High-Grade, Nonsarcomatoid Chromophobe Renal Cell Carcinoma: A Series of 22 Cases With Novel Molecular Features on a Subset.

Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of renal cell carcinoma and typically exhibits indolent behavior, though a rare subset can exhibit high-grade morphologic features and is associated with a poor prognosis. Although there are limited data on the molecular characteristics of metastatic and sarcomatoid ChRCC, the molecular features of high-grade, nonsarcomatoid ChRCC remain unexplored. Herein, we characterize 22 cases of ChRCC with high-grade, nonsarcomatoid components. High-grade ChRCC frequently demonstrated advanced stage at diagnosis (64% ≥pT3a or N1), with regions of extrarenal extension, nodal metastases, and vascular invasion consisting solely of high-grade ChRCC morphologically. We performed spatially guided panel-based DNA sequencing on 11 cases comparing high-grade and low-grade regions (n = 22 samples). We identified recurring somatic alterations emblematic of ChRCC, including deletions of chromosomes 1, 2, 6, 10, 13, 17, and 21 in 91% (10/11) of cases and recurring mutations in TP53 (81.8%, n = 9/11) and PTEN (36.4%, n = 4/11). Notably, although PTEN and TP53 alterations were found in both high-grade and low-grade regions, private mutations were identified in 3 cases, indicating convergent evolution. Finally, we identified recurring RB1 mutations in 27% (n = 3) of high-grade regions leading to selective protein loss by immunohistochemistry not observed in adjacent low-grade regions. This finding was confirmed in The Cancer Genome Atlas cohort where 2 of 66 cases contained RB1 mutations and demonstrated unequivocal high-grade, nonsarcomatoid morphology. We also detected multiple chromosomal gains confined to the high-grade regions, consistent with imbalanced chromosome duplication. These findings broaden our understanding of the molecular pathogenesis of ChRCC and suggest that subclonal RB1 mutations can drive the evolution to high-grade, nonsarcomatoid ChRCC.

Undifferentiated round cell sarcoma with CRTC1::SS18 fusion: Expanding clinicopathologic features of a rare translocation sarcoma with prominent desmoplastic stroma.

Undifferentiated round cell sarcomas (URCS) represent a diverse group of tumors, including conventional Ewing sarcoma, round cell sarcoma with EWSR1/FUS-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR alterations. Since 2018, three cases of URCS with a novel CRTC1::SS18 gene fusion have been reported in the literature. Herein, we report three additional cases of CRTC1::SS18 sarcoma, thereby doubling the number of described cases and expanding the clinicopathologic features of this rare translocation sarcoma. Together with the previously reported cases, we show that the male-to-female ratio is 1:2 with a median age of 34 years (range: 12 to 42 years). Tumors occurred primarily in intramuscular locations involving the lower extremity. Histologically, all tumors contained uniform round to epithelioid cells with a moderate amount of eosinophilic cytoplasm growing in sheets and nests with prominent desmoplastic stroma reminiscent of desmoplastic small round cell tumor (DSRCT). Immunohistochemical results were non-specific, demonstrating variable expression of CD99 (patchy), ALK, GATA3, and cyclin D1. RNA sequencing revealed CRTC1::SS18 gene fusions in all cases, involving exon 1-2 of CRTC1 (the 5' partner gene) on chromosome 19 and either exon 2 or exon 4 of SS18 (the 3' partner gene) on chromosome 18. The clinical course was variable. While one previously reported case demonstrated aggressive behavior with fatal outcome, two others had a relatively indolent course with gradual growth for 6-7 years prior to resection. Two cases developed metastatic disease, including one case with bilateral lung metastasis and one with locoregional spread to a lymph node. By analyzing the clinicopathologic features, we aim to improve recognition of this rare translocation sarcoma to better understand its biologic potential, optimize patient management, and expand the current classification of URCS.

Adrenal cysts less than 10 cm can be safely observed.

BACKGROUND: Adrenal cysts are rare and appropriate management is unclear due to a lack of data on their natural history. Understanding adrenal cyst growth patterns would assist in clinical management. METHODS: This single-institution study included all adult patients diagnosed with simple adrenal cysts between 2004 and 2021. Baseline characteristics and outcomes of those who underwent resection (ADX) or observation (OBS) were compared using the chi-squared test, student's t-test, and Wilcoxon rank-sum test. Growth curves and sensitivity analysis were plotted for all patients who had follow-up imaging. RESULTS: We identified 77 patients with imaging-confirmed adrenal cysts. The majority were female (75.3%) and more than half were white (55.8%). One-third of patients underwent ADX, and the remaining were observed. ADX patients were younger (median age [IQR]: 55.5 y [45.0-68.2 y] vs. 44.2 y [38.7-55.0 y], p = 0.01) and more likely to be Hispanic (12% vs. 0%, p = 0.05). ADX patients presented with larger cysts (5.6 vs. 2.6 cm, p = 0.002). The median time from diagnosis to last follow-up was 1.1 y for ADX and 4.1 y for OBS. Average growth for OBS was 0.3 cm/y, while average growth for ADX was 3.9 cm/y. In ADX patients, cysts >10 cm grew significantly faster than cysts <10 cm (median growth rate 13.2 cm/y vs. 0.3 cm/y, p < 0.05). There was no adrenal malignancy diagnosis, hyperfunctionality, or observation-related complications (e.g., rupture). CONCLUSION: While size >4-6 cm has guided surgical referral for solid adrenal masses, this study demonstrates a size threshold of 10 cm, below which asymptomatic, simple adrenal cysts can safely be observed.

Identifying Men Who Can Remain on Active Surveillance Despite Biopsy Reclassification to Grade Group 2 Prostate Cancer.

PURPOSE: Men on active surveillance with Grade Group 1 prostate cancer who reclassify to Grade Group 2 on surveillance biopsy often leave active surveillance. We aimed to identify subgroups of men who can safely remain on active surveillance despite preoperative reclassification to Grade Group 2. MATERIALS AND METHODS: We studied 249 active surveillance patients with surveillance biopsies classified as Grade Group 1 or Grade Group 2 who underwent radical prostatectomy. Perineural invasion, cancer volume, linear length and maximum percentage of Gleason pattern 4, and prostate-specific antigen density were evaluated. Radical prostatectomy adverse pathology was defined by any of: pN1; ≥pT3; ≥Grade Group 2 with ≥20% Gleason pattern 4; intraductal carcinoma; large cribriform glands. RESULTS: A multivariable logistic regression model incorporating prostate-specific antigen density and perineural invasion stratified radical prostatectomy adverse pathology risk among Grade Group 1 and Grade Group 2 active surveillance patients. 57% (39/68) of Grade Group 1 men reclassified to Grade Group 2 while on active surveillance had favorable radical prostatectomy pathology. Those without biopsy perineural invasion and with low prostate-specific antigen density were more likely to have favorable radical prostatectomy pathology. CONCLUSIONS: Most Grade Group 1 men who enter active surveillance and subsequently reclassify to Grade Group 2 have favorable findings at radical prostatectomy and can remain on active surveillance. Among patients reclassified to Grade Group 2, those with low prostate-specific antigen density and without perineural invasion had the lowest risk of radical prostatectomy adverse pathology, comparable to (or below) that of Grade Group 1 patients who were not reclassified to Grade Group 2 preoperatively. Prostate-specific antigen density and perineural invasion stratify risk in active surveillance patients reclassified to Grade Group 2 and, if concordant with other clinicopathological and radiographic findings, can enable more patients to remain on active surveillance. Reclassification to Grade Group 2 alone should not disqualify men from remaining on active surveillance.

Developing Asymmetries without Sonographic Correlate at Digital Breast Tomosynthesis.

Background Digital breast tomosynthesis (DBT) has improved the accuracy of mammography, including resolving many breast asymmetries as overlapping breast tissue. The pathologic outcomes of persistent developing asymmetries visualized at DBT are not well established. Purpose To characterize the outcomes and the predictors of malignancy for developing asymmetries visualized at DBT without a sonographic correlate. Materials and Methods This retrospective study included all tomosynthesis-guided biopsies of developing asymmetries performed at a single institution from May 2017 through January 2020. A reader study including three breast imaging radiologists determined interrater agreement and inclusion into the study. Electronic medical records were used to extract patient characteristics, imaging characteristics, and pathologic diagnoses. The Wilcoxon rank sum test, Fisher exact test, and χ2 test were used to analyze correlations of patient and imaging characteristics with likelihood of malignancy. Results The reader study included 95 DBT examinations with moderate interrater reliability (Fleiss κ = 0.45). There was majority reader agreement in 85 of the 95 DBT examinations (89%) of 83 women (median age, 56 years; interquartile range, 47-69 years), and this finalized the study data set. At pathologic examination, most asymmetries (68 of 85, 80%) were benign, with common diagnoses being fibrocystic change (n = 20), stromal fibrosis (n = 10), and fat necrosis (n = 10). The overall malignancy rate was 20% (17 of 85 asymmetries; 95% CI: 12, 29); 15 of the 17 malignancies (88%) were invasive cancers. Malignancies were more common in women with a personal history of breast cancer (35% vs 10%, P = .02). Conclusion In 85 developing asymmetries visualized at digital breast tomosynthesis without a sonographic correlate, there was a 20% (95% CI: 12, 29) malignancy rate, which was higher than the rates of malignancy for a developing asymmetry detected at digital mammography. © RSNA, 2021 See also the editorial by Skaane in this issue.

The "Far Left" of the Morphologic Spectrum of Ovarian High-grade Serous Carcinoma: Case Report of a Purely Noninvasive High-grade Serous Carcinoma Mimicking an Ovarian Serous Borderline Tumor.

High-grade serous carcinoma has a variety of different growth patterns, but is typically easily recognizable to pathologists and rarely confused with serous borderline tumors. We report a case of a 71-yr-old woman with a unilateral 5.1 cm ovarian cyst with small papillary projections on contrast-enhanced magnetic resonance imaging of the pelvis. Histologic examination showed a noninvasive papillary neoplasm with hierarchical branching and epithelial proliferation, and thus, at low magnification, bearing a striking resemblance to a serous borderline tumor. However, a more careful examination demonstrated high-grade cytologic features, nuclear pleomorphism, and abundant mitotic activity, suggestive of high-grade serous carcinoma. The morphology and immunohistochemical profile of this lesion is consistent with a rare, purely noninvasive growth pattern of high-grade serous carcinoma. This lesion represents the "far left" of the high-grade ovarian serous carcinoma morphologic spectrum and can mimic a serous borderline tumor.

Dedifferentiated and undifferentiated neoplasms: A conceptual approach.

This review provides a conceptual approach to dedifferentiation across a variety of tumor types, with particular attention to genetic events that tie together morphologically disparate areas of these neoplasms. First, working definitions of the terms differentiated, undifferentiated, and dedifferentiated are developed. Then, specific examples of tumors with a particular propensity for undergoing dedifferentiation are highlighted, with emphasis on both immunohistochemical studies and molecular lesions that enable surgical pathologists to establish diagnostic clarity in morphologically vexing situations. Throughout this review, the historical arc of the literature is followed, and therefore the discussion of specific tumor types begins with dedifferentiated chondrosarcoma, the neoplasm that inspired the terminology regarding dedifferentiation that remains in use today. Selected other sarcomas with well-established pathways of dedifferentiation are subsequently discussed, followed by descriptions of this process in subtypes of carcinoma and melanoma.

Cyclin D1 expression and novel mutational findings in Rosai-Dorfman disease.

Rosai-Dorfman disease (RDD) is an enigmatic histiocytic disorder classically diagnosed by a distinctive combination of pathological features: emperipolesis, or migration of intact haematological cells through the voluminous cytoplasm of lesional histiocytes, and expression of S100 by these histiocytes. The pathogenesis has long been elusive until the recent detection of recurrent and mutually exclusive mutations in several oncogenes in the mitogen-activated protein kinase (MAPK) pathway. Based on these findings, we investigated a cohort of 21 RDD patients and found that the lesional histiocytes in 86% (18/21) of patients exhibited strong and diffuse nuclear Cyclin D1 expression, which not only may provide a diagnostic marker for this sometimes pathologically challenging disease, but also probably reflects constitutive MAPK pathway activation because we additionally identified phosphorylated-ERK expression in 90% (19/21) of cases. Further, we performed massively parallel sequencing on a subset (6/18) of the CyclinD1 positive cases, identifying several mutations that have not been previously reported in RDD. Taken together, our findings bolster the concept of RDD as a disease of MAPK activation in a substantial percentage of cases and enhance the current understanding of the pathogenesis of RDD.

Clinical, immunophenotypic, and genomic findings of acute undifferentiated leukemia and comparison to acute myeloid leukemia with minimal differentiation: a study from the bone marrow pathology group.

Acute undifferentiated leukemia is a rare type of acute leukemia that shows no evidence of differentiation along any lineage. Clinical, immunophenotypic and genetic data is limited and it is uncertain if acute undifferentiated leukemia is biologically distinct from acute myeloid leukemia with minimal differentiation, which also shows limited myeloid marker expression and has been reported to have a poor prognosis. We identified 92 cases initially diagnosed as acute undifferentiated leukemia or acute myeloid leukemia with minimal differentiation from pathology databases of nine academic institutions with available diagnostic flow cytometric data, cytogenetic findings, mutational and clinical data. Outcome analysis was performed using Kaplan Meier test for the 53 patients who received induction chemotherapy. Based on cytogenetic abnormalities (N = 30) or history of myelodysplastic syndrome (N = 2), 32 cases were re-classified as acute myeloid leukemia with myelodysplasia related changes. The remaining 24 acute undifferentiated leukemia patients presented with similar age, blood counts, bone marrow cellularity, and blast percentage as the remaining 30 acute myeloid leukemia with minimal differentiation patients. Compared to acute myeloid leukemia with minimal differentiation, acute undifferentiated leukemia cases were characterized by more frequent mutations in PHF6 (5/15 vs 0/19, p = 0.016) and more frequent expression of TdT on blasts (p = 0.003) while acute myeloid leukemia with minimal differentiation cases had more frequent CD123 expression (p = 0.042). Outcome data showed no difference in overall survival, relapse free survival, or rates of complete remission between acute undifferentiated leukemia and acute myeloid leukemia with minimal differentiation groups (p > 0.05). Acute myeloid leukemia with myelodysplasia-related changes patients showed shorter survival when censoring for bone marrow transplant as compared to acute undifferentiated leukemia (p = 0.03) and acute myeloid leukemia with minimal differentiation (p = 0.002). In this largest series to date, the acute undifferentiated leukemia group shows distinct characteristics from acute myeloid leukemia with minimal differentiation, including more frequent PHF6 mutations and expression of TdT.

Pathogenesis of Testicular Germ Cell Neoplasia: A Conceptual Approach.

Testicular germ cell tumors are a diverse group of neoplasms, consisting of the prepubertal type 1 tumors, pure teratoma, and pure yolk sac tumor, the type 2 tumors, which are biologically malignant, preceded by germ cell neoplasia in situ, and harbor chromosome 12p abnormalities, and the type 3 tumor, spermatocytic tumor, which features chromosome 9p amplification. These arise in distinct clinical settings, and harbor distinct genetic abnormalities, immunohistochemical properties, and morphologic features. Here we have attempted to unify embryology, morphology, immunohistochemistry, and genetics in order to distill this fascinating group of neoplasms into what we hope is a useful framework for understanding their classification.

MYB rearrangement and immunohistochemical expression in adenomyoepithelioma of the breast: a comparison with adenoid cystic carcinoma.

AIMS: Adenomyoepithelioma (AME) and adenoid cystic carcinoma (ACC) of the breast have been noted to occur simultaneously, raising the possibility that AME may represent a related or precursor lesion to ACC. ACC frequently harbours genetic rearrangement of the MYB gene. We sought to clarify the relationship between AME and ACC by comparing their rates of MYB expression by IHC and MYB rearrangement by FISH. METHODS AND RESULTS: IHC and FISH for MYB rearrangement were performed on paraffin-embedded sections of 11 breast ACCs, 11 non-breast ACCs and 11 breast-AMEs. Using FISH, five of eight (63%) interpretable breast ACCs demonstrated MYB gene rearrangement. Nine of 11 (81%) breast ACCs demonstrated MYB expression (range = 20-95%). Of the three FISH-negative breast ACCs, two were solid variant and demonstrated strong MYB expression by IHC. Of the 10 interpretable non-breast ACCs, six showed MYB rearrangement, all of which were conventional type. Nine of these 11 (81%) cases showed MYB immunoexpression (range = 10-90%), including three solid-variant cases which were negative by FISH. No MYB rearrangements were detected by FISH in 10 interpretable AMEs. However, three of 11 cases (27%) showed weak to moderate MYB expression by IHC (range = 10-40%). CONCLUSIONS: Our results indicate that AMEs do not harbour MYB gene rearrangement. IHC for MYB may be helpful in diagnosing FISH-negative cases of ACC, particularly the diagnostically more difficult solid variants. However, weak to moderate MYB expression in a subset of AMEs highlights not only a potential diagnostic pitfall, but also shared pathophysiology with ACC worth investigating further at the genomic level.

Current Advances in the Management of Nonurothelial Subtypes of Bladder Cancer.

Urothelial cancer (UC) is the most common histology seen in bladder tumors. The 2022 WHO classification of urinary tract tumors includes a list of less common subtypes (formerly known as variants) for invasive UC which are considered high-grade tumors. This review summarizes the most recent advances in the management of selected nonurothelial subtypes of bladder cancer: squamous cell carcinoma, small cell carcinoma, sarcomatoid urothelial carcinoma, micropapillary carcinoma, plasmacytoid carcinoma, adenocarcinoma, and urachal carcinoma. The role of neoadjuvant and adjuvant chemotherapy has not been well characterized for most of these histologies, and prospective data are extremely limited. Participation in clinical trials is recommended in advanced disease.

Benign Islet Cells Within Peripancreatic Lymph Nodes: A Potential Diagnostic Pitfall.

The presence of epithelial cells within lymph node parenchyma is typically indicative of a metastatic malignancy. However, there are rare instances in which non-neoplastic epithelial or epithelioid cells may be found within lymph nodes, either due to aberrant embryologic migration, mechanical displacement, or physiological trafficking. These can potentially lead to serious potential diagnostic pitfalls, as when such situations are encountered by surgical pathologists, there is substantial risk of overdiagnosing these as metastatic malignancy. Herein, we describe 2 cases of benign pancreatic islet cells within peripancreatic lymph nodes, and underscore the potential for misdiagnosis of this phenomenon as foci of metastatic well-differentiated neuroendocrine tumor. The benign nature of these intranodal islet cells was supported by: (1) the absence of a well-differentiated neuroendocrine tumor in the entirely submitted concomitant pancreatic resection specimen and (2) the presence of an admixture of insulin and glucagon expressing cells by immunohistochemistry in a distribution characteristic of non-neoplastic pancreatic islets. Both cases were incidental microscopic findings in pancreatic resections for intraductal papillary mucinous neoplasms that were previously biopsied and showed associated microscopic areas of fibrosis and chronic pancreatitis and thus this phenomenon may be related to mechanical displacement from prior injury and/or biopsy.

Prognostic significance of pT3a staging subclassifications in renal cell carcinoma: Not all pT3a are equal.

OBJECTIVE: To examine the prognostic significance of perinephric fat, renal sinus fat, and renal vein invasion in patients with pT3a renal cell carcinoma (RCC) by histologic type. METHODS: A population-based retrospective cohort study of patients with pT3aN0M0 RCC was performed using Surveillance, Epidemiology, and End Results (SEER) data for the years 2010 through 2019. Cox proportional hazards models were used to examine the relationship between pT3a subclassification groups and cancer-specific survival (CSS) by histological subtype (clear cell, papillary, chromophobe, and other). RESULTS: The cohort consisted of 10,170 patients with pT3a RCC, including 8,446 (83.0%) with clear cell RCC and 1,724 (17.0%) with nonclear cell RCC (nccRCC). Median follow up was 36 months. Differences in CSS by pT3a subclassification groups were observed in all histological subtypes but were most pronounced in nccRCC, specifically papillary RCC. Compared to perinephric fat (PF) invasion only, renal vein (RV) invasion (HR = 4.9, 95%CI: 2.5-9.3, P < 0.01), renal sinus fat invasion (HR = 3.0, 95%CI: 1.4-6.2), RV and PF invasion (HR = 7.5, 95%CI: 3.5-16.0), and combination of all three characteristics (HR = 4.4, 95%CI: 1.2-15.5) were associated with worse CSS in patients with papillary RCC. CONCLUSION: We examined the prognostic role of pT3a staging subclassifications in RCC by histologic subtype and observed survival differences, particularly in papillary RCC. Our findings highlight the need to refine pT3a staging criteria to help guide individualized, multimodal treatment strategies for locally advanced RCC.

Cushing Syndrome Due to a Corticotropin-Releasing Hormone- and Adrenocorticotropic Hormone-Secreting Silent Pheochromocytoma.

Background/Objective: Ectopic cosecretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in silent (ie, non-catecholamine-secreting) pheochromocytoma is a rare cause of Cushing syndrome. Case Report: A 57-year-old woman rapidly developed hypercortisolism, clinically manifesting as fatigue, muscle weakness, weight gain, and worsening hypertension and biochemically characterized by hypokalemia and marked increases in the serum cortisol and plasma ACTH levels. This acute presentation suggested a diagnosis of ectopic ACTH syndrome (EAS). Imaging studies revealed a right adrenal mass that enhanced after administration of the radioisotope gallium-68-DOTATATE. Plasma metanephrines were normal in 2 separate measurements. The possibility of a silent pheochromocytoma was considered. After controlling her hypercortisolism with metyrapone and surgical preparation with alpha blockade, the patient underwent elective right adrenalectomy. Pathology revealed a pheochromocytoma that stained focally for ACTH and CRH. Postoperatively, the cortisol levels normalized, the hypothalamic-pituitary-adrenal axis was not suppressed, and clinical symptoms from hypercortisolism abated. Discussion: Patients who exhibit a rapid progression of ACTH-dependent hypercortisolism should be screened for EAS. The use of functional imaging radioisotopes (eg, gallium DOTA-peptides) improves the detection of ACTH-secreting tumors. Preoperative treatment with steroidogenesis inhibitors helps control clinical and metabolic derangements associated with severe hypercortisolemia, whereas alpha blockade prevents the onset of an adrenergic crisis. Conclusion: We present a rare case of EAS due to a silent pheochromocytoma that cosecreted ACTH and CRH. Pheochromocytoma should be considered in patients with EAS who have an adrenal mass even in the absence of excessive catecholamine secretion.

Cinematic rendering of primary adrenal lymphoma.

Primary adrenal lymphoma (PAL) is a particularly rare subset of malignant adrenal neoplasms, accounting for ∼1% of all non-Hodgkin's lymphomas. Reported outcomes of PAL, though limited, are dismal, with a 12-month survival rate of ∼20%. PAL is treated with polychemotherapy and early tissue diagnosis to allow initiation of chemotherapy is associated with improved outcomes. Early and accurate radiological diagnosis of PAL is therefore essential in improving outcomes through informing decisions to biopsy and thereby facilitating timely initiation of chemotherapy. To date, however, imaging features of PAL have not been conclusively defined, and a range of divergent imaging appearances have been reported. Cinematic rendering (CR) is a 3D post-processing technique that simulates the propagation and interaction of photons as they pass through the imaged volume. This results in the generation of more photorealistic images that may allow for more comprehensive visualization, description and interpretation of anatomical structures. This manuscript presents the first characterization of the various CR appearances of PAL in the reported literature and provides commentary on the clinical opportunities afforded by CR in the workup of these heterogenous tumors.

TFE3 -Rearranged PEComa/PEComa-like Neoplasms : Report of 25 New Cases Expanding the Clinicopathologic Spectrum and Highlighting its Association With Prior Exposure to Chemotherapy.

Since their original description as a distinctive neoplastic entity, ~50 TFE3 -rearranged perivascular epithelioid cell tumors (PEComas) have been reported. We herein report 25 new TFE3 -rearranged PEComas and review the published literature to further investigate their clinicopathologic spectrum. Notably, 5 of the 25 cases were associated with a prior history of chemotherapy treatment for cancer. This is in keeping with prior reports, based mainly on small case series, with overall 11% of TFE3 -rearranged PEComas being diagnosed postchemotherapy. The median age of our cohort was 38 years. Most neoplasms demonstrated characteristic features such as nested architecture, epithelioid cytology, HMB45 positive, and muscle marker negative immunophenotype. SFPQ was the most common TFE3 fusion partner present in half of the cases, followed by ASPSCR1 and NONO genes. Four of 7 cases in our cohort with meaningful follow-up presented with or developed systemic metastasis, while over half of the reported cases either recurred locally, metastasized, or caused patient death. Follow-up for the remaining cases was limited (median 18.5 months), suggesting that the prognosis may be worse. Size, mitotic activity, and necrosis were correlated with aggressive behavior. There is little evidence that treatment with MTOR inhibitors, which are beneficial against TSC -mutated PEComas, is effective against TFE3 -rearranged PEComas: only one of 6 reported cases demonstrated disease stabilization. As co-expression of melanocytic and muscle markers, a hallmark of conventional TSC -mutated PEComa is uncommon in the spectrum of TFE3 -rearranged PEComa, an alternative terminology may be more appropriate, such as " TFE3 -rearranged PEComa-like neoplasms," highlighting their distinctive morphologic features and therapeutic implications.

Xyolide, a bioactive nonenolide from an Amazonian endophytic fungus, Xylaria feejeensis.

Endophytes isolated from tropical plants represent a largely untapped reservoir of bioactive secondary metabolites. We screened a library of fungal endophyte extracts for inhibition of the plant pathogen, Pythium ultimum, and purified an active compound using bioassay-guided fractionation. A new nonenolide, (4S,7S,8S,9R)-4-O-succinyl-7,8-dihydroxy-9-heptyl-nonen-9-olide, was isolated and named xyolide. The structure was elucidated by a combination of 1D and 2D NMR methods and the absolute configuration was determined by exciton-coupled circular dichroism. The MIC of xyolide against P. ultimum was 425 µM.

Robotic-assisted cytoreductive partial nephrectomy for metastatic sarcomatoid renal cell carcinoma following dramatic response to combination immunotherapy in a young female.

Novel immune checkpoint inhibitors (ICI) have yielded remarkable response rates in metastatic renal cell carcinoma (RCC), including sarcomatoid RCC (sRCC). Here, we show the feasibility and efficacy of robotic-assisted cytoreductive partial nephrectomy (cPN) following a remarkable response to combination ICI for metastatic sRCC in a young female. A female in her late 40s presented with poor-risk, metastatic sRCC emanating from a 6.5 cm left renal mass including pulmonary involvement, retroperitoneal lymphadenopathy, and a scalp metastasis. She received 4 cycles of combination ipilimumab and nivolumab followed by maintenance nivolumab with a remarkable and durable response. Given the apparent downstaging of her primary tumor, a robotic cPN was pursued for residual ypT1aNoRo sRCC and found to be both feasible and safe with exceptional perioperative outcomes. She has since done well clinically and oncologically. Our unique case of metastatic sRCC in a young female highlights several aspects pertinent to the contemporary management of metastatic RCC including the role for cytoreductive nephrectomy in selected patients, the safety and feasibility of a nephron-sparing and minimally-invasive approach to cytoreduction after downstaging with ICI, and remarkable sensitivity of sRCC-a classically aggressive entity-to ICI.

MED15::TFE3 Renal Cell Carcinomas: Report of Two New Cases and Review of the Literature Confirming Nearly Universal Multilocular Cystic Morphology.

We report two novel cases of Xp11 translocation renal cell carcinomas with the MED15::TFE3 gene fusion in adult females aged 40 and 74 years. Both cases were extensively cystic and contained only minimal clear cells lining cysts and within septal walls, raising the differential diagnosis of multilocular cystic renal neoplasm of low malignant potential. By immunohistochemistry, both neoplasms labeled for PAX8, TFE3, cathepsin K and Melan A but not for HMB45. On review of the published literature and the two cases reported herein, over 90% of MED15::TFE3 renal cell carcinomas (RCCs) have been described as cystic. The correlation of the MED15::TFE3 fusion with extensively cystic morphology represents the strongest association of TFE3 fusion partner with clinicopathological features among TFE3-rearranged RCC reported to date.