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.

Context-dependent roles for ubiquitous mitochondrial creatine kinase CKMT1 in breast cancer progression.

Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and metastasize. We show that creatine levels in metastatic breast cancer cell lines and secondary metastatic tumors are driven by the ubiquitous mitochondrial creatine kinase (CKMT1). We discover that, while CKMT1 is highly expressed in primary tumors and promotes cell viability, it is downregulated in metastasis. We further show that CKMT1 downregulation, as seen in breast cancer metastasis, drives up mitochondrial reactive oxygen species (ROS) levels. CKMT1 downregulation contributes to the migratory and invasive potential of cells by ROS-induced upregulation of adhesion and degradative factors, which can be reversed by antioxidant treatment. Our study thus reconciles conflicting evidence about the roles of metabolites in the creatine metabolic pathway in breast cancer progression and reveals that tight, context-dependent regulation of CKMT1 expression facilitates cell viability, cell migration, and cell invasion, which are hallmarks of metastatic spread.

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.

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.

Clinicopathologic Classification of Renal Cell Carcinoma in Patients ≤40 Years Old From Peru.

INTRODUCTION: There are scant data on renal cell carcinoma (RCC) from relatively younger patients in South America using contemporary classification. METHODS: Fifty-nine consecutively treated patients with RCC (≤40 years old) were assessed from the National Institute of Neoplastic Diseases in Peru from 2008 to 2020 (34 males; 25 females), age range of 13 to 40 years. RESULTS: Most common presenting symptoms were flank pain (n = 40), hematuria (n = 19), and weight loss (n = 12). Associated conditions included 4 patients with proven or presumed tuberous sclerosis and 1 patient with von Hippel Lindau syndrome, all with clear cell RCC. Tumor histopathology was clear cell RCC in 32 of 59 (54%), chromophobe RCC in 6 of 59 (10%), and 5 of 59 (8%) each of papillary RCC and MiT family translocation-associated RCC. Four of 59 (7%) were FH-deficient RCC and 2 of 59 (3%) remained unclassified. The remaining tumors were isolated examples of clear cell papillary renal cell tumor, eosinophilic solid and cystic RCC (ESC RCC), RCC with fibromyomatous stroma, sarcomatoid RCC, and sarcomatoid clear cell RCC. Of the 4 FH-deficient RCCs, none had the classic morphology. The 5 MiT family translocation RCCs had variable morphology. There were 41 tumors without recurrence or metastases, 3 tumors with local recurrence only, 8 tumors with metastases only, and 7 tumors with both local recurrence and metastases. CONCLUSIONS: The current study demonstrates the importance of special studies in accurately classifying RCC in younger individuals. The distribution of RCC subtypes in younger individuals is similar between 2 representative large institutions of the United States and Peru.

Hybrid Oncocytic Tumors (HOTs) in Birt-Hogg-Dubé Syndrome Patients-A Tale of Two Cities: Sequencing Analysis Reveals Dual Lineage Markers Capturing the 2 Cellular Populations of HOT.

Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of multifocal renal tumors, including hybrid oncocytic tumor (HOT) and chromophobe renal cell carcinoma (chRCC). HOT exhibits heterogenous histologic features overlapping with chRCC and benign renal oncocytoma, posing challenges in diagnosis of HOT and renal tumor entities resembling HOT. In this study, we performed integrative analysis of bulk and single-cell RNA sequencing data from renal tumors and normal kidney tissues, and nominated candidate biomarkers of HOT, L1CAM, and LINC01187 , which are also lineage-specific markers labeling the principal cell and intercalated cell lineages of the distal nephron, respectively. Our findings indicate the principal cell lineage marker L1CAM and intercalated cell lineage marker LINC01187 to be expressed mutually exclusively in a unique checkered pattern in BHD-associated HOTs, and these 2 lineage markers collectively capture the 2 distinct tumor epithelial populations seen to co-exist morphologically in HOTs. We further confirmed that the unique checkered expression pattern of L1CAM and LINC01187 distinguished HOT from chRCC, renal oncocytoma, and other major and rare renal cell carcinoma subtypes. We also characterized the histopathologic features and immunophenotypic features of oncocytosis in the background kidney of patients with BHD, as well as the intertumor and intratumor heterogeneity seen within HOT. We suggest that L1CAM and LINC01187 can serve as stand-alone diagnostic markers or as a panel for the diagnosis of HOT. These lineage markers will inform future studies on the evolution and interaction between the 2 transcriptionally distinct tumor epithelial populations in such tumors.

EWSR1::WT1 Fusions in Neoplasms Other Than Conventional Desmoplastic Small Round Cell Tumor: Three Tumors Occurring Outside the Female Genital Tract.

Desmoplastic small round cell tumor (DSRCT) is a high-grade, primitive round cell sarcoma classically associated with prominent desmoplastic stroma, coexpression of keratin and desmin, and a characteristic EWSR1::WT1 gene fusion. DSRCT typically arises in the abdominopelvic cavity of young males with diffuse peritoneal spread and poor overall survival. Although originally considered to be pathognomonic for DSRCT, EWSR1::WT1 gene fusions have recently been detected in rare tumors lacking the characteristic morphologic and immunohistochemical features of DSRCT. Here, we report 3 additional cases of neoplasms other than conventional DSCRCT with EWSR1::WT1 gene fusions that occurred outside the female genital tract. Two occurred in the abdominopelvic cavities of a 27-year-old man and a 12-year-old girl, whereas the third arose in the axillary soft tissue of an 85-year-old man. All cases lacked prominent desmoplastic stroma and were instead solid and cystic with peripheral fibrous pseudocapsules and occasional intervening fibrous septa. Necrosis was either absent (1/3) or rare (2/3), and mitotic activity was low (<1 to 3 per 10 hpf). In immunohistochemical studies, there was expression of smooth muscle actin (3/3) and desmin (3/3), rare to focal reactivity for EMA (2/3), and variable expression of CK AE1/AE3 (1/3). Myogenin and MyoD1 were negative, and C-terminus-specific WT1 was positive in both cases tested (2/2). All 3 tumors followed a more indolent clinical course with 2 cases demonstrating no evidence of disease at 20 and 44 months after resection. The patient from case 3 died of other causes at 14 months with no evidence of recurrence. DNA methylation profiling showed that the 3 cases clustered with DSRCT; however, they demonstrated fewer copy number variations with 2 cases having a flat profile (0% copy number variation). Differential methylation analysis with hierarchical clustering further showed variation between the 3 cases and conventional DSRCT. Although further study is needed, our results, in addition to previous reports, suggest that EWSR1::WT1 gene fusions occur in rare and seemingly distinctive tumors other than conventional DSRCT with indolent behavior. Proper classification of these unusual soft tissue tumors with EWSR1::WT1 gene fusions requires direct correlation with tumor morphology and clinical behavior, which is essential to avoid overtreatment with aggressive chemotherapy.

Molecular Characterization of TFE3-Rearranged Renal Cell Carcinoma: A Comparative Study With Papillary and Clear Cell Renal Cell Carcinomas.

TFE3-rearranged renal cell carcinoma (rRCC) is a rare subtype of renal cell carcinomas belonging to the MiT family translocation RCC. To further elucidate the co-alterations that occur along with TFE3 fusions in rRCC, we characterized the genomic, transcriptional, and immune landscapes in comparison to clear cell (ccRCC) and papillary renal cell carcinoma (pRCC). Next-generation sequencing of RNA (whole transcriptome) and DNA (592-gene panel or whole exome) for rRCC (N = 20), pRCC (N = 20), and ccRCC samples (N = 392) was performed. Patients with rRCC were significantly younger and more frequently female (median 44.5 years, 75.0% female) as compared with patients with pRCC (68.5 years, 25.0% female; P < .05) and ccRCC (62.0 years, 27.8% female; P < .05). A total of 8 unique fusion partners were observed, including a novel fusion with SRRM2::TFE3 in 2 patients. ccRCC exhibited significantly higher mutation rates of VHL (0% rRCC, 0% pRCC, 78.7% ccRCC; P < .05) and PBMR1 (0% rRCC, 5.0% pRCC, 49.4% ccRCC; P < .05). The genomic landscapes of rRCC were sparse with no mutations occurring with a prevalence higher than 10% other than pTERT (18.2% rRCC, 0% pRCC, 9.2% ccRCC). rRCC were associated with significantly less M1 macrophages (0.8%) as compared with pRCC (1.4%) and ccRCC (2.7%) (P < .05), suggesting a cold tumor-immune microenvironment. However, rRCC were more commonly PD-L1+ (rRCC 50%, pRCC 19.0%, ccRCC 12.2%; P < .05). Gene set enrichment analysis showed that rRCC are enriched in genes related to oxidative phosphorylation when compared with both ccRCC and pRCC. Despite having a colder tumor-immune microenvironment than pRCC and ccRCC, increased PDL1+ rates in rRCC suggest a potential benefit from immune checkpoint inhibitor therapy.

Uterine MEIS1::NCOA2 Fusion Sarcoma With Lung Metastasis: A Case Report and Review of the Literature.

MEIS1::NCOA1/2 fusion sarcomas are a recently described novel entity arising in a variety of locations with a predilection for the genitourinary tract and gynecologic organs. Despite multiple locoregional recurrences, these tumors are thought to behave in a low-grade malignant manner. Here we report a uterine MEIS1::NCOA2 fusion sarcoma with lung metastasis. The patient was a 47-yr-old woman with a history of abnormal uterine bleeding who was found to have a myometrial mass confirmed by pathology to be uterine sarcoma. The tumor was predominantly composed of monotonous spindle cells with scant cytoplasm, crowded nuclei, and brisk mitotic activity, growing in a fascicular and streaming pattern. The morphologic and immunophenotypic features were nonspecific and a diagnosis of high-grade uterine sarcoma with a differential of leiomyosarcoma versus high-grade endometrial stromal sarcoma was rendered. At the 27-mo follow-up, the patient was found to have a lung metastasis consisting of a monotonous round cell sarcoma. A retrospective RNA-based and DNA-based next-generation sequencing of the primary uterine sarcoma revealed a MEIS1::NCOA2 gene fusion, a c.94G>C/p.D32H mutation in exon 3 of CTNNB1 gene, HMGA2 , and CDK4 gene amplification, and an intermediate/marginal level of MDM2 gene amplification. Polymerase chain reaction-based molecular analysis further demonstrated that the MEIS1::NCOA2 gene fusion and CTNNB1 somatic mutation were also present in the lung metastasis. This case represents the first case of such gynecologic sarcoma with distant (lung) metastasis, and the second metastatic case among all reported MEIS1::NCOA1/2 fusion sarcomas, highlighting the malignant metastatic potential of this emerging entity. Our case also indicates that HMGA2/CDK4/MDM2 region amplification and CTNNB1 somatic mutation might be recurrent genetic events in this rare sarcoma subtype.

Clear Cell Renal Cell Carcinoma with Prominent Micropapillary Pattern: A Case Report of a Previously Undescribed Morphology.

The classic morphology of clear cell renal cell carcinoma consists of nests of cells with clear cytoplasm. Nevertheless, other histologic patterns may be seen including cells with eosinophilic cytoplasm, bizarre multinucleated giant tumor cells and pseudopapillary structures. In this article, we present the first case of clear cell renal cell carcinoma with a prominent micropapillary pattern.

Positive GPNMB Immunostaining Differentiates Renal Cell Carcinoma With Fibromyomatous Stroma Associated With TSC1/2/MTOR Alterations From Others.

Renal cell carcinoma with fibromyomatous stroma (RCCFMS) include ELOC/TCEB1 -mutated renal cell carcinoma (RCC) and those with TSC1/2 / MTOR alterations. Besides morphologic similarity, most of these tumors is known to be diffusely positive for carbonic anhydrase IX and cytokeratin 7 by immunohistochemistry. We previously showed strong and diffuse expression of GPNMB (glycoprotein nonmetastatic B) in translocation RCC and eosinophilic renal neoplasms with known TSC1/2/MTOR alterations. We retrospectively identified molecularly confirmed cases of TCEB1/ELOC -mutated RCC (7 tumors from 7 patients), and RCCFMS with alterations in TSC1/2/MTOR (6 tumors from 5 patients, 1 patient with tuberous sclerosis syndrome). In addition, we included 7 clear cell papillary renal cell tumors (CCPRCTs) and 8 clear cell RCC, as they can also present morphologic overlap with RCCFMS. Morphologically, RCCs with TSC1/2/MTOR alterations and those with TCEB1/ELOC mutations were indistinguishable and characterized by papillary, nested, or tubular architecture, with tumor cells with clear cytoplasm and low nuclear grade. By immunohistochemistry, cytokeratin 7 was positive in 5/7 (71%) of TCEB1/ELOC -mutated RCCs, 6/6 (100%) of RCCs with TSC1/2/mTOR alterations, and 7/7 (100%) of CCPRCTs ( P =not significant). Carbonic anhydrase IX was positive in 7/7 TCEB1/ELOC -mutated RCCs, 6/6 (100%) of RCCs with TSC1/2/MTOR alterations, and 7/7 (100%) of CCPRCTs ( P =NS). GPNMB was strongly and diffusely positive in all tumors with TSC1/2/MTOR alterations (6/6), while negative in all TCEB1/ELOC -mutated RCCs (0/6), or CCPRCTs (0/7) ( P =0.002). Two of 8 clear cell RCC showed focal weak staining, while 6/8 were negative. In conclusion, the results support the use of GPNMB to distinguish RCCFMS with TSC1/2/MTOR alterations from others with similar morphology.

"Oncocytoid Renal Cell Carcinomas After Neuroblastoma" Represent TSC -mutated Eosinophilic Solid and Cystic Renal Cell Carcinomas : Association With Prior Childhood Malignancy and Multifocality With Therapeutic Implications.

The concept of oncocytoid renal cell carcinoma in patients who have survived neuroblastoma as a distinct biologic entity has been controversial since its original description in 1999. This is in part because similar oncocytoid renal cell carcinomas have been described in association with other pediatric cancers, and also because other renal cell carcinoma subtypes (such as MiT family translocation renal cell carcinoma) have been described in children who have survived neuroblastoma. We identified an index case of a child who survived medulloblastoma and developed multifocal bilateral oncocytoid renal cell carcinomas with morphology and immunophenotype compatible with eosinophilic solid and cystic renal cell carcinoma (ESC RCC) and demonstrated that both neoplasms harbored distinctive mutations in the TSC1/TSC2 genes. Remarkably, the child's remaining bilateral multifocal renal neoplasms completely responded to MTOR inhibitor therapy without need for further surgery. To confirm our hypothesis that oncocytoid renal cell carcinomas after childhood cancer represent ESC RCC, we obtained formalin-fixed paraffin-embedded tissue blocks from 2 previously published cases of oncocytoid renal cell carcinoma after neuroblastoma, confirmed that the morphology and immunophenotype was consistent with ESC RCC, and demonstrated that both cases harbored somatic TSC gene mutations. Both expressed markers previously associated with neoplasms harboring TSC gene mutations, glycoprotein nonmetastatic B, and cathepsin K. Of note, one of these patients had 2 ESC RCC which harbored distinctive TSC2 mutations, while the background kidney of the other patient had multiple small cysts lined by similar oncocytoid cells which showed loss of TSC2 protein. We then reviewed 3 of 4 cases from the original 1999 report of oncocytoid renal cell carcinomas after neuroblastoma, found that all 3 demonstrated morphology (including basophilic cytoplasmic stippling) that is characteristic of ESC RCC, showed that all 3 overexpressed glycoprotein nonmetastatic B, and showed that both cases with adequate material demonstrated loss of TSC2 protein and expressed cytokeratin 20 and cathepsin K by immunohistochemistry. In summary, "oncocytoid renal cell carcinomas after neuroblastoma" represent ESC RCC which are often multifocal in patients who have survived childhood cancer, likely representing an incompletely characterized tumor predisposition syndrome. MTOR-targeted therapy represents an effective therapeutic option for such patients to preserve functional nephrons.

Vascular Expression of Prostate-specific Membrane Antigen (PSMA) in MiTF Family Translocation Renal Cell Carcinoma and Related Neoplasms.

Multiple studies have demonstrated prostate-specific membrane antigen (PSMA) expression in the neo-vasculature of non-prostate tumors including clear cell renal cell carcinoma (ccRCC). However, PSMA expression in rare renal tumors including MiTF family translocation renal cell carcinoma has not been previously characterized. We examined PSMA expression by immunohistochemistry in a series of MiTF family translocation renal cell carcinomas as well as in several genetically related tumors including alveolar soft part sarcoma and PEComas with TFE3 rearrangements. PSMA expression was also studied in several cases of ccRCC and papillary RCC. Overall, PSMA immunohistochemistry was performed in 61 samples from 58 patients. Vascular PSMA expression was seen with the highest frequency in ccRCC [88% (14/16)] (38% focal, 50% diffuse). Translocation RCC (tRCC) demonstrated the second highest frequency of PSMA expression [71% (22/28)] (57% focal, 14% diffuse), followed by alveolar soft part sarcoma [50% (4/8)] (38% focal, 12% diffuse). No PSMA expression was seen in PEComas with TFE3 rearrangement (0/3) or papillary RCC (0/6). PSMA expression was only present in tumor-associated neo-vasculature. A patient with oligometastatic tRCC underwent 68 Ga-PSMA-11 PET imaging which detected multiple putative metastatic lesions not detected on conventional computed tomography imaging performed 2 weeks prior, supporting the potential utility of PSMA imaging in tRCC. These findings have potential implications for the utility of PSMA guided diagnostic and therapeutic agents in both common and uncommon renal cell carcinoma subtypes as well as genetically related mesenchymal neoplasms.

Renal Neoplasia Occurring in Patients With PTEN Hamartoma Tumor Syndrome : Clinicopathologic Study of 12 Renal Cell Carcinomas From 9 Patients and Association With Intrarenal "Lipomas".

The aim of this study was to assess the histopathologic spectrum of renal tumors in patients with PTEN hamartoma tumor syndrome (PHTS), with a specific focus on potential features predictive of the underlying syndrome. A multi-institutional study was conducted to obtain clinical and pathologic data on renal tumors arising in patients with PHTS, either diagnosed by germline mutational analysis or clinical criteria for Cowden syndrome. Histologic sections of the renal tumors were re-reviewed for classification. Twelve renal epithelial tumors from 9 patients were identified (4 males and 5 females, with a mean age of 41.8 y), 7 of whom carried germline PTEN mutations. All 12 renal epithelial tumors were renal cell carcinomas (RCCs): 5 were chromophobe RCCs, 4 papillary RCCs, and 3 RCC not otherwise specified. Pathologic stage distribution was: 7 (59%) pT1a, 2 (17%) pT1b, 1 (8%) pT2a, 1 (8%) pT2b, and 1 (8%) pT3a. World Health Organization/International Society of Urological Pathology (WHO/ISUP) histologic grade was applicable in 7 (54%) nonchromophobe tumors: 4 (57%) G2, 2 (29%) G3, and 1 (14%) G4. An unexpected histologic finding was the presence of 2 patients with incidental microscopic collections of intrarenal adipocytes that had no features of angiomyolipoma (and were negative with 2 sensitive PEComa markers: cathepsin-K and GPNMB); both were classified as lipoma/"lipomatous hamartomas." The average follow-up interval was 67.8 months (13 to 172 mo): 5 patients had no evidence of disease, 2 were lost to follow-up, 1 died of other (non-PHTS) causes (ie, prostate cancer), and 1 was alive with metastatic RCC to the lung (RCC not otherwise specified with rhabdoid differentiation). All tumors showed loss of nuclear PTEN staining by immunohistochemistry. Fumarate hydratase was retained and 2SC was negative in all papillary RCCs. CK7 was moderate-strong/diffuse positive in 4 of 5 chromophobe RCCs and in 3 of 4 papillary RCCs. Renal epithelial tumors associated with PHTS represent a heterogeneous group of RCCs, but classic chromophobe and papillary RCC are most common. The majority have a favorable clinical behavior as would be predicted by subtype. In contrast to other hereditary renal neoplasia syndromes, morphologic features of the RCCs do not allow identification of PHTS-associated neoplasia with any degree of specificity in the absence of clinical setting and/or prior history, but the presence of microscopic "lipomas" within the kidney may provide a clue in rare cases. Therefore, clinical suspicion and genetic counseling with germline testing remain necessary for identifying PHTS-associated RCC.

Ossifying Fibromyxoid Tumor of the Genitourinary Tract: Report of 4 Molecularly Confirmed Cases of a Diagnostic Pitfall.

Ossifying fibromyxoid tumors (OFMTs) are rare mesenchymal neoplasms which typically present in the superficial subcutaneous tissues and have not been reported to arise in visceral organs. We now report 4 molecularly confirmed cases of OFMT involving the genitourinary tract. All patients were males, ranging in age from 20 to 66 years (mean: 43 y). One case each arose in the kidney, ureter, perirenal soft tissue, and penis. All neoplasms demonstrated bland epithelioid to spindled cells set in a variably fibrous to fibromyxoid stroma, and only 1 had a peripheral shell of lamellar bone. All cases appeared well-circumscribed on gross/radiologic examination, though the primary renal neoplasm permeated between native renal tubules. By immunohistochemistry, S100 protein was negative in all 4 cases, while desmin was positive in 2 cases. In 2 cases, the Illumina TruSight RNA Fusion Panel demonstrated a PHF1::TFE3 and EP400::PHF1 fusion, respectively. In the remaining 2 cases, PHF1 gene rearrangement was confirmed by fluorescence in situ hybridization analysis. Due to unusual clinical presentation, lack of S100 positivity, and only occasional bone formation, the correct diagnosis was challenging in the absence of molecular testing. In summary, OFMT may rarely present primarily in the genitourinary tract. Given their nonspecific morphology and immunophenotype, molecular analysis is crucial to establish the correct diagnosis.

Nephrogenic rest vs immature teratoma associated with lumbosacral lipomyelomeningocele: a case report and review of the literature.

BACKGROUND: Lipomyelomeningoceles (LMMs) are subcutaneous lipomas with dural penetration that often present with spinal cord tethering and may lead to neurological deterioration if untreated. This report describes a rare case of an LMM associated with immature nephroblastic tissue, representing a nephrogenic rest (NR) or, less likely, an immature teratoma. CLINICAL PRESENTATION: An 8-day-old infant girl presented to the clinic with a sacral dimple. Imaging demonstrated a tethered spinal cord with low-lying conus medullaris and an LMM. A firm mass was noted in the subcutaneous lipoma. Detethering surgery and removal of the lipoma and mass were performed at the age of 6 months. Pathological examination identified the mass as cartilage, fat, and immature nephroblastic tissue consistent with NR tissue or, less likely, a teratoma with renal differentiation. CONCLUSION: This presentation of an LMM associated with an immature teratoma or NR poses a risk of malignant transformation in patients. As a result, careful surgical dissection, resection, and close clinical follow-up are recommended for these patients.

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.

Characterization of protein S-(2-succino)-cysteine (2SC) succination as a biomarker for fumarate hydratase-deficient renal cell carcinoma.

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is an aggressive, rare genetic disease affecting the kidney and other organ systems. We constructed a specialized multi-institutional cohort of 20 primary FH-deficient RCC cases with aims of characterizing a new commercially available antibody, S-(2-succino)-cysteine (2SC). Herein, we present our findings on the biomarker characterization and performance of 2SC expression by immunohistochemistry (IHC) in FH-deficient RCC and other common and rare RCC subtypes. Morphological assessment revealed characteristic cytomorphologic features and a majority (55%) of FH-deficient RCC had mixed architectural growth patterns. We observed predominantly diffuse and strong cytoplasmic staining with limited nuclear positivity for 2SC staining on IHC. Receiver operating characteristic curves (ROC) for 2SC identified the threshold IHC score (cutoff) as 90, with the sensitivity and specificity being 100% and 91%, respectively. The findings of the present study along with the prior evidence in literature encourage utilization of 2SC as a positive marker along with the loss of FH expression by anti-FH IHC staining as a negative marker, in clinical and/or pathologic scenarios when considering FH-deficient RCC in the differential diagnosis. FH-/2SC+ may serve as a comprehensive IHC panel in identifying such cases and excluding morphologically similar entities.

Characterization of Intercalated Cell Markers KIT and LINC01187 in Chromophobe Renal Cell Carcinoma and Other Renal Neoplasms.

Introduction. Chromophobe renal cell carcinoma (chromophobe RCC) is the third major subcategory of renal tumors after clear cell RCC and papillary RCC, accounting for approximately 5% of all RCC subtypes. Other oncocytic neoplasms seen commonly in surgical pathology practice include the eosinophilic variant of chromophobe RCC, renal oncocytoma, and low-grade oncocytic unclassified RCC. Methods. In our recent next-generation sequencing based study, we nominated a lineage-specific novel biomarker LINC01187 (long intergenic non-protein coding RNA 1187) which was found to be enriched in chromophobe RCC. Like KIT (cluster of differentiation 117; CD117), a clinically utilized chromophobe RCC related biomarker, LINC01187 is expressed in intercalated cells of the nephron. In this follow-up study, we performed KIT immunohistochemistry and LINC01187 RNA in situ hybridization (RNA-ISH) on a cohort of chromophobe RCC and other renal neoplasms, characterized the expression patterns, and quantified the expression signals of the two biomarkers in both primary and metastatic settings. Results. LINC01187, in comparison to KIT, exhibits stronger and more uniform expression within tumors while maintaining temporal and spatial consistency. LINC01187 also is devoid of intra-tumoral heterogeneous expression pattern, a phenomenon commonly noted with KIT. Conclusions. LINC01187 expression can augment the currently utilized KIT assay and help facilitate easy microscopic analyses in routine surgical pathology practice.