The road ahead: a brief guide to navigating the 2022 WHO classification of endocrine and neuroendocrine tumours.

The most recent WHO classification of endocrine and neuroendocrine tumours has brought about significant changes in the diagnosis and grading of these lesions. For instance, pathologists now have the ability to stratify subsets of thyroid and adrenal neoplasms using various histological features and composite risk assessment models. Moreover, novel recommendations on how to approach endocrine neoplasia involve additional immunohistochemical analyses, and the recognition and implementation of these key markers is essential for modernising diagnostic capabilities. Additionally, an improved understanding of tumour origin has led to the renaming of several entities, resulting in the emergence of terminology not yet universally recognised. The adjustments in nomenclature and prognostication may pose a challenge for the clinical team, and care providers might be eager to engage in a dialogue with the diagnosing pathologist, as treatment guidelines have not fully caught up with these recent changes. Therefore, it is crucial for a surgical pathologist to be aware of the knowledge behind the implementation of changes in the WHO classification scheme. This review article will delve into the most significant diagnostic and prognostic changes related to lesions in the parathyroid, thyroid, adrenal glands and the gastroenteropancreatic neuroendocrine system. Additionally, the author will briefly share his personal reflections on the clinical implementation, drawing from a couple of years of experience with these new algorithms.

Lung Carcinoids: A Comprehensive Review for Clinicians.

Lung carcinoids are neuroendocrine tumors, categorized as typical or atypical carcinoids based on their histological appearance. While most of these tumors are slow-growing neoplasms, they still possess malignant potential. Many patients are diagnosed incidentally on chest X-rays or CT scans. Presenting symptoms include cough, hemoptysis, wheezing, dyspnea, and recurrent pneumonia. Endocrine symptoms, such as carcinoid syndrome or ectopic Cushing's syndrome, are rare. Surgery is the primary treatment and should be considered in all patients with localized disease, even when thoracic lymph node metastases are present. Patients with distant metastases may be treated with somatostatin analogues, chemotherapy, preferably temozolomide-based, mTOR inhibitors, or peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. Most patients have an excellent prognosis. Poor prognostic factors include atypical histology and lymph node metastases at diagnosis. Long-term follow-up is mandatory since metastases may occur late.

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 [...].

On the Chopping Block: Overview of DICER1 Mutations in Endocrine and Neuroendocrine Neoplasms.

Mutational inactivation of the DICER1 gene causes aberrant micro-RNA maturation, which in turn may have consequences for the posttranscriptional regulation of gene expression, thereby contributing to tumor formation in various organs. Germline DICER1 mutations cause DICER1 syndrome, a pleiotropic condition with an increased risk of various neoplastic conditions in the pleura, ovaries, thyroid, pituitary, pineal gland, and mesenchymal tissues. Somatic DICER1 mutations are also frequently observed in a wide variety of solid tumors, thereby highlighting the importance of this gene in tumor development. In this review, the importance of DICER1 inactivation in endocrine tumors is discussed.

Advances in Adrenal and Extra-adrenal Paraganglioma: Practical Synopsis for Pathologists.

Adrenal paraganglioma (or "pheochromocytoma") and extra-adrenal paraganglioma, collectively abbreviated PPGL, are rare but spectacular nonepithelial neuroendocrine neoplasms. These are the most inheritable neoplasia of all, with a metastatic potential in a varying degree. As of such, these lesions demand careful histologic, immunohistochemical, and genetic characterization to provide the clinical team with a detailed report taking into account the anticipated prognosis and risk of syndromic/inherited disease. While no histologic algorithm, immunohistochemical biomarker, or molecular aberration single-handedly can identify potentially lethal cases upfront, the combined analysis of various risk parameters may stratify PPGL patients more stringently than previously. Moreover, the novel 2022 WHO Classification of Endocrine and Neuroendocrine Tumors also brings some new concepts into play, not least the reclassification of special neuroendocrine neoplasms (cauda equina neuroendocrine tumor and composite gangliocytoma/neuroma-neuroendocrine tumor) previously thought to belong to the spectrum of PPGL. This review focuses on updated key diagnostic and prognostic concepts that will aid when facing this rather enigmatic tumor entity in clinical practice.

Metastatic Neuroendocrine Neoplasms of Unknown Primary: Clues from Pathology Workup.

Neuroendocrine neoplasms (NENs) are diverse tumors arising in various anatomical locations and may therefore cause a variety of symptoms leading to their discovery. However, there are instances in which a NEN first presents clinically as a metastatic deposit, while the associated primary tumor is not easily identified using conventional imaging techniques because of small primary tumor sizes. In this setting (which is referred to as a "NEN of unknown primary"; NEN-UP), a tissue biopsy is often procured to allow the surgical pathologist to diagnose the metastatic lesion. If indeed a metastatic NEN-UP is found, several clues can be obtained from morphological assessment and immunohistochemical staining patterns that individually or in concert may help identify the primary tumor site. Herein, histological and auxiliary analyses of value in this context are discussed in order to aid the pathologist when encountering these lesions in clinical practice.

Whole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer.

Breast cancer is the most prevalent malignancy among women worldwide and hereditary breast cancer (HBC) accounts for about 5−10% of the cases. Today, the most recurrent genes known are BRCA1 and BRCA2, accounting for around 25% of familial cases. Although thousands of loss-of-function variants in more than twenty predisposing genes have been found, the majority of familial cases of HBC remain unexplained. The aim of this study was to identify new predisposing genes for HBC in three non-BRCA families with autosomal dominant inheritance pattern using whole-exome sequencing and functional prediction tools. No pathogenic variants in known hereditary cancer-related genes could explain the breast cancer susceptibility in these families. Among 2122 exonic variants with maximum minor allele frequency (MMAF) < 0.1%, between 17−35 variants with combined annotation-dependent depletion (CADD) > 20 segregated with disease in the three analyzed families. Selected candidate genes, i.e., UBASH3A, MYH13, UTP11L, and PAX7, were further evaluated using protein expression analysis but no alterations of cancer-related pathways were observed. In conclusion, identification of new high-risk cancer genes using whole-exome sequencing has been more challenging than initially anticipated, in spite of selected families with pronounced family history of breast cancer. A combination of low- and intermediate-genetic-risk variants may instead contribute the breast cancer susceptibility in these families.

Pheochromocytomas and Abdominal Paragangliomas: A Practical Guidance.

Pheochromocytomas and abdominal paragangliomas (PPGLs) are rare tumors arising from the adrenal medulla or the sympathetic nervous system. This review presents a practical guidance for clinicians dealing with PPGLs. The incidence of PPGLs has risen. Most cases are detected via imaging and less present with symptoms of catecholamine excess. Most PPGLs secrete catecholamines, with diffuse symptoms. Diagnosis is made by imaging and tests of catecholamines. Localized disease can be cured by surgery. PPGLs are the most heritable of all human tumors, and germline variants are found in approximately 30-50% of cases. Such variants can give information regarding the risk of developing recurrence or metastases as well as the risk of developing other tumors and may identify relatives at risk for disease. All PPGLs harbor malignant potential, and current histological and immunohistochemical algorithms can aid in the identification of indolent vs. aggressive tumors. While most patients with metastatic PPGL have slowly progressive disease, a proportion of patients present with an aggressive course, highlighting the need for more effective therapies in these cases. We conclude that PPGLs are rare but increasing in incidence and management should be guided by a multidisciplinary team.

Cyto-morphological features of parathyroid lesions: Fine-needle aspiration cytology series from an endocrine tumor referral center.

BACKGROUND: Descriptions of parathyroid cell cyto-morphology are limited. Fine-needle aspiration cytology (FNAC) with immunocytochemistry (ICC) or biochemical PTH measurements may help verify the parathyroid origin in extraordinary cases, although these methods are nowadays largely replaced by imaging techniques. METHODS: We collected all available FNAC reports of parathyroid lesions from our department spanning 20 years, to characterize the clinical use of parathyroid FNAC, and to assess morphological correlates between cytology and subsequent histopathology. RESULTS: Twenty-eight cases with assessable cytological smears were found, of which 21 cases were surgically resected and 20 available for histological review (15 adenomas, 2 carcinomas, 2 atypical tumors and a single case with secondary hyperplasia). FNAC was predominantly performed to localize the diseased gland in cases with inconclusive imaging, in cases with a suspicion of intrathyroidal localization or in cases with persistent hypercalcemia following unsuccessful surgery. The diagnosis was verified using either PTH ICC and/or PTH measurements for most cases, and the procedure affected the clinical decision-making for the majority of patients in this selected cohort. Cytological differences between parathyroid adenomas and carcinomas were found, as only carcinomas showed pleomorphism with irregular nuclei and prominent nucleoli. Morphologically, no correlations to predominant cell types or growth patterns visualized at histological investigations among adenomas were noted, and biopsy artifacts were evident in 40% of cases. CONCLUSIONS: Parathyroid FNAC could be considered as a complementary analysis for a small group of selected patients, but benefits have to be weighed against the risk of biopsy artifacts in histological preparations.

Second-Generation Neuroendocrine Immunohistochemical Markers: Reflections from Clinical Implementation.

When analyzing tumors by histopathology, endocrine pathologists have traditionally been restricted to a few key immunohistochemical markers related to secretory vesicles in order to pinpoint neuroendocrine differentiation-most notably Chromogranin A (CGA) and Synaptophysin (SYP). Although proven of great clinical utility, these markers sometimes exhibit tissue-specific patterns depending on tumor origin, and non-neuroendocrine tumors might sometimes display focal expression. Moreover, CGA and SYP might be partially or totally absent in highly proliferative neuroendocrine carcinomas, making the diagnosis particularly challenging on small biopsies of metastatic lesions with unknown location of the primary tumor. The advent of second-generation neuroendocrine markers ISL LIM Homeobox 1 (ISL1), INSM Transcriptional Repressor 1 (INSM1) and Secretagogin (SECG) have expanded the pathology toolbox considerably, constituting markers that often retain expression even in poorly differentiated neuroendocrine carcinomas. As non-neuroendocrine tumors seldom express these antigens, the specificity of ISL1, INSM1 and SECG make them welcome additions to clinical practice. In this commentary, recent advances of this field as well as initial clinical experiences from a tertiary neuroendocrine center are discussed.

Adrenal myelolipomas.

Adrenal myelolipomas are benign, lipomatous tumours with elements of myeloid cells, most of which present as adrenal incidentalomas and comprise 3·3-6·5% of all adrenal masses. Adrenal myelolipomas are usually unilateral (in 95% of cases), variable in size, most often found during midlife, and affect both sexes almost equally. On imaging, adrenal myelolipomas show pathognomonic imaging features consistent with the presence of macroscopic fat. Large adrenal myelolipomas can cause symptoms of mass effect, and can occasionally be complicated by haemorrhage. In the event of a concomitant adrenal cortical adenoma or hyperplasia, adrenal hormone excess might be detected in patients with adrenal myelolipoma. Patients with congenital adrenal hyperplasia exhibit a higher prevalence of adrenal myelolipomas than other patient groups, and are at risk of developing large and bilateral lesions. This Review discusses the pathogenesis, clinical presentation, and management of adrenal myelolipomas.

Metastatic Pheochromocytomas and Abdominal Paragangliomas.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are believed to harbor malignant potential; about 10% to 15% of pheochromocytomas and up to 50% of abdominal paragangliomas will exhibit metastatic behavior. EVIDENCE ACQUISITION: Extensive searches in the PubMed database with various combinations of the key words pheochromocytoma, paraganglioma, metastatic, malignant, diagnosis, pathology, genetic, and treatment were the basis for the present review. DATA SYNTHESIS: To pinpoint metastatic potential in PPGLs is difficult, but nevertheless crucial for the individual patient to receive tailor-made follow-up and adjuvant treatment following primary surgery. A combination of histological workup and molecular predictive markers can possibly aid the clinicians in this aspect. Most patients with PPGLs have localized disease and may be cured by surgery. Plasma metanephrines are the main biochemical tests. Genetic testing is important, both for counseling and prognostic estimation. Apart from computed tomography and magnetic resonance imaging, molecular imaging using 68Ga-DOTATOC/DOTATATE should be performed. 123I-MIBG scintigraphy may be performed to determine whether 131I-MIBG therapy is a possible option. As first-line treatment in patients with metastatic disease, 177Lu-DOTATATE or 131I-MIBG is recommended, depending on which shows best expression. In patients with very low proliferative activity, watch-and-wait or primary treatment with long-acting somatostatin analogues may be considered. As second-line treatment, or first-line in patients with high proliferative rate, chemotherapy with temozolomide or cyclophosphamide + vincristine + dacarbazine is the therapy of choice. Other therapies, including sunitinib, cabozantinib, everolimus, and PD-1/PDL-1 inhibitors, have shown modest effect. CONCLUSIONS: Metastatic PPGLs need individualized management and should always be discussed in specialized and interdisciplinary tumor boards. Further studies and newer treatment modalities are urgently needed.

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.

Highly proliferative anal neuroendocrine carcinoma: molecular and clinical features of a rare, recurrent case in complete remission.

BACKGROUND: Poorly differentiated anal neuroendocrine carcinomas (ANECs) are rare lesions with poor prognosis, and the molecular etiology is only partially understood. CASE PRESENTATION: At our institution, we have treated and followed a patient with such a rare ANEC. He had primarily surgery followed by three rounds of repeated surgery for loco-regional recurrences. He also received three different combinations of chemotherapy and external beam radiation. At last follow-up 13 years since the primary diagnosis, the patient had been in complete remission for nine years. The patient's medical files were re-examined, including laboratory, radiology and clinical examinations. Histopathology was re-assessed, and expanded immunohistochemistry was performed from tissue specimens from the four surgical procedures. In addition, the molecular genetic status was evaluated through next-generation sequencing. The initial tumor was consistent with a 59 mm small cell neuroendocrine cancer with a Ki-67 index of 80%. Regional lymph node metastases were evident, and immunohistochemistry supported a neuroendocrine origin. A PCR screening detected human papilloma virus type 45 DNA (high-risk subtype), and focused next-generation sequencing found a missense mutation in the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) gene. In tissues representing subsequent recurrences, the Chromogranin A expression was lost, and the Ki-67 index increased to 90%. CONCLUSIONS: For the first time, we report the detection of HPV45 in a case of ANEC. To our belief, PIK3CA mutations have also not been previously demonstrated in this tumor entity. In highly malignant ANECs, cure can in rare cases be achieved. Although speculative, expression of HPV45 and/or the PIK3CA mutation may have contributed to the favorable outcome.

Clinical Routine Application of the Second-generation Neuroendocrine Markers ISL1, INSM1, and Secretagogin in Neuroendocrine Neoplasia: Staining Outcomes and Potential Clues for Determining Tumor Origin.

Neuroendocrine neoplasms (NENs) have traditionally been identified via expression of proteins associated to the regulation of secretory vesicles and granules. We report the clinical usage of the "second-generation" proteins ISL LIM homeobox 1 (ISL1), INSM transcriptional repressor 1 (INSM1), and secretagogin (SECG) as immunohistochemical markers of neuroendocrine differentiation since their introduction in clinical routine and compare the results with the established proteins chromogranin A (CGA) and synaptophysin (SYP). In total, 161 tumors, including 139 NENs and 22 "non-NENs" (unrelated tumors with an initial suspicion of NEN), were informatively stained for ISL1, and subsets were also interrogated for INSM1 and/or SECG. Diffuse or focal positive immunoreactivity was noted for ISL1 in 91/139 NENs (65%) and in 6/22 (27%) non-NENs, for INSM1 in 76/85 NENs (89%) and in 2/5 (40%) non-NENs, and for SECG in 49 out of 64 NENs (77%) and in 0/5 non-NENs (0%). Generally, ISL1, INSM1, and SECG exhibited sensitivities in line with or slightly below that of CGA and SYP-largely attributable to tissue-specific patterns regarding tumoral origin. Moreover, for pancreatic and small intestinal NENs, the two largest subgroups, ISL1 staining results were consistent irrespectively of tumor source and WHO grade. We verify previously suggested immunohistochemical schemes of neuroendocrine markers of first- and second-generations to facilitate the diagnostic process for NENs and confirm that the second-generation neuroendocrine markers display tissue-specific patterns. We therefore recommend their implementation in tertiary endocrine pathology centers, not least to aid in the identification of primary tumors when analyzing metastases.

Metastatic malignant melanoma with neuroendocrine differentiation: a case report and review of the literature.

BACKGROUND: Metastatic neuroendocrine carcinoma often presents as carcinoma of unknown primary. Although most cases display immunohistochemical positivity for neuroendocrine markers, subsets of cases display reduced or negative expression for some of these proteins. The identification of metastatic neuroendocrine carcinomas is even more complicated by the occurrence of unrelated tumor types with focal neuroendocrine differentiation. CASE PRESENTATION: Our patient was a 74-year-old man of Middle Eastern ethnicity. An initial biopsy of a soft tissue metastasis displayed a neuroendocrine profile indicative of a metastatic neuroendocrine carcinoma, positive for CD56 and synaptophysin, and focally for ISL LIM homeobox 1 and insulinoma-associated protein 1. The Ki-67 index was 50%. Chemotherapy was initiated, but our patient progressed. Scrapings from a pathological hip fracture 3 months later revealed focal synaptophysin immunoreactivity and widespread melanoma antigen, human melanoma black 45, and SOX10 positivity, which are indicative of metastatic malignant melanoma with focal neuroendocrine differentiation. CONCLUSIONS: Malignant melanoma may display neuroendocrine differentiation, and the entity should be considered a rare differential diagnosis when assessing biopsies of suspected neuroendocrine carcinomas.

Merkel cell polyomavirus oncoproteins induce microRNAs that suppress multiple autophagy genes.

Viruses can inhibit host autophagy through multiple mechanisms, and evasion of autophagy plays an important role in immune suppression and viral oncogenesis. Merkel cell polyomavirus (MCPyV) T-antigens are expressed and involved in the pathogenesis of a large proportion of Merkel cell carcinoma (MCC). Yet, how MCPyV induces tumorigenesis is not fully understood. Herein, we show that MCPyV T-antigens induce miR-375, miR-30a-3p and miR-30a-5p expressions, which target multiple key genes involved in autophagy, including ATG7, SQSTM1 (p62) and BECN1. In MCC tumors, low expression of ATG7 and p62 are associated with MCPyV-positive tumors. Ectopic expression of MCPyV small T-antigen and truncated large T-antigen (LT), but not the wild-type LT, resulted in autophagy suppression, suggesting the importance of autophagy evasion in MCPyV-mediated tumorigenesis. Torin-1 treatment induced cell death, which was attenuated by autophagy inhibitor, but not pan-caspase inhibitor, suggesting a potential role of autophagy in promoting cell death in MCC. Conceptually, our study shows that MCPyV oncoproteins suppress autophagy to protect cancer cells from cell death, which contribute to a better understanding of MCPyV-mediated tumorigenesis and potential MCC treatment.

Aberrant DNA repair as a potential contributor for the clonal evolution in subsets of anaplastic thyroid carcinomas arising through dedifferentiation: implications for future therapeutic algorithms?

Well-differentiated thyroid carcinoma (WDTC, including papillary thyroid carcinoma and follicular thyroid carcinoma) are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy. Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), of which especially the latter has an exceptionally poor patient outcome. The underlying genetics responsible for this tumor progression is only partly understood, and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable, pre-existing WDTC. Even so, recent advances using next generation sequencing (NGS) techniques have identified a genetic link between WDTCs and ATCs, suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases. In this Commentary, recent findings from an NGS study on synchronous FTC, PDTC, and ATC tumor components from the same patient are highlighted. By using whole-genome data, clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair, with sub-clones in each tumor component that were identified also in the less differentiated, neighboring tumor. Moreover, mutational signatures suggested a general mismatch repair (MMR) deficiency along with microsatellite instability. These findings support the chained progression model of dedifferentiation in thyroid cancer, and pinpoint a central role for defective DNA repair. Since effective treatment modalities for ATCs are urgently needed, studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.

Synchronous aldosterone- and cortisol-producing adrenocortical adenomas diagnosed using CYP11B immunohistochemistry.

Immunohistochemistry with antibodies targeting enzymes responsible for the final conversion steps of cortisol (CYP11B1) and aldosterone (CYP11B2) is gaining ground as an adjunct tool in the postoperative evaluation of adrenocortical nodules. The method allows the pathologist to visualize hormone production for each lesion, thereby permitting a more exact assessment regarding the distinction between adrenocortical adenomas and adrenocortical hyperplasia, with implications for patient follow-up. We describe how immunohistochemistry facilitated the histopathological diagnosis of twin adenoma (one cortisol- and one aldosterone-producing) from suspected hyperplasia in a patient with hypertension, mild autonomous cortisol secretion and concurrent adrenocorticotropic hormone-producing adrenomedullary hyperplasia. As the nodules were similar in size and displayed rather analogous histology, CYP11B1 and B2 immunohistochemistry was needed to exclude adrenocortical hyperplasia, allowing us to discharge the patient from further surveillance. We conclude that the application of functional immunohistochemistry has direct clinical consequences and advocates the prompt introduction of these markers in clinical routine.

Clinical Routine TERT Promoter Mutational Screening of Follicular Thyroid Tumors of Uncertain Malignant Potential (FT-UMPs): A Useful Predictor of Metastatic Disease.

Mutations of the Telomerase reverse transcriptase (TERT) gene promoter are recurrently found in follicular thyroid carcinoma (FTC) and follicular tumors of uncertain malignant potential (FT-UMP), but nearly never in follicular thyroid adenoma (FTA). We, therefore, believe these mutations could signify malignant potential. At our department, postoperative TERT promoter mutational testing of FT-UMPs was implemented in 2014, with a positive mutation screening leading to vigilant follow-up and sometimes adjuvant treatment. To date, we screened 51 FT-UMPs and compared outcomes to 40 minimally invasive FTCs (miFTCs) with known TERT genotypes. Eight FT-UMPs (16%) displayed TERT promoter mutations, of which four cases underwent a completion lobectomy at the discretion of the patient, and a single patient also opted in for radioiodine (RAI) treatment. Three mutation-positive patients developed distant metastases, registered in one patient receiving a completion lobectomy and in two patients with no additional treatment. Three out of four patients who received additional surgery, including the RAI-treated patient, are still without metastatic disease. We conclude that FT-UMPs with TERT promoter mutations harbor malignant potential and exhibit at least similar recurrence rates to TERT-promoter-mutated miFTCs. Mutational screening should constitute a cornerstone analysis in the histopathological work-up of FT-UMPs.