Genomic analysis of spermatocytic tumors demonstrates recurrent molecular alterations in cases with malignant clinical behavior.

Spermatocytic tumor (ST) is a rare type of germ cell tumor that occurs exclusively in the postpubertal testis and typically affects elderly men. Most STs are benign, but rare cases exhibit aggressive clinical behavior, often in association with transition to sarcomatoid histology. Limited molecular analyses have been performed on STs; therefore, their genomic and epigenomic features remain incompletely described. Twenty-seven samples from 25 individual patients were analyzed with a combination of DNA sequencing panels, genomic methylation profiling, SNP array, isochromosome (12p) [i(12p)] FISH, and immunohistochemistry. The series included five metastasizing tumors (three with sarcomatoid transformation, one anaplastic, and one conventional) and 20 non-metastasizing tumors (14 anaplastic and six conventional). Anaplastic tumors comprised a monomorphic population of intermediate-sized neoplastic cells, as previously described. Multiomic analyses demonstrated that there were two genomic subgroups of STs: one with diploid genomes and hotspot RAS/RAF variants and the other with global ploidy shift and absence of recurrent mutations. Relative gain of chromosome 9 was a consistent finding in both subgroups. A comparison of metastasizing and non-metastasizing cases demonstrated that aggressive behavior was associated with the acquisition of pathogenic TP53 mutations and/or relative gains of 12p/i(12p). In cases with sarcomatoid transformation, TP53 mutations seem to underlie the transition to sarcomatoid histology. Genomic methylation analysis demonstrated that aggressive cases with gains of 12p cluster closer to pure seminomas than to STs without gains of 12p. In conclusion, STs include two genomic subgroups, characterized by global ploidy shifts without recurrent mutations and diploid genomes with RAS/RAF hotspot mutations, respectively. Biologic progression was associated with relative gains of 12p and TP53 mutations. The findings in STs with relative gains of 12p suggest that they may exhibit biologic characteristics akin to those seen in germ cell neoplasia in situ-related germ cell tumors rather than non-germ cell neoplasia in situ-derived STs. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Columnar Cell Thyroid Carcinoma: A Heterogeneous Entity Demonstrating Overlap Between Papillary Thyroid Carcinoma and Follicular Neoplasms.

BACKGROUND: Columnar cell papillary thyroid carcinoma (CC-PTC) is a morphologic subtype of papillary thyroid carcinoma with a variable prognosis. It is characterized by neoplastic thyroid follicular-derived cells with pseudostratified columnar morphology arranged in papillary or follicular structures with supranuclear or subnuclear vacuoles. The molecular profile of this subtype has only recently come under scrutiny, with mixed results. The aim of this study is to further explore the morphologic, immunohistochemical, and genetic profile of CC-PTC, as well as to correlate these features with clinical outcomes. METHODS: CC-PTC cases were identified from 3 institutions. Immunohistochemistry (ER, CDX2) and molecular testing (DNA and RNA sequencing) were performed. Clinicopathologic parameters and patient outcomes were recorded. RESULTS: Twelve cases (2006-2023) were identified, all in adults (age 45-91). Two presented with disease outside the thyroid gland (neck and mediastinum) and two presented with distant metastasis. Four were high-grade differentiated thyroid carcinomas (necrosis or mitoses), one of which died of disease. Four were noninvasive or minimally invasive, one of which locally recurred. Three patients had lymph node metastases. ER and CDX2 were positive in 73% and 50%, respectively. Pathogenic mutations were found in TERT promoter (n = 3), RAS (n = 2), ATM, NOTCH1, APC, and ESR1, along with cases bearing AGK::BRAF fusion (n = 1), BRAF VE1 expression (n = 1), and NF2 loss (n = 1). CONCLUSIONS: This study represents the largest molecularly defined cohort of non-oncocytic thyroid carcinomas with columnar cell morphology. These tumors represent a genetically and behaviorally heterogeneous group of neoplasms, some of which have RAS-like or follicular neoplasm-like genetics, some of which have BRAF-p.V600E-like or classic papillary thyroid carcinoma-like genetics, and some of which remain unclear. Noninvasive or minimally invasive tumors showed an indolent course compared to those with angioinvasion, gross extrathyroidal growth, or high-grade morphology. Consideration could be given to reclassification of this neoplasm outside of the subtyping of papillary thyroid carcinoma in light of its genetic diversity, distinct morphology, and clinical behavior more closely aligned with follicular thyroid neoplasms.

Detection of RAS p.Q61R by Immunohistochemistry in Practice: A Clinicopathologic Study of 217 Thyroid Nodules with Molecular Correlates.

RAS p.Q61R is the most prevalent hot-spot mutation in RAS and RAS-like mutated thyroid nodules. A few studies evaluated RAS p.Q61R by immunohistochemistry (RASQ61R-IHC). We performed a retrospective study of an institutional cohort of 150 patients with 217 thyroid lesions tested for RASQ61R-IHC, including clinical, cytologic and molecular data. RASQ61R-IHC was performed on 217 nodules (18% positive, 80% negative, and 2% equivocal). RAS p.Q61R was identified in 76% (n = 42), followed by RAS p.Q61K (15%; n = 8), and RAS p.G13R (5%; n = 3). NRAS p.Q61R isoform was the most common (44%; n = 15), followed by NRAS p.Q61K (17%; n = 6), KRAS p.Q61R (12%; n = 4), HRAS p.Q61R (12%; n = 4), HRAS p.Q61K (6%; n = 2), HRAS p.G13R (6%; n = 2), and NRAS p.G13R (3%; n = 1). RASQ61R-IHC was positive in 47% of noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP; 17/36), 22% of follicular thyroid carcinomas (FTC; 5/23), 10% of follicular thyroid adenomas (FTA; 4/40), and 8% of papillary thyroid carcinomas (PTC; 9/112). Of PTC studied (n = 112), invasive encapsulated follicular variant (IEFVPTC; n = 16) was the only subtype with positive RASQ61R-IHC (56%; 9/16). Overall, 31% of RAS-mutated nodules were carcinomas (17/54); and of the carcinomas, 94% (16/17) were low-risk per American Thyroid Associated (ATA) criteria, with only a single case (6%; 1/17) considered ATA high-risk. No RAS-mutated tumors recurred, and none showed local or distant metastasis (with a follow-up of 0-10 months). We found that most RAS-mutated tumors are low-grade neoplasms. RASQ61R-IHC is a quick, cost-effective, and reliable way to detect RAS p.Q61R in follicular-patterned thyroid neoplasia and, when malignant, guide surveillance.

Malignant Epithelioid Mesenchymal Neoplasm with FUS::CREM Gene Fusion Arising in the Tongue: A Case Report Detailing Clinicopathological, Imaging, and Molecular Features.

FUS::CREM fusion is a distinct primary driver in rare neoplasms of the head and neck and other anatomic sites. Herein, we describe the clinicopathological, imaging, and molecular features of a malignant epithelioid mesenchymal neoplasm harboring FUS::CREM fusion, arising in the tongue of a 46-year-old male. Clinically, the patient presented with a left upper neck mass. Imaging revealed a 4.0 cm mass at the left base of tongue. Histologically, the tumor consisted of sheets of loosely cohesive, small round to ovoid cells with moderate cytoplasm, small nuclei with coarse chromatin, frequent nuclear pseudoinclusions, and dense peripheral lymphoplasmacytic and histiocytic infiltrates. Malignant features, including tumor necrosis, perineural invasion, and increased mitotic activity were observed; however, lymphovascular invasion was absent with no evidence metastatic disease in the examined lymph nodes. A comprehensive panel of immunohistochemical stains showed positivity for synaptophysin and ALK, with negative results for all other markers. RNA-based next-generation sequencing using anchored multiplex polymerase chain reaction (PCR) was performed and detected FUS::CREM fusion gene. The patient was treated by excision and postsurgical chemoradiation with no evidence of recurrence after four months. Additional cases supported by comprehensive clinical data collected over an extended period are necessary to precisely characterize epithelioid mesenchymal neoplasms harboring FUS::CREM fusion in the head and neck.

Sinonasal (Schneiderian) Tumors in the Temporal Bone: Case Series and Systematic Review.

BACKGROUND: Neoplasms derived from the sinonasal epithelium are a rare finding in the temporal bone, and their origins are controversial. PURPOSE: To review the characteristics of sinonasal epithelial (previously known as Schneiderian) tumors occurring in the temporal bone. DATA SOURCE: This was a 2-center case series and systematic review of MEDLINE, EMBASE, and the Web of Science through May 2021. STUDY SELECTION: Patients with clinicopathologic evidence of temporal bone involvement by neoplasms of sinonasal epithelial origin were selected, with or without a history of prior primary sinonasal epithelial tumors. DATA ANALYSIS: Clinical, radiologic, and pathologic data were extracted. DATA SYNTHESIS: The systematic review included 56 studies and our 8 unpublished cases, totaling 76 cases of papillomas or squamous cell carcinomas in the temporal bone. Of these, 51% occurred secondary to sinonasal tumors, and 49% occurred primarily. Secondary tumors were usually metachronous (77%), with a median delay of 1 year from sinonasal-to-temporal bone tumor diagnosis. Most cases were unilateral (90%); bilateral temporal bone involvement occurred only as secondary ("trilateral") tumors. Unilateral secondary tumors had ipsilateral (81%) or bilateral (19%) sinonasal counterparts. Secondary tumors were more likely to be malignant (OR, 6.7, P < .001). LIMITATIONS: The review was based on case reports and small case series, which are subject to reporting bias. CONCLUSIONS: The observed tumor patterns support the hypothesis that the Eustachian tube facilitates the spread of sinonasal epithelium-derived neoplasms from the sinonasal cavity to the temporal bone. Transtubal spread of sinonasal epithelium-derived neoplasms should be considered among the rare causes of middle ear masses.

FGFR Alterations in Thyroid Carcinoma: A Novel Class of Primary Drivers with Significant Therapeutic Implications and Secondary Molecular Events Potentially Mediating Resistance in Thyroid Malignancy.

Background: Diagnostic classification of thyroid malignancy is primarily accomplished through examination of histomorphological features and may be substantiated and clarified by molecular data. Individual molecular drivers show relatively robust and specific associations with histological subtypes of thyroid malignancy, including BRAF sequence variants and kinase gene fusions in papillary thyroid carcinoma, predominantly RAS variants in follicular-patterned neoplasia, and additional "late" mutations affecting TERT promoter, TP53, and the PI3K/AKT/PTEN pathway in high-grade malignancies. Given the oncogenic role of FGFR, particularly FGFR1-3, the goal of this study was to explore the role of FGFR in thyroid carcinoma biology. Methods: We completed a multicenter retrospective observational study for thyroid carcinomas with pathogenic alterations in the FGFR gene family. We performed this study by querying the molecular data accumulated for thyroid carcinomas from each center. Results: Overall, 5030 sequenced thyroid malignancies were reviewed, yielding 17 tumors with FGFR alterations, including 11 where FGFR was the primary molecular driver and 6 where FGFR was a secondary pathogenic alteration, with a subset for which there was available clinical follow-up data. Of the 11 carcinomas with an FGFR driver, 9 were gene fusions involving FGFR2:VCL (4 tumors), TG::FGFR1 (3 tumors), FGFR2::CIT, and FGFR2::SHTN1, and the remaining 2 were driven by FGFR1 amplification. In the 6 tumors where a canonical driver of thyroid neoplasia was present (5 cases) or no clear primary driver was detected (1 case), sequencing detected secondary FGFR2 p.W290C, p.Y375C, and p.N549K, as well as FGFR1 p.N546K in the respective tyrosine kinase domains, some at subclonal variant allele frequencies. Conclusions: This study presents the first description of a collection of thyroid carcinomas grouped by primary driver alterations in FGFR, as well as a cohort of thyroid tumors with secondary alterations that potentially lead to tumor progression or resistance to targeted therapy. Given the availability of small molecular inhibitors targeting oncogenic FGFR, this study emphasizes the significant implications for patients from identification of FGFR alterations as they are currently under-recognized in the literature and, most importantly, have potential novel treatment options.

Molecular Alterations and Comprehensive Clinical Management of Oncocytic Thyroid Carcinoma: A Review and Multidisciplinary 2023 Update.

Importance: Oncocytic (Hürthle cell) thyroid carcinoma is a follicular cell-derived neoplasm that accounts for approximately 5% of all thyroid cancers. Until recently, it was categorized as a follicular thyroid carcinoma, and its management was standardized with that of other differentiated thyroid carcinomas. In 2022, given an improved understanding of the unique molecular profile and clinical behavior of oncocytic thyroid carcinoma, the World Health Organization reclassified oncocytic thyroid carcinoma as distinct from follicular thyroid carcinoma. The International Thyroid Oncology Group and the American Head and Neck Society then collaborated to review the existing evidence on oncocytic thyroid carcinoma, from diagnosis through clinical management and follow-up surveillance. Observations: Given that oncocytic thyroid carcinoma was previously classified as a subtype of follicular thyroid carcinoma, it was clinically studied in that context. However, due to its low prevalence and previous classification schema, there are few studies that have specifically evaluated oncocytic thyroid carcinoma. Recent data indicate that oncocytic thyroid carcinoma is a distinct class of malignant thyroid tumor with a group of distinct genetic alterations and clinicopathologic features. Oncocytic thyroid carcinoma displays higher rates of somatic gene variants and genomic chromosomal loss of heterozygosity than do other thyroid cancers, and it harbors unique mitochondrial DNA variations. Clinically, oncocytic thyroid carcinoma is more likely to have locoregional (lymph node) metastases than is follicular thyroid carcinoma-with which it was formerly classified-and it develops distant metastases more frequently than papillary thyroid carcinoma. In addition, oncocytic thyroid carcinoma rarely absorbs radioiodine. Conclusions and Relevance: The findings of this review suggest that the distinct clinical presentation of oncocytic thyroid carcinoma, including its metastatic behavior and its reduced avidity to radioiodine therapy, warrants a tailored disease management approach. The reclassification of oncocytic thyroid carcinoma by the World Health Organization is an important milestone toward developing a specific and comprehensive clinical management for oncocytic thyroid carcinoma that considers its distinct characteristics.