Pedram Argani

Background: Well-differentiated pancreatic neuroendocrine tumors (PanNETs) develop in ~80% of patients with multiple endocrine neoplasia type 1 (MEN1) and remain the leading cause of MEN1-related mortality. Whether MEN1-associated PanNETs display distinct clinicopathologic or prognostic characteristics compared with non-MEN1 PanNETs remains incompletely defined. Methods: We retrospectively reviewed clinical, pathological, and outcome data from 817 patients who underwent surgical resection for well-differentiated PanNETs, including 39 MEN1-associated and 778 non-MEN1 PanNETs, with a total of 7752 person-years of follow-up. Tumor characteristics, stage, and survival outcomes were compared between two groups. Results: MEN1-associated PanNETs represented 4.8% of the cohort and included both functional and non-functional tumors. Patients with MEN1 more frequently had functional tumors, with insulinomas and gastrinomas predominating. Patients with MEN1 were significantly younger at surgery. Tumor size and grade distribution were similar between the two groups, although tumors >2 cm were more prevalent in patients with MEN1. MEN1-associated tumors demonstrated significantly lower rates of lymphovascular and perineural invasion, but similar rates of lymph node metastasis and stage III disease when only lymph node metastases attributable to a pancreatic primary were included. Long-term overall survival, disease-specific survival, and cumulative incidence of relapses did not differ significantly between MEN1 and non-MEN1 patients. Conclusions: In this retrospective cohort of surgically resected, well-differentiated PanNETs, MEN1-associated tumors exhibited similar histologic grade and tumor size distributions to non-MEN1 PanNETs. MEN1 status was associated with a higher prevalence of functional tumors and lymph node metastases, but lower rates of vascular and perineural invasion. Despite these features, no statistically significant differences in long-term overall survival, disease-specific survival, or cumulative incidence of relapse were observed between surgically resected patients with and without MEN1, though the study was underpowered to detect modest differences.

Synovial sarcoma is a rare malignant mesenchymal neoplasm that typically occurs in soft tissue sites, and the kidney is an uncommon primary location. Previous studies of primary renal synovial sarcoma are limited by small sample sizes, and our understanding remains incomplete. Here, we present the largest multi-institutional case series to date of primary renal synovial sarcoma, with a focus on novel and molecular findings. A total of 70 cases were contributed by multiple institutions. Comprehensive clinical and histopathologic data were collected and analyzed. The mean patient age was 40 years, with a male-to-female ratio of 1.9:1. The most common presenting signs and symptoms were pain and hematuria. The mean tumor size was 11.6 cm (range: 2.3 to 26 cm), with frequent cystic change and necrosis. The mean follow-up was 29 months (range: 2 to 129 mo), and the rates of metastasis, recurrence, and death due to disease were 62.7%, 33.3%, and 50.0%, respectively. Histologically, 56.1% were monophasic synovial sarcoma, 15.1% were biphasic, and 28.8% were poorly differentiated or showed round cell features. Molecularly, SS18::SSX2 fusion was detected in the majority of cases assessed (n=19), followed by SS18::SSX1 fusion (n=6) and a rare SS18::NEDD4 fusion (n=1). Given the morphologic and immunohistochemical overlaps with many other neoplasms, accurate diagnosis with preferably molecular techniques is crucial for appropriate prognostication and treatment of this aggressive tumor.

Background: Well-differentiated pancreatic neuroendocrine tumors (PanNETs) develop in ~80% of patients with multiple endocrine neoplasia type 1 (MEN1) and remain the leading cause of MEN1-related mortality. Whether MEN1-associated PanNETs display distinct clinicopathologic or prognostic characteristics compared with sporadic PanNETs remains incompletely defined. Methods: We retrospectively reviewed clinical, pathological, and outcome data from 817 patients who underwent surgical resection for well-differentiated PanNETs, including 39 MEN1-associated and 778 non-MEN1 tumors, with a total of 7,752 person-years of follow-up. Tumor characteristics, stage, and survival outcomes were compared between two groups. Results: MEN1-associated PanNETs represented 4.8% of the cohort and included both functional and non-functional tumors. Patients with MEN1 more frequently had functional tumors, with insulinomas and gastrinomas pre-dominating. Patients with MEN1 were significantly younger at surgery. Tumor size and grade distribution were similar between two groups, although tumors >2 cm were more prevalent in patients with MEN1. MEN1-associated tumors demonstrated significantly lower rates of lymphovascular and perineural invasion, but similar rates of lymph node metastasis and stage III disease when only lymph node metastases attributa-ble to a pancreatic primary were included. Long-term overall survival, disease-specific survival, and cumula-tive incidence of relapses did not differ significantly between MEN1 and non-MEN1 patients. Conclusions: Surgically resected MEN1-associated PanNETs show comparable histologic grade and tumor size to sporadic PanNETs. MEN1 is associated with more functional tumors and lymph node metastases, but less vascu-lar/perineural invasion. Despite these features, long-term overall survival, disease-specific survival and cu-mulative incidence of relapse are comparable between surgically resected patients with and without MEN1.

MEIS1::NCOA2 is a recurrent gene fusion that has been predominantly identified in primitive sarcomas arising within the genitourinary and gynecological tracts. Since its initial description in 2018, an increasing number of cases have been reported, further defining the clinicopathological spectrum of this entity. We report a case of an MEIS1::NCOA2 ‐rearranged low‐grade myxoid spindle cell neoplasm arising in the vulva of a 31‐year‐old female, presenting as a polypoid mass. Histologically, the lesion was composed predominantly of hypocellular spindle‐cell areas, with focal hypercellular and focal myxoid regions. Immunohistochemistry was nonspecific, demonstrating weak, variable expression of estrogen receptor (ER) and focal positivity for desmin, WT1, smooth muscle actin, and h‐caldesmon. RNA‐based next‐generation sequencing identified a MEIS1::NCOA2 fusion transcript, which was subsequently confirmed by fluorescence in situ hybridization (FISH), demonstrating NCOA2 rearrangement. This case demonstrates remarkably bland, low‐grade cytological features and appears to represent the least cytologically atypical example of this neoplasm described to date. As such, it further extends the known morphological spectrum and contributes to our evolving understanding of this entity. Given the deceptively benign histological appearance and the absence of overt sarcomatous features, we favor the designation of “ MEIS1::NCOA2‐ rearranged low‐grade myxoid spindle cell neoplasm” rather than sarcoma.

Renal well-differentiated neuroendocrine tumors (RenNETs) are rare primary renal neoplasms with enigmatic histogenesis. To define the molecular features of RenNETs and clarify their relationship to neuroendocrine tumors (NETs) from other sites, we performed whole-exome DNA sequencing and transcriptomic profiling on six RenNETs. In one case, adjacent non-neuroendocrine cystic epithelium and a regional lymph node metastasis were independently analyzed. RenNETs demonstrated a low-to-intermediate tumor mutational burden and recurrent copy number alterations, including losses involving chromosomes 3, 11, and 18 and gains involving chromosomes 1, 2, 8, and 14, partially overlapping those reported in gastroenteropancreatic NETs, in the absence of alterations in canonical NET-associated driver genes. RNA sequencing revealed marked upregulation of genes involved in neuroendocrine differentiation, peptide processing, and pancreatic beta cell function, accompanied by loss of renal lineage markers, indicating a neuroendocrine transcriptional program distinct from other primary renal neoplasms. RenNETs showed heterogeneous activation of hormone related transcriptional programs, rather than conforming to a discrete EC-cell or L-cell signature. Immunohistochemistry confirmed strong membranous expression of somatostatin receptor 2A (SSTR2A) in all cases, supporting established imaging and therapeutic paradigms used for NETs. Notably, two RenNETs were associated with adjacent CDX2-positive epithelial-lined cysts with intestinal differentiation. In one case, a shared somatic mutation was identified across the epithelial cyst, the adjacent RenNET, and a nodal metastasis, providing genetic evidence of a common clonal origin and implicating gastrointestinal-type epithelium as a potential precursor lesion in a subset of cases. Features supporting teratomatous origin, such as chromosome 12p gains or other germ cell tumor elements, were not identified. Together, these findings demonstrate that RenNETs exhibit convergent transcriptomic and phenotypic neuroendocrine programs, along with partial copy number overlap, with well-differentiated gastroenteropancreatic NETs, and support a model in which RenNETs may arise from developmentally displaced or aberrantly differentiated epithelial precursors with gastrointestinal-type differentiation, although this hypothesis requires validation in larger cohorts.

So-called hybrid oncocytic tumor (HOT) is the renal neoplasm most commonly associated with the germline folliculin ( FLCN ) mutations that define Birt-Hogg-Dubé syndrome. However, the spectrum of renal epithelial neoplasms associated with FLCN gene mutations has recently expanded to include neoplasms with somatic FLCN mutations and those with variant morphology. Some of these FLCN -mutated neoplasms overlap morphologically and immunohistochemically with TSC/MTOR -mutated and TFE3/TFEB fusion renal cell carcinomas, which makes sense given their overlapping genetic pathways. One morphology that has been reported in 1 to 2 cases each across multiple studies is that of a “histiocyte-rich” renal epithelial neoplasm, characterized by acinar spaces lined by neoplastic oncocytic epithelial cells variably distended by luminal histiocytes. An unanswered question is how frequently this morphology is associated with FLCN mutations. We identified 11 previously unreported cases of histiocyte-rich renal epithelial neoplasms and performed immunohistochemistry and next-generation sequencing. Five out of 11 cases (45%) demonstrated FLCN mutations, including at least 3 cases with evidence supporting occult Birt-Hogg-Dubé syndrome. All FLCN- mutated neoplasms were diffusely immunoreactive for glycoprotein nonmetastatic B (GPNMB), but so were 3 of the 6 morphologically similar cases in which FLCN mutations were not detected. The 2 syndromic cases with adequate surrounding kidney for evaluation demonstrated GPNMB-positive cysts lined by cells with similar cytology to that of the neoplasms, possibly representing precursor lesions. In summary, histiocyte-rich renal epithelial neoplasm is a morphologic pattern that is strongly but not invariably associated with FLCN mutations. Recognition of this pattern is helpful in that it may provide the first clue to the presence of occult Birt-Hogg-Dubé syndrome.

Purpose:Fusion-positive myoepithelial tumors (MET) are clinicopathologically heterogeneous and variably termed mixed tumors and myoepithelial carcinomas. As FET-rearranged METs lack ductal/epithelial differentiation, we test whether FET-rearranged METs are epigenetically distinct from adnexal PLAG1-rearranged METs, which we hypothesize to be analogues of salivary gland METs.Experimental Design:DNA methylation profiling from a multi-institutional cohort of 52 fusion-positive skin, soft-tissue, and bone MET cases was performed and compared with diverse tumor types, including salivary METs. The MET subgroups harbored EWSR1::KLF15, EWSR1/FUS::KLF17, EWSR1::PBX1, EWSR1::PBX3, EWSR1/FUS::POU5F1, SS18::POU5F1, EWSR1::ZNF444, and PLAG1 rearrangements. Pooled clinicopathologic and outcome analysis with new and published cases (total 185) was performed.Results:The MET subgroups showed significant heterogeneity in age, site, and histology. Specifically, EWSR1::KLF15 METs affected predominantly young children (<5 years); EWSR1::PBX1/PBX3 METs were enriched in skin/bone; and EWSR1/FUS::POU5F1, SS18::POU5F1, and EWSR1::KLF15 METs tended to display malignant histology. Conversely, PLAG1-rearranged tumors were predominantly benign, arising in older adults and located in the skin. DNA methylation profiling revealed that FET-rearranged METs were epigenetically related to SS18::POU5F1 METs and FET::NFATC2 sarcomas but entirely distinct from PLAG1-rearranged adnexal and salivary METs. Histologic features were correlated with the degree of genome-wide copy-number variation. The median disease-specific survival was shortest in SS18::POU5F1 (31 months), EWSR1::PBX3 (38 months), and EWSR1::KLF15 (45 months) METs. On multivariate analysis, age <25 years was a significant predictor of worse progression-free survival.Conclusions:FET-rearranged METs are epigenetically unrelated to cutaneous and salivary gland METs, and their malignant counterparts are best classified as sarcomas rather than carcinomas.

Suppl. Figure S2. Unsupervised hierarchical clustering heatmap of DNA methylation beta values (top 5000 by variance) across selected tumor types. Shown are the genes corresponding to the top 100 cpg sites.

Suppl. Table S1. Clinicopathologic features of new and published cases of EWSR1/FUS::POU5F1-rearranged MET Suppl. Table S2. Clinicopathologic features of new and published cases of SS18::PBX1/3-rearranged MET Suppl. Table S3. Clinicopathologic features of new and published cases of EWSR1::KLF15-rearranged MET Suppl. Table S4. Clinicopathologic features of new and published cases of EWSR1/FUS::KLF17-rearranged MET Suppl. Table S5. Clinicopathologic features of new and published cases of EWSR1::ZNF444-rearranged MET Suppl. Table S6. Clinicopathologic features of new and published cases of EWSR1::PBX1/3-rearranged MET Suppl. Table S7. Clinicopathologic features of new and published cases of PLAG1-altered MET Suppl. Table S8. Clinicopathologic summary of fusion-positive myoepithelial tumors (new and published cases) Suppl. Table S9. Significant differentially methylated regions: ENT and cutaneous PLAG1-rearranged vs FET-rearranged myoepithelial tumors Suppl. Table S10. Univariate and Multivariate Survival Analysis for Disease-specific Survival (DSS) and Progression-free Survival (PFS)