Preservation of truncal genomic alterations in clear cell and papillary renal cell carcinomas with sarcomatoid features: An intra- and intertumoral, multifocal fluorescence in situ hybridization analysis reveals limited genetic heterogeneity.

Understanding tumor genomic heterogeneity may offer vital information in an age of targeted therapy for renal cell carcinoma. We sought to investigate hallmark truncal chromosomal alterations between conventional, sarcomatoid, and matched metastatic tumor foci in clear cell and papillary renal cell carcinomas. A retrospective review identified 58 cases including clear cell (CCRCC) and papillary renal cell carcinomas (PRCC). All cases contained sarcomatoid transformation. Additionally, 10 of 58 patients had matched metastatic disease available for analysis. Three separate foci of conventional and sarcomatoid morphologies were analyzed in each tumor using dual color interphase fluorescence in situ hybridization. In the CCRCC cohort, hallmark chromosome 3p deletion was identified in 71% of cases (37/52). Complete concordance of chromosomal status between intratumoral foci in sarcomatoid and conventional foci was 89% and 86%, respectively. Overall chromosome 3p status between matched conventional and sarcomatoid morphologies was identified in 98% of cases (51/52). Hallmark 3p deletion was present in 91% of CCRCC metastatic samples (10/11) and was concordant with the matched primary CCRCC tumor in 91% (10/11). In the PRCC cohort, trisomy 7 and 17 was identified in all six cases (6/6). Complete concordance between intratumoral foci of trisomy 7 and 17 was 83% (5/6). Trisomy 7 and 17 were identified in all metastatic PRCC samples with 100% concordance with the matched primary tumor. These data show the relative preservation of truncal chromosomal abnormalities between conventional and sarcomatoid morphologic as well as matched metastatic settings.

Acquired cystic disease associated renal cell carcinoma: A clinicopathologic and molecular study of 31 tumors.

Acquired cystic disease associated renal cell carcinomas (ACD-RCC) are rare and their molecular and histopathological characteristics are still being explored. We therefore investigated the clinicopathologic and molecular characteristics of 31 tumors. The patients were predominantly male (n = 30), with tumors mainly left-sided (n = 17), unifocal (n = 19), and unilateral (n = 29) and a mean tumor size of 25 mm (range, 3-65 mm). Microscopically, several histologic patterns were present, including pure classic sieve-like (n = 4), and varied proportions of mixed classic sieve-like with papillary (n = 23), tubulocystic (n = 9), compact tubular (n = 4) and solid (n = 1) patterns. Calcium-oxalate crystals were seen in all tumors. Molecular analysis of 9 tumors using next generation sequencing showed alterations in SMARCB1 in 3 tumors (1 with frameshift deletion and 2 with copy number loss in chromosome 22 involving SMARCB1 region), however, INI1 stain was retained in all. Nonrecurrent genetic alterations in SETD2, NF1, NOTCH4, BRCA2 and CANT1 genes were also seen. Additionally, MTOR p.Pro351Ser was identified in one tumor. Copy number analysis showed gains in chromosome 16 (n = 5), 17 (n = 2) and 8 (n = 2) as well as loss in chromosome 22 (n = 2). In summary, ACD-RCC is a recognized subtype of kidney tumors, with several histological architectural patterns. Our molecular data identifies genetic alterations in chromatin modifying genes (SMARCB1 and SETD2), which may suggest a role of such genes in ACD-RCC development.

Evidence-Based Alignment of Pathology Residency With Practice II: Findings and Implications.

This article presents findings from a 4-year series of surveys of new-in-practice pathologists, and a survey of physician employers of new pathologists, assessing how pathology graduate medical education prepares its graduates for practice. Using the methodology described in our previous study, we develop evidence for the importance of residency training for various practice areas, comparing findings over different practice settings, sizes, and lengths of time in practice. The principal findings are (1) while new-in-practice pathologists and their employers report residency generally prepared them well for practice, some areas-billing and coding, laboratory management, molecular pathology, and pathology informatics-consistently were identified as being important in practice but inadequately prepared for in residency; (2) other areas-autopsy pathology, and subspecialized apheresis and blood donor center blood banking services-consistently were identified as relatively unimportant in practice and excessively prepared for in residency; (3) the notion of a single comprehensive model for categorical training in residency is challenged by the disparity between broad general practice in some settings and narrower subspecialty practice in others; and (4) the need for preparation in some areas evolves during practice, raising questions about the appropriate mode and circumstance for training in these areas. The implications of these findings range from rebalancing the emphasis among practice areas in residency, to reconsidering the structure of graduate medical education in pathology to meet present and evolving future practice needs.

Diagnostic approach in TFE3-rearranged renal cell carcinoma: a multi-institutional international survey.

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.

The Significance of Spermatic Cord Involvement by Testicular Germ Cell Tumors: Should We Be Staging Discontinuous Invasion From Involved Lymphovascular Spaces Differently From Direct Extension?

The recent 8th edition of the American Joint Committee on Cancer (AJCC) staging manual had multiple changes concerning how pathologists should stage germ cell tumors (GCTs) of the testis. A significant one concerns the impact of different types of spermatic cord involvement, specifically direct tumor extension versus discontinuous involvement by invasion through lymphovascular spaces. We compared clinicopathologic findings and outcome data between 2 cohorts with these findings to evaluate the validity of the change in the AJCC 8th edition manual. GCTs (seminomatous and nonseminomatous) of the testis were identified that had previously been staged as pT3 due to involvement of the spermatic cord. Pathologic, radiographic, and clinical findings were reviewed. Tumors were restaged based on AJCC 8th edition criteria and the cohorts were split into direct extension by tumor into the spermatic cord (pT3), spermatic cord soft tissue invasion via spread from discontinuously involved lymphovascular spaces (pT2pM1), or a combination of both (pT3pM1). One hundred cases of primary GCTs of the testis, previously classified as pT3 by the AJCC 6th or 7th cancer staging manuals from 2007 to 2015, were selected. Mixed malignant GCTs were the predominant tumor type, comprising 66% of all cases. Pure tumor morphologies included embryonal carcinoma (n=17), seminoma (n=14), teratoma (n=2), and yolk sac tumor (n=1). The tumors either directly invaded into the spermatic cord (n=78), involved the cord discontinuously via spread from lymphovascular spaces (n=18), or had both findings (n=4). Overall, 93% of patients presented at advanced clinical stage (CS). Using the AJCC 8th parameters, 12% of all tumors were upstaged. Changes included CSI (n=1) and CSII (n=11) tumors being reclassified as prognostic stage group III. Clinical and/or pathologic recurrence was identified in 19% of all patients, including 12 pT3 and 7 pM1 patients (P=0.11). Overall mean time to recurrence was 24.6 months, with a mean of 28.0 months for pT3 tumors and 18.9 months for pM1 tumors. Five patients were dead at the time of this study, including 3 (4%) with pT3 tumors and 2 (9%) in the pM1 cohort. Our findings support that seminomatous and nonseminomatous GCTs with spermatic cord invasion have a high frequency of advanced CS at presentation, regardless of involvement by direct extension or discontinuous spread via invasion from lymphovascular spaces. By designating the latter as M1, a spurious upstaging to prognostic stage group III is required by the AJCC 8th edition. We were unable to identify statistically significant difference between the 2 groups as it pertained to CS at presentation and likelihood of recurrence. Conversely, statistical trends favor that pM1 patients have more likely recurrence and worse prognosis than pT3 patients.

Evidence-Based Alignment of Pathology Residency With Practice: Methodology and General Consideration of Results.

Few medical specialties engage in ongoing, organized data collection to assess how graduate medical education in their disciplines align with practice. Pathology educators, the American Board of Pathology, and major pathology organizations undertook an evidence-based, empirical assessment of what all pathologists need to learn in categorical residency. Two challenges were known when we commenced and we encountered 2 others during the project; all were ultimately satisfactorily addressed. Initial challenges were (1) ensuring broad representation of the new-in-practice pathologist experience and (2) adjusting for the effect on this experience of subspecialty fellowship(s) occurring between residency and practice. Additional challenges were (3) needing to assess and quantify degree and extent of subspecialization in different practice settings and (4) measuring changing practice responsibilities with increasing time in practice. We instituted annual surveys of pathologists who are relatively new (<10 years) in practice and a survey of physician employers of new pathologists. The purpose of these surveys was to inform (1) the American Board of Pathology certification process, which needs to assess the most critical knowledge, judgment, and skills required by newly practicing pathologists, and (2) pathology graduate medical education training requirements, which need to be both efficient and effective in graduating competent practitioners. This article presents a survey methodology to evaluate alignment of graduate medical education training with the skills needed for new-in-practice physicians, illustrates an easily interpreted graphical format for assessing survey data, and provides high-level results showing consistency of findings between similar populations of respondents, and between new-in-practice physicians and physician-employers.

Complexity of the genomic landscape of renal cell carcinoma: Implications for targeted therapy and precision immuno-oncology.

The topic of tumoral heterogeneity at the genetic level has become relevant in various solid origin tumors, particularly in an age of targeted treatment. Renal cell carcinoma is known for a sizable subset of tumors presenting at advanced clinical stage, further highlighting the importance and timeliness of this topic and its potential impact on adjuvant therapy. Recent studies have shown that molecular aberrations in renal cell carcinoma go beyond known truncal mutations and that downstream, subclonal aberrations are spatially heterogenous. Intratumoral heterogeneity as well as the differences in the molecular landscape between primary and metastatic lesions remains underappreciated, often due to inadequate sampling of tumors. The overall effect of these factors on the efficacy of current treatment options in renal cell carcinoma remains unknown; however, several recent studies have attempted to elucidate the extent and impact genetic heterogeneity in renal cell neoplasia may have on patient treatment and prognosis.

Müllerian Adenosarcoma of the Urinary Bladder: Clinicopathologic and Immunohistochemical Features With Novel Genetic Aberrations.

BACKGROUND: Müllerian adenosarcoma is a biphasic neoplasm most commonly occurring in the uterus and less frequently of the ovary. It has been rarely described to occur in other sites such as peritoneum and liver. PATIENTS AND METHODS: In this study, we report the clinicopathologic, immunohistochemical and molecular features of a primary Müllerian adenosarcoma of the urinary bladder in a 62-year-old woman. To our knowledge, this is the first report of detailed pathologic characterization of Müllerian adenosarcoma primary to the urinary bladder in the literature. RESULTS: Light microscopy showed a biphasic epithelial and stromal tumor with benign-appearing glands surrounded by densely cellular endometrial-type stroma that is densely cellular with increased mitotic figures. The stroma surrounding the glands was more cellular than the intervening areas, which were more loose and edematous. Immunohistochemistry staining revealed positive staining for Pax-2/8 within the glands, for positive CD10 and WT-1 within the spindle cell stroma, and for estrogen and progesterone receptors in both. Staining for desmin, GATA3, p63, and human papillomavirus was negative. Molecular analyses identified mutations in protein kinase B E17K, fms related tyrosine kinase 3 D835N, KRAS proto-oncogene, GTPase G12D, and HRAS proto-oncogene, GTPase G12S. These novel molecular aberrations have yet to be reported in the medical literature. X chromosome inactivation analysis revealed a clonal pattern in the stromal component and a nonclonal pattern in the epithelial component. Currently, the patient is disease/recurrence-free after regular follow-up of approximately 84 months. CONCLUSION: This case represents, to our knowledge, the first reported diagnosis of Müllerian adenosarcoma arising in the urinary bladder with extensive clinicopathologic, immunohistochemical, and molecular analyses.

Do Nonseminomatous Germ Cell Tumors of the Testis With Lymphovascular Invasion of the Spermatic Cord Merit Staging as pT3?

The staging of testicular nonseminomatous germ cell tumors (NSGCTs) with lymphovascular invasion (LVI) of the spermatic cord in the absence of cord parenchymal involvement remains controversial. Our previous study showed that tumors with spermatic cord LVI present at a higher clinical stage than tumors with LVI confined to the testis (pT2). We compared NSGCTs with LVI of the spermatic cord without direct involvement of the spermatic cord soft tissues to pT3 tumors to help clarify the appropriate staging of this histologic finding. A retrospective, multi-institutional review was performed to identify cases of NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord. The clinical-pathologic findings were compared with NSGCTs with spermatic cord soft tissue invasion (pT3). We identified 38 pT2 NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord and 89 pT3 tumors. There were no significant differences in patient age, tumor size, or clinical stage at presentation between the 2 groups. There were no significant differences in dominant histologic subtype, rete testis invasion, hilar soft tissue invasion, or margin status. There were no significant differences in disease recurrence/progression (P=0.63), recurrence/progression after chemotherapy (P=0.35), or death (P=0.51) between patients with only spermatic cord LVI versus patients with cord soft tissue invasion. In patients with pT2 NSGCTs according to the current staging, LVI in the spermatic cord without cord soft tissue invasion is comparable with pT3 tumors in terms of clinical stage at presentation as well as disease recurrence and survival.

Sarcomatoid Urothelial Carcinoma of the Bladder: Analysis of 28 Cases With Emphasis on Clinicopathologic Features and Markers of Epithelial-to-Mesenchymal Transition.

CONTEXT: -Sarcomatoid urothelial carcinoma (UCa) is a rare but aggressive variant of bladder cancer that can show diagnostic challenges even using ancillary techniques. OBJECTIVE: -To examine immunohistochemical markers in the context of sarcomatoid UCa, including those associated with epithelial-to-mesenchymal transition. DESIGN: -Twenty-eight cases of sarcomatoid UCa were rereviewed. Clinical outcomes were obtained through database search. Immunohistochemistry for clinical and epithelial-to-mesenchymal transition markers was performed. RESULTS: -All patients had biopsy-proven invasive UCa; 61% (17 of 28) had sarcomatoid UCa at initial diagnosis. A recognizable epithelial component(s) was present in 17 lesions. The sarcomatoid component accounted for 65% of the lesion (average), with heterologous elements present in 3 of 28 cases (11%). The morphologic spectrum of the sarcomatoid element included spindled not otherwise specified, myxoid, pseudoangiosarcomatous, and malignant fibrous histiocytoma-like undifferentiated features. The sarcomatoid component was immunoreactive for pancytokeratin (22 of 26; 85%), p63 (20 of 26; 77%), cytokeratin 903 (17 of 26; 65%), cytokeratin 7 (16 of 26; 62%), GATA3 (16 of 26; 62%), and cytokeratin 5/6 (16 of 26; 62%). STAT-6, CD31, CD34, and HMB45 were all nonreactive, whereas smooth muscle actin often showed at least focal immunoreactivity (22 of 26; 85%). Epithelial-to-mesenchymal transition markers were frequently expressed, including vimentin (26 of 26; 100%), FoxC2 (26 of 26; 100%), SNAIL (23 of 26; 88.5%), and ZEB1 (18 of 26; 69.2%). Follow-up was available for 24 patients (median, 7 months). Sixteen of 28 patients (57%) died of disease (overall mean survival, 9.1 months). The presence of myxoid or chordoid features was associated with reduced survival (P < .05). CONCLUSIONS: -Sarcomatoid UCa is an aggressive form of UCa that frequently expresses epithelial-to-mesenchymal transition markers, suggesting a possible mechanism associated with aggressive tumor behavior.

Long-term Survival From Muscleinvasive Bladder Cancer With Initial Presentation of Symptomatic Cerebellar Lesion: The Role of Selective Surgical Extirpation of the Primary and Metastatic Lesion.

A 59-year-old man was diagnosed with urothelial carcinoma involving an isolated cerebellar metastasis after presenting to the emergency department for headache complaints. After selective surgical excision of the symptomatic brain lesion and delayed cystectomy due to intractable hematuria, he survived 11 years without evidence of recurrence or subsequent systemic chemotherapy. He eventually expired after delayed recurrence in the lung, supraclavicular lymph node, and brain. To our knowledge, this is the only case of prolonged survival from urothelial carcinoma after selective surgical extirpation of the primary and metastatic lesion without subsequent systemic chemotherapy.

Diagnostically challenging cases: what are atypia and dysplasia?

This article addresses the spectrum of atypia and dysplasia within the bladder epithelium and the diagnostic categories developed to further classify challenging lesions. In addition, the effects of inflammation, specific therapies, and instrumentation on the bladder mucosa as well as the associated difficulty in achieving the appropriate diagnosis are also discussed.