials for urachal adenocarcinoma with regard to patient grouping and choice of therapy.

Successful secure high-definition streaming telecytology for remote cytologic evaluation

Background: The use of minimally invasive procedures to obtain material for diagnostic purposes has become more prevalent in recent years. As such, there is increased demand for immediate cytologic adequacy assessment of minimally invasive procedures. The array of different locations in which rapid on-site evaluation (ROSE) is expected requires an ever-increasing number of cytology personnel to provide support for adequacy assessment. In our study, we describe the implementation process of a telecytology (TC) system in a high case volume setting and evaluate the performance of this activity. Methods: We performed retrospectively an analysis of all consecutive remote TC ROSE evaluations obtained for 15 months. The specimens were evaluated using a TC system. The ROSE adequacy assessment obtained at the time of the procedure was compared to the final cytopathologist-rendered adequacy assessment when all the material was available for review, including the alcohol-fixed preparations. Results: A total of 8106 distinct cases were analyzed. TC-assisted preliminary adequacy assessment was highly concordant with the final cytopathologist-rendered adequacy assessment. Perfect concordance or accuracy was at 93.1% (7547/8106). The adequacy upgrade rate (inadequate specimen became adequate) was 6.8% (551/8106), and the initial adequacy downgrade (adequate specimen became inadequate) was <0.1% (8/8106). Conclusions: The TC outcome demonstrates high concordance between the initial adequacy assessment and final cytopathologist-rendered adequacy assessment. Adequacy upgrades were minor but, more importantly, our results demonstrate a minimal adequacy downgrade. The process implemented effectively eliminated the need for an attending pathologist to be physically present onsite during a biopsy procedure.

Oncocytoma-Like Renal Tumor With Transformation Toward High-Grade Oncocytic Carcinoma A Unique Case With Morphologic, Immunohistochemical, and Genomic Characterization

AbstractRenal oncocytoma is a benign tumor with characteristic histologic findings. We describe an oncocytoma-like renal tumor with progression to high-grade oncocytic carcinoma and metastasis.A 74-year-old man with no family history of cancer presented with hematuria. Computed tomography showed an 11 cm heterogeneous multilobulated mass in the right kidney lower pole, enlarged aortocaval lymph nodes, and multiple lung nodules. In the nephrectomy specimen, approximately one third of the renal tumor histologically showed regions classic for benign oncocytoma transitioning to regions of high-grade carcinoma without sharp demarcation.With extensive genomic investigation using single nucleotide polymorphism-based array virtual karyotyping, multiregion sequencing, and expression array analysis, we were able to show a common lineage between the benign oncocytoma and high-grade oncocytic carcinoma regions in the tumor. We were also able to show karyotypic differences underlying this progression. The benign oncocytoma showed no chromosomal aberrations, whereas the high-grade oncocytic carcinoma showed loss of the 17p region housing FLCN (folliculin [Birt–Hogg–Dubé protein]), loss of 8p, and gain of 8q. Gene expression patterns supported dysregulation and activation of phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (Akt), mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK), and mechanistic target of rapamycin (serine/threonine kinase) (mTOR) pathways in the high-grade oncocytic carcinoma regions. This was partly attributable to FLCN underexpression but further accentuated by overexpression of numerous genes on 8q. In the high-grade oncocytic carcinoma region, vascular endothelial growth factor A along with metalloproteinases matrix metallopeptidase 9 and matrix metallopeptidase 12 were overexpressed, facilitating angiogenesis and invasiveness.Genetic molecular testing provided evidence for the development of an aggressive oncocytic carcinoma from an oncocytoma, leading to aggressive targeted treatment but eventual death 39 months after the diagnosis.

Robotic telecytology for remote cytologic evaluation without an on-site cytotechnologist or cytopathologist: A tale of implementation and review of constraints

Background: The first satellite center to offer interventional radiology procedures at Memorial Sloan Kettering Cancer Center opened in October 2014. Two of the procedures offered, fine needle aspirations and core biopsies, required rapid on-site cytologic evaluation of smears and biopsy touch imprints for cellular content and adequacy. The volume and frequency of such evaluations did not justify hiring on-site cytotechnologists, and therefore, a dynamic robotic telecytology (TC) solution was created. In this technical article, we present a detailed description of our implementation of robotic TC. Methods: Pathology devised the remote robotic TC solution after acknowledging that it would not be cost effective to staff cytotechnologists on-site at the satellite location. Sakura VisionTek was selected as our robotic TC solution. In addition to configuration of the dynamic robotic TC solution, pathology realized integrating the technology solution into operations would require a multidisciplinary effort and reevaluation of existing staffing and workflows. Results: Extensively described are the architectural framework and multidisciplinary process re-design, created to navigate the constraints of our technical, cultural, and organizational environment. Also reviewed are the benefits and challenges associated with available desktop sharing solutions, particularly accounting for information security concerns. Conclusions: Dynamic robotic TC is effective for immediate evaluations performed without on-site cytotechnology staff. Our goal is providing an extensive perspective of the implementation process, particularly technical, cultural, and operational constraints. Through this perspective, our template can serve as an extensible blueprint for other centers interested in implementing robotic TC without on-site cytotechnologists.

Robotic telecytology for remote cytologic evaluation without an on-site cytotechnologist or cytopathologist: an active quality assessment and experience of over 400 cases

Background: The first satellite center to offer interventional radiology procedures at Memorial Sloan Kettering Cancer Center opened in October 2014. Two of the procedures offered, fine needle aspirations and core biopsies, required a rapid on-site cytologic evaluation of smears and biopsy touch imprints for cellular content and adequacy. The volume and frequency of such evaluations did not justify hiring on-site cytotechnologists, and therefore, a dynamic robotic telecytology (TC) solution was created. In this article, we provide data on our experience with this active implementation. Sakura VisionTek was selected as our robotic TC solution. Methods: A retrospective analysis of all TC evaluations from this satellite site was performed. Information was collected on demographics, lesion location, imaging modality; a comparison of TC-assisted adequacy with final adequacy was also conducted. Results: An analysis of 439 cases was performed over a period of 23 months with perfect correlation in 92.7% (407/439) of the cases. An adequacy upgrade (inadequate specimen becomes adequate) in 6.6% (29/439) of the cases. An adequacy downgrade (adequate specimen becomes inadequate), is near zero at 0.7% (3/439) of the cases. Conclusions: Dynamic robotic TC is effective for immediate evaluations performed without on-site cytotechnology staff. The overall intent of this article is to present data and concordance rates as outcome metrics. Thus far, such outcome metrics have exceeded our expectations. Our TC implementation shows high, perfect concordance. Adequacy upgrades are minor but more relevant and impressive is a near zero adequacy downgrade. Our full implementation has been so successful that plans are in place for configurations at future satellite sites.

Hemophagocytic tumor cells in carcinosarcoma bone marrow metastasis.

A 72-year-old woman with a diagnosis of uterine carcinosarcoma (malignant mixed Müllerian tumor) 1 month prior was transferred to our institution for evaluation of thrombocytopenia (16,000 platelets per microliter). She was also anemic and had a markedly elevated lactate dehydrogenase (2,108 U/l). Examination of the peripheral blood revealed circulating nucleated red blood cells and occasional immature myeloid cells (leukoerythroblastosis). A bone marrow biopsy was performed to evaluate her thrombocytopenia. The marrow space was nearly replaced by malignant epithelioid tumor cells with focal spindling (Image 1). By immunohistochemistry, the tumor cells did not express antigens associated with acute leukemia (CD117, CD34, CD45), melanoma (S-100 protein), carcinoma (cytokeratin AE1/ AE3, cytokeratin 7, epithelial membrane antigen), or histocytes (CD68). The tumor had strong positive staining for p53. Comparison with the prior uterus resection showed a tumor of similar morphology with more spindling (sarcomatous differentiation) and the same immunohistochemical profile, thus confirming the tumor in bone as a carcinosarcoma metastasis. Evaluation of the aspirate smears revealed large atypical cells with irregular nuclei, prominent nucleoli, and agranular cytoplasm with some vacuolization (Image 2). Several of the tumor cells had prominent hemophagocytosis, evidenced by the presence of red blood cells, erythroid precursors, and myeloid cells in the cytoplasm. Nuclear fragments and degenerating myeloid cells were seen in the tumor cell cytoplasm, thus favoring phagocytosis over emperipolesis. Hemophagocytosis is associated with neoplastic (e.g., leukemia, lymphoma, histocytic tumors) and non-neoplastic conditions (e.g., infection), but in the majority of the cases it is non-neoplastic macrophages that are ingesting the patient’s cells. Phagocytosis of blood elements by solid tumor cells is very rare and has been previously described in a few case reports [1–5]. The underlying mechanism by which the tumor cells obtain phagocytic characteristics is unknown.