Adrenal tumors in patients with neuroendocrine neoplasms.

PURPOSE: To study the prevalence of primary adrenal tumors and adrenal metastases in patients with neuroendocrine neoplasms (NENs) and describe these in detail. NENs can be further divided into neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC). METHODS: A review of medical files was conducted for all patients who underwent a 68Gallium-DOTATOC-PET/CT during 2010-2023 or adrenalectomy during 1999-2023 at the Karolinska University Hospital. RESULTS: In total, 68Gallium-DOTATOC-PET/CT was performed on 1750 individuals with NEN, among whom 12 (0.69%) had adrenal tumors. Of these, 9 (0.51%) were NEN metastases. Out of 1072 adrenalectomies, 4 (0.37%) showed evidence of NEN metastases. Thus, 16 patients with NEN exhibited adrenal tumors. The adrenal tumors were found on average 5 years after the NEN diagnosis and 19% of the adrenal tumors with simultaneous NEN were benign. Few had all adrenal hormones measured. None had an adrenal insufficiency nor an adrenal biopsy. Another synchronous metastasis was found in 69% at the time of the adrenal tumor discovery. During the median 2-year follow-up, 38% of the subjects had deceased (with the exclusion of individuals presenting supposedly benign adrenal tumors 31%) all due to tumor complications. A comparison between individuals identified through 68Gallium-DOTATOC-PET/CT and those who underwent adrenalectomy revealed a higher prevalence of NETs in the former group and NECs in the latter group. CONCLUSION: Adrenal primary tumors and adrenal metastases are infrequent occurrences in patients with NEN. Most cases involved the presence of NEN metastasis upon the initial discovery of adrenal tumors. The overall prognosis was found to be favorable.

Atrophic changes in thyroid tumors are strong indicators of underlying DICER1 mutations: a bi-institutional genotype-phenotype correlation study.

Somatic and biallelic DICER1 mutations are reported in subsets of thyroid tumors, supporting the role of this gene in thyroid tumor development. As recent studies have brought attention to macrofollicular patterns, atrophic changes, and papillary structures as being associated with DICER1 mutations, we sought to explore these observations in a bi-institutional cohort. A total of 61 thyroid lesions (54 tumors and 7 cases of thyroid follicular nodular disease; TFND), including 26 DICER1 mutated and 35 DICER1 wildtype controls were subjected to histological re-investigation and clinical follow-up. DICER1-mutated lesions showed a statistically significant association with younger age at surgery (29.2 ± 12.5 versus 51.3 ± 18.8, p = 0.0001), a predominant macrofollicular growth pattern (20/26 mutated cases versus 18/35 wildtype; p = 0.01) and atrophic changes (20/26 mutated cases versus 2/35 wildtype; p = 0.0001). Similar results were obtained when excluding TFND cases. We also present clinical and histological triaging criteria for DICER1 sequencing of thyroid lesions, which led to the identification of DICER1 variants in 16 out of 26 cases (62%) when followed. Among these, 3 out of 12 cases with available data were found to carry a constitutional DICER1 mutation. This observation suggests that the majority of DICER1 mutations are somatic-however implies that sequencing of constitutional tissues could be clinically motivated. We conclude that DICER1 mutations are amassed in younger patients with macrofollicular-patterned tumors and, most strikingly, atrophic changes. Given the rate of constitutional involvement, our findings could be of clinical value, allowing the pathologist to triage cases for genetic testing based on histological findings.

Novel Insights in the Genomics of Anaplastic Thyroid Carcinoma: A Role for Cyclin-Dependent Kinase Inhibition?

Anaplastic thyroid carcinoma (ATC) stands as a rare but extraordinarily lethal tumor, marked by its limited treatment options [...].

Adrenal and periadrenal schwannoma: histological, molecular and clinical characterization of an institutional case series.

PURPOSE: Adrenal schwannoma (AS) and periadrenal schwannoma (PAS) are exceedingly rare Schwann cell tumors that develop from the adrenal medulla and periadrenal peripheral nerves respectively. The underlying genetic events are elusive. METHODS: We searched our institutional database for AS/PAS cases and reviewed the histology and clinical outcome. Comprehensive molecular work-up was performed. RESULTS: We found reports of 4 AS/PAS cases diagnosed between 1992 and 2022 among the 1248 adrenal lesions submitted for histopathology during the same time period (0.32%). Two patients were male, two were female, and the age span was 59-80 years. Median size was 70 mm (range 50-100 mm), and from a radiology perspective, the lesions were initially suspected of malignant lesions originating from either adrenals or kidneys. Hormonal analyses were normal in all cases. Histologically, three cases were annotated as cellular AS or PAS, and one case was annotated as microcystic AS. Molecular characterization using focused next-generation sequencing did not identify SMARCB1 or NF2 mutations, alterations previously associated to schwannoma at other anatomical sites. The postoperative period was without complications for all patients, and follow-up did not show any signs of relapse or metastatic disease. CONCLUSION: AS/PAS are rare neoplasms that are most often benign, and the molecular etiology is most likely not related to mutations in established schwannoma-related genes. Since these tumors may be misinterpreted as malignant, knowledge of this entity is essential for radiologists, endocrinologists, surgeons and pathologists.

[Adrenohepatic fusion - an unknown but not uncommon phenomenon of clinical importance]. / Adrenohepatisk fusion ­ ett okänt fenomen med klinisk betydelse.

Adrenohepatic fusion (AHF) is a union of the right adrenal gland and the liver with intermingling of parenchymal adrenal and liver cells. The phenomenon can be of clinical importance when evaluating patients with adrenal tumors. Using conventional imaging techniques such as computed tomography, a benign adrenal adenoma developing in an adrenohepatic fusion may mimic an invasive hepatocellular carcinoma or adrenal cortical carcinoma. This study presents a comprehensive review of the literature and shows a prevalence of 5.6 percent in autopsy studies. Moreover, 19 patients with adrenal masses in AHF are presented together with their clinical data.

Immunohistochemical characterization of a steroid-secreting oncocytic adrenal carcinoma responsible for paraneoplastic hyperparathyroidism.

We report a unique case of a 44-year-old man with paraneoplastic hyperparathyroidism due to an oncocytic adrenocortical carcinoma (stage pT3N0R0M0, ENSAT 2 with a 4% Ki-67). Paraneoplastic hyperparathyroidism was associated with mild adrenocorticotropic hormone (ACTH)-independent hypercortisolism and increased estradiol secretion responsible for gynecomastia and hypogonadism. Biological investigations performed in blood samples from peripheral and adrenal veins revealed that the tumor secreted parathyroid hormone (PTH) and estradiol. Ectopic PTH secretion was confirmed by abnormally high expression of PTH mRNA and clusters of PTH immunoreactive cells in the tumor tissue. Double-immunochemistry studies and analysis of contiguous slides for the expression of PTH and steroidogenic markers (scavenger receptor class B type 1 [SRB1], 3ß-hydroxysteroid dehydrogenase [3ß-HSD], and aromatase) were performed. The results suggested the presence of two tumor cells subtypes with large cells with voluminous nuclei producing only PTH and that were distinct from steroid-producing cells.

Digital droplet PCR TERT promoter mutational screening in fine needle aspiration cytology of thyroid lesions: A highly specific technique for pre-operative identification of high-risk cases.

BACKGROUND: Despite the advent of comprehensive molecular testing in surgical pathology, most centers still rely on the morphological assessment of fine-needle aspiration cytology (FNAC) to triage patients with thyroid nodules for surgery. Subsets of patients could benefit from the inclusion of molecular testing to increase the diagnostic and/or prognostic properties of the cytology analysis, including the assessment of TERT promoter mutations, an event coupled with thyroid malignancy, and poor prognosis. METHODS: In this prospective study, preoperative FNAC material from 65 cases was assessed for TERT promoter hotspot mutations C228T and C250T using the digital droplet PCR (ddPCR) technique on frozen pellets and re-evaluated postoperatively. RESULTS: Our cohort consisted of 15 B-III (23%), 26 B-IV (40%), 1 B-V (2%), and 23 (35%) B-VI lesions according to the Bethesda System for Reporting Thyroid Cytopathology. TERT promoter mutations were detected in 7 cases; 4 papillary thyroid carcinomas (all with preoperative B-VI status), two follicular thyroid carcinomas (one B-IV and one B-V status), and one poorly differentiated thyroid carcinoma (with B-VI status). All mutated cases were verified by mutational analysis of tumor tissue derived from postoperative formalin-fixed paraffin-embedded tissue, while all cases identified as wild-type on FNAC remained wild-type postoperatively. Moreover, the occurrence of a TERT promoter mutation was significantly associated with malignant disease and higher Ki-67 proliferation indices. CONCLUSION: In the present cohort, we found that ddPCR is a highly specific method for detecting high-risk TERT promoter mutations on thyroid FNAC material that could guide different surgical approaches in subsets of indeterminate lesions if reproduced in larger materials.

TOP2A Expression in Pheochromocytoma and Abdominal Paraganglioma: a Marker of Poor Clinical Outcome?

Pheochromocytoma and abdominal paraganglioma (PPGL) are rare neuroendocrine tumors originating from chromaffin cells. Even though only 10-15% of the tumors metastasize, all PPGLs are considered potentially malignant. Topoisomerase 2A (TOP2A) is a protein involved in cell proliferation and has been found to be over-expressed in metastatic PPGL. To provide support whether TOP2A could serve as a prognostic marker, 88 PPGLs (of which 8 metastatic/relapsing) and 10 normal adrenal gland samples were assessed for TOP2A mRNA expression using quantitative real-time PCR (qRT-PCR) and TOP2A immunohistochemistry. Comparisons to clinical parameters connected to metastatic behavior were made, and The Cancer Genome Atlas was used for validation of the results. A significant association between high TOP2A mRNA expression in primary PPGL and subsequent metastatic events (p = 0.008) was found, as well as to specific histological features and clinical parameters connected to metastatic behavior and mutations in SDHB. TOP2A immunoreactivity was calculated as an index of positive nuclei divided by the total amount of nuclei, and this index associated with TOP2A mRNA levels (p = 0.023) as well as the Ki-67 labeling index (p = 0.001). To conclude, TOP2A is a potential prognostic marker as it is frequently elevated in PPGL displaying subsequent metastatic disease, and future studies in larger cohorts are warranted to determine if a TOP2A index as assessed by immunohistochemistry could be a marker of poor outcome. Additionally, elevated levels of TOP2A could indicate a potential actionable event, and future studies with topoisomerase inhibitors would be of interest.

Prognostic Utility of the Ki-67 Labeling Index in Follicular Thyroid Tumors: a 20-Year Experience from a Tertiary Thyroid Center.

Follicular thyroid tumors pose a diagnostic challenge on the preoperative level, as the discrimination between follicular thyroid carcinoma (FTC) and adenoma (FTA) demands careful histopathological investigation. Moreover, prognostication of FTCs is mostly based on tumor size and extent of invasive properties, while immunohistochemical markers pinpointing high-risk cases are lacking. We have routinely established a Ki-67 labeling index for follicular thyroid tumors since 1999. To assess the potential value of Ki-67 as an adjunct tool to (1) correctly separate FTCs from FTAs and (2) help identify poor-prognosis FTCs, we collected histopathological and clinical data from 818 follicular thyroid tumors with a histological Ki-67 labeling index established in clinical routine practice (516 FTAs, 252 FTCs, and 50 follicular thyroid tumors of uncertain malignant potential (FT-UMPs)). The Ki-67 labeling index was higher in FTCs (mean 5.8%) than in FTAs (mean 2.6%) (P < 0.001), and a receiver operating characteristic curve analysis revealed a cut-off value of 4% to separate FTC from FTA with a sensitivity and specificity of 65% and 83%, respectively. Similarly, a Ki-67 labeling index above 4% was found to identify FTCs that later metastasized from clinically indolent FTCs with a sensitivity and specificity of 80% and 48%, respectively. Ki-67 constituted an independent predictor of future FTC metastases/recurrence and death of disease, and a value > 4% was a reliable prognostic marker within individual pT staging groups. We conclude that Ki-67 is a potentially valuable marker for the prognostication of FTCs, and future implementation in the histopathological assessments of follicular thyroid tumors could be beneficial if reproduced in international series.

Seasonal variation in calcium treatment after thyroidectomy as surrogate for post-operative hypocalcemia: a retrospective register-based national cohort study.

BACKGROUND: Hypocalcemia is one of the most common complications of thyroidectomy, and vitamin D deficiency has been found to be an independent risk factor. Sweden is located north of the 55th latitude, resulting in a significant seasonal variation in sun exposure, thereby large variation in the naturally occurring levels of vitamin D. This study aimed to determine if there is a correlation between season of surgery and post-thyroidectomy hypocalcemia. METHODS: We conducted a retrospective register-based observation study on patients who had undergone total thyroidectomy during 2008-2015. In total, 7125 patients operated in Swedish facilities were identified via the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery (SQRTPA). Patients operated during February-April were included in the dark group and patients operated during August-October were included in the bright group. Further stratification was made on the indication for surgery. The primary outcome was post-operative calcium treatment due to hypocalcemia, defined as having received calcium orally or intravenously before discharge. RESULTS: The risk of receiving post-operative calcium treatment was significantly lower in the bright group (29.7%) compared to the dark group (35.1%), with a relative risk of 0.846 (P < 0.001). This correlation held true if the indication for surgery was goiter or thyrotoxicosis. For malignancy, there was no significant difference between the groups. CONCLUSION: In this cohort, total thyroidectomy performed during August-October was associated with a lower rate of calcium treatment given post-operatively when compared to total thyroidectomy performed during February-April. This would indicate a decreased risk of post-operative hypocalcemia if surgery was carried out after the brighter season.

Synchronous lateral lymph node metastases from papillary and follicular thyroid carcinoma: case report and review of the literature.

BACKGROUND: Follicular thyroid carcinomas (FTCs) rarely metastasize to regional lymph nodes, and descriptions of synchronous lateral lymph node metastases of FTC and papillary thyroid carcinoma (PTC) are lacking. CASE PRESENTATION: We describe a 43-year-old female with a preoperative cytology indicating a right-sided PTC with lateral lymph node metastases. She underwent a total thyroidectomy and central and lateral lymph node dissection, and histopathology confirmed a multifocal tall cell variant PTC together with a 12 mm minimally invasive FTC in the ipsilateral lobe. While the central compartment demonstrated metastatic PTC, the lateral compartment contained PTC metastases alongside a 15 mm large follicular-patterned mass in a separate lymph node. As the cells lacked PTC associated nuclear changes, the possibility of a lateral lymph node metastasis of FTC was considered, with the possibility of ectopic thyroid tissue as a differential diagnosis. By utilizing next-generation sequencing, a Q61R NRAS mutation was pinpointed, thus proving the tissue as tumorous. The patient underwent radioiodine treatment and is currently monitored following a negative whole-body scan. CONCLUSIONS: This is probably the first case report of a patient with co-existing lateral lymph node PTC and FTC metastases. Consulting previous publications, there is currently a gap of knowledge in terms of how patients with regional FTC metastases should be followed-up and treated, especially when co-occurring with spread high-risk PTC subtypes. Moreover, what guides a seemingly indolent FTC to spread via the lymphatic system remains to be defined from a molecular standpoint.

Pan-Genomic Sequencing Reveals Actionable CDKN2A/2B Deletions and Kataegis in Anaplastic Thyroid Carcinoma.

Anaplastic thyroid carcinoma (ATC) is a lethal malignancy characterized by poor response to conventional therapies. Whole-genome sequencing (WGS) analyses of this tumor type are limited, and we therefore interrogated eight ATCs using WGS and RNA sequencing. Five out of eight cases (63%) displayed cyclin-dependent kinase inhibitor 2A (CDKN2A) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the CDKN2A locus (encoding p16 and p14arf) also exhibited loss of the neighboring CDKN2B gene (encoding p15ink4b), and displayed reduced CDKN2A/2B mRNA levels. Mutations in established ATC-related genes were observed, including TP53, BRAF, ARID1A, and RB1, and overrepresentation of mutations were also noted in 13 additional cancer genes. One of the more predominant mutational signatures was intimately coupled to the activity of Apolipoprotein B mRNA-editing enzyme, the catalytic polypeptide-like (APOBEC) family of cytidine deaminases implied in kataegis, a focal hypermutation phenotype, which was observed in 4/8 (50%) cases. We corroborate the roles of CDKN2A/2B in ATC development and identify kataegis as a recurrent phenomenon. Our findings pinpoint clinically relevant alterations, which may indicate response to CDK inhibitors, and focal hypermutational phenotypes that may be coupled to improved responses using immune checkpoint inhibitors.

Development of metastatic poorly differentiated thyroid cancer from a sub-centimeter papillary thyroid carcinoma in a young patient with a germline MET mutation - association or random chance?

BACKGROUND: Thyroid cancer dedifferentiation is an unusual observation among young patients and is poorly understood, although a recent correlation to DICER1 gene mutations has been proposed. CASE PRESENTATION: A 28-year old patient presented with a sub-centimeter cytology-verified primary papillary thyroid carcinoma (PTC) and a synchronous lateral lymph node metastasis. Following surgery, histopathology confirmed a 9 mm oxyphilic PTC and a synchronous metastasis of poorly differentiated thyroid carcinoma (PDTC). Extensive molecular examinations of both lesions revealed wildtype DICER1 sequences, but identified a somatic ETV6-NTRK3 gene fusion and a MET germline variant (c.1076G > A, p.Arg359Gln). MET is an established oncogene known to be overexpressed in thyroid cancer, and this specific alteration was not reported as a single nucleotide polymorphism (SNP), suggestive of a mutation. Both the primary PTC and the metastatic PDTC displayed strong MET immunoreactivity. A validation cohort of 50 PTCs from young patients were analyzed using quantitative real-time PCR, revealing significantly higher MET gene expression in tumors than normal thyroid controls, a finding which was particularly pronounced in BRAF V600E mutated cases. No additional tumors apart from the index case harbored the p.Arg359Gln MET mutation. Transfecting PTC cell lines MDA-T32 and MDA-T41 with a p.Arg359Gln MET plasmid construct revealed no obvious effects on cellular migratory or invasive properties, whereas overexpression of wildtype MET stimulated invasion. CONCLUSIONS: The question of whether the observed MET mutation in any way influenced the dedifferentiation of a primary PTC into a PDTC metastasis remains to be established. Moreover, our data corroborate earlier studies, indicating that MET is aberrantly expressed in PTC and may influence the invasive behavior of these tumors.

Macrofollicular variant follicular thyroid tumors are DICER1 mutated and exhibit distinct histological features.

AIMS: DICER1 germline mutations cause DICER1 syndrome, in which multinodular goitre is a common feature. Recently, somatic DICER1 mutations have been reported in sporadic thyroid carcinomas, of which the newly described macrofollicular variant of follicular thyroid carcinoma (MV-FTC) seems particularly enriched for this aberrancy. We report here histological and genetic findings in five follicular thyroid tumours with macrofollicular architecture (four carcinomas and one adenoma). METHODS AND RESULTS: We have diagnosed five cases during a year-long period at the Karolinska University Hospital, a tertiary thyroid cancer center with a catchment area of approximately 2.3 million inhabitants. Tumour DNA was interrogated using a commercially available massive parallel sequencing platform. All cases were female patients, ranging from 13 to 33 years at surgery. A single patient was a DICER1 syndrome carrier; the others were sporadic cases. All tumours displayed a macrofollicular architecture with a broad capsule. The MV-FTCs displayed capsular invasion, but never vascular invasion. Areas with degenerative changes (microinfarctions) were noted in all cases, and focal papillary growth was observed in the majority. The Ki-67 proliferation index was always above 4%. All cases displayed DICER1 gene mutations, of which four of five cases displayed RNase IIIb hot-spot missense mutations adjoined by a second, deleterious variant in three of five tumouurs. CONCLUSIONS: Macrofollicular variants of follicular thyroid tumours are predominantly found in younger females and are strongly linked to somatic DICER1 gene mutations. Histological features such as a broad tumorous capsule, focal infarctions and areas with papillae could constitute clues prompting further genetic analyses.

Nuclear-specific accumulation of telomerase reverse transcriptase (TERT) mRNA in TERT promoter mutated follicular thyroid tumours visualised by in situ hybridisation: a possible clinical screening tool?

AIMS: Upregulation of the telomerase reverse transcriptase (TERT) gene is a frequent finding in follicular thyroid carcinomas (FTCs) with metastatic features. The augmented expression is usually caused by TERT promoter mutations. As TERT protein immunohistochemistry might not correlate to TERT mRNA levels in follicular thyroid tumours, we therefore sought to determine if visualisation of TERT mRNA through in situ hybridisation could highlight high-risk cases. METHODS: We collected formalin-fixated paraffin-embedded tissues from 26 follicular thyroid tumours; 7 FTCs, 2 follicular thyroid tumours of uncertain malignant potential (FT-UMPs) and a single Hürthle cell carcinoma with established TERT promoter mutations and gene expression, as well as 16 FTCs with no TERT gene aberrancy or gene expression, and assessed them using RNA Scope in situ hybridisation (ISH) and TERT probes targeting the two main TERT transcripts (TERT1 and TERT2). RESULTS: TERT 1 and/or 2 mRNA was found by ISH in 8/10 cases with established promoter mutations and mRNA expression, whereas all 16 cases without TERT gene aberrancies or gene expression were negative (Fisher's exact p<0.001). Strikingly, TERT mRNA was visualised in the nuclear compartment only, thereby corroborating earlier studies suggesting a non-conventional role for TERT in tumour biology. Moreover, TERT mRNA expression was scattered across the tissue sections and only found in a few percentages of tumour nuclei. CONCLUSIONS: TERT mRNA seems to be focally expressed and localised exclusively to the nucleus in TERT promoter mutated follicular thyroid tumours, possibly reflecting a true biological and unorthodox phenomenon worthy of further investigations.

Pan-genomic characterization of high-risk pediatric papillary thyroid carcinoma.

Pediatric papillary thyroid carcinomas (pPTCs) are often indolent tumors with excellent long-term outcome, although subsets of cases are clinically troublesome and recur. Although it is generally thought to exhibit similar molecular aberrancies as their counterpart tumors in adults, the pan-genomic landscape of clinically aggressive pPTCs has not been previously described. In this study, five pairs of primary and synchronously metastatic pPTC from patients with high-risk phenotypes were characterized using parallel whole-genome and -transcriptome sequencing. Primary tumors and their metastatic components displayed an exceedingly low number of coding somatic mutations and gross chromosomal alterations overall, with surprisingly few shared mutational events. Two cases exhibited one established gene fusion event each (SQSTM1-NTRK3 and NCOA4-RET) in both primary and metastatic tissues, and one case each was positive for a BRAF V600E mutation and a germline truncating CHEK2 mutation, respectively. One single case was without apparent driver events and was considered as a genetic orphan. Non-coding mutations in cancer-associated regions were generally not present. By expressional analyses, fusion-driven primary and metastatic pPTC clustered separately from the mutation-driven cases and the sole genetic orphan. We conclude that pPTCs are genetically indolent tumors with exceedingly stable genomes. Several mutations found exclusively in the metastatic samples which may represent novel genetic events that drive the metastatic behavior, and the differences in mutational compositions suggest early clonal divergence between primary tumors and metastases. Moreover, an overrepresentation of mutational and expressional dysregulation of immune regulatory pathways was noted among fusion-positive pPTC metastases, suggesting that these tumors might facilitate spread through immune evasive mechanisms.

Aberrant splicing in neuroblastoma generates RNA-fusion transcripts and provides vulnerability to spliceosome inhibitors.

The paucity of recurrent mutations has hampered efforts to understand and treat neuroblastoma. Alternative splicing and splicing-dependent RNA-fusions represent mechanisms able to increase the gene product repertoire but their role in neuroblastoma remains largely unexplored. Here we investigate the presence and possible roles of aberrant splicing and splicing-dependent RNA-fusion transcripts in neuroblastoma. In addition, we attend to establish whether the spliceosome can be targeted to treat neuroblastoma. Through analysis of RNA-sequenced neuroblastoma we show that elevated expression of splicing factors is a strong predictor of poor clinical outcome. Furthermore, we identified >900 primarily intrachromosomal fusions containing canonical splicing sites. Fusions included transcripts from well-known oncogenes, were enriched for proximal genes and in chromosomal regions commonly gained or lost in neuroblastoma. As a proof-of-principle that these fusions can generate altered gene products, we characterized a ZNF451-BAG2 fusion, producing a truncated BAG2-protein which inhibited retinoic acid induced differentiation. Spliceosome inhibition impeded neuroblastoma fusion expression, induced apoptosis and inhibited xenograft tumor growth. Our findings elucidate a splicing-dependent mechanism generating altered gene products in neuroblastoma and show that the spliceosome is a potential target for clinical intervention.

Metastatic-prone telomerase reverse transcriptase (TERT) promoter and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutated tall cell variant of papillary thyroid carcinoma arising in ectopic thyroid tissue: A case report.

RATIONALE: Mutations of the v-Raf murine sarcoma viral oncogene homolog B (BRAF) oncogene and telomerase reverse transcriptase (TERT) promoter region are indicators of poor prognosis in papillary thyroid carcinoma (PTC) and might predict future occurrences of distant metastases. However, the clinical significance of these genetic aberrancies in PTCs arising in ectopic locations is not well established. PATIENT CONCERNS: We describe a patient with a previous history of radioiodine (RAI)-treated hyperthyroidism and a surgically resected right-sided follicular thyroid adenoma. In 2013, a 6 mm follicular variant papillary thyroid carcinoma was diagnosed following a left-sided thyroid lobectomy. The central compartment displayed 9 tumor-free lymph nodes, and no adjuvant treatment was planned. DIAGNOSES: Three years later, a 26 mm pre-tracheal relapse was noted, however, the excised lesion was consistent with a tall cell variant of papillary thyroid carcinoma (TCV-PTC) arising in ectopic thyroid tissue. RAI treatment was commenced. Four years later, a 5 mm subcutaneous lesion in the anterior neck was surgically removed and diagnosed as metastatic TCV-PTC with a codon 600 BRAF mutation and a C228T TERT promoter mutation. INTERVENTIONS: RAI treatment was re-initiated. Molecular re-examination of the primary follicular variant papillary thyroid carcinoma demonstrated a codon 600 BRAF mutation and a TERT promoter wildtype sequence, while the primary TCV-PTC was positive for mutations in both codon 600 of BRAF as well as the TERT promoter. OUTCOMES: The patient is alive and well without signs of relapse 7 months after the latest round of RAI. LESSONS: We conclude that the occurrence of combined BRAF and TERT promoter mutations in the primary lesion from 2016 was associated to the manifestation of distant metastases 4 years later, strengthening the benefit of mutational screening of these genes in clinical routine for thyroid carcinomas arising in aberrant locations.

TERT promoter mutations in primary and secondary WHO grade III meningioma.

PURPOSE: TERT promoter mutation (TERTpMut ) has a strong association to recurrence and has been suggested to act as a driver mutation for malignant transformation of WHO grade I and II meningiomas. TERTpMut has been investigated in selected high-grade meningioma samples. The existence of TERTpMut across recurrent tumors in a population-based cohort needs to be investigated in order to identify when TERTpMut emerges across recurrent samples and to validate prognostic impact among WHO grade III tumors. METHODS: We gathered material from a consecutive single-center cohort of 40 patients with malignant meningioma (WHO grade III) treated between 2000 and 2018, including specimens from primary and secondary malignant meningiomas with the corresponding earlier benign specimens and later malignant recurrences. In total 107 tumor samples were studied by Sanger sequencing for TERT promoter mutational status. RESULTS: Seven of 40 patients (17.5%) harbored TERTpMut thus validating the incidence of TERTpMut in previous non-population-based cohorts. In 6/7 patients, the TERTpMut was present at initial surgery (WHO grade I-III) while in one patient the TERTpMut was found de novo when the meningioma became malignant. The incidences were 2/1.000.000/year for TERTpMut WHO grade III meningioma and 8/1.000.000/year for TERTpwt WHO grade III meningioma in our catchment area. We found a 1.7 times higher recurrence rate (CI 95% 0.65-4.44) and a 2.5 higher mortality rate per 10 person-years (CI 95% 1.01-6.19) for TERTpMut compared to TERTpwt . CONCLUSION: TERTpMut can occur independently of malignant progression in meningioma and was most often present from the first tumor sample across recurring tumors. TERTpMut in WHO grade III may represent a marker of an aggressive subset of tumors.