Carl Christofer Juhlin

• Associate Professor, MD, PhD
• Professor (Associate) at Karolinska Institutet

Mutations in the miRNA enzyme gene DICER1 have been reported in several endocrine malignancies and is associated to the rare tumour-predisposing DICER1 syndrome. DICER1 mutations have been reported in subsets of follicular thyroid carcinoma (FTC), but the role of DICER1 in follicular thyroid tumorigenesis has not been extensively studied. In this s...

The genetics underlying thyroid cancer dedifferentiation is only partly understood and has not yet been characterized using comprehensive pan‐genomic analyses. We investigated a unique case with synchronous follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), as well as regional...

Context Follicular thyroid cancer (FTC) is classified into minimally invasive (miFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wiFTC) subtypes, according to the 2017 World Health Organization (WHO) guidelines. The genetic signatures of these subtypes may be crucial for diagnosis, prognosis, and treatment, but have not been describe...

Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequ...

Context: Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood. Objective: To utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations present in ACC. Design: Screening for so...

Papillary thyroid carcinoma (PTC) is the most common form of well-differentiated thyroid cancer (WDTC) and generally has a favorable prognosis. However, subsets of these tumors can metastasize, leading to aggressive disease progression and poorer clinical outcomes. Radioactive iodine (RAI) therapy is routinely given in the adjuvant setting followin...

Anaplastic thyroid cancer (ATC) is a rare but severe form of thyroid cancer responsible for approximately 50% of thyroid cancer deaths. Consequently, the identification of innovative therapies remains crucial for the effective treatment of ATC. Molecular radiotherapy is a rapidly growing field within oncology and the cell surface antigen CD44v6, wh...

In recent years, germline mutations in the microRNA (miRNA) processor genes DICER1 and DGCR8 have been coupled to the development of thyroid follicular nodular disease (TFND), thereby casting new light on the etiology of this enigmatic, benign condition in non-iodine deficient regions. Moreover, DICER1 and DGCR8 mutations have also been reported in...

Introduction: Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer in adults, presents significant challenges owing to its resistance to conventional therapies. Standard treatment primarily revolves around surgical methods, particularly nephrectomy, which is critical for managing localized diseases. Despite recent advancem...

De-escalation of thyroid cancer treatment is crucial to prevent overtreatment of indolent disease, but it remains important to identify clinically aggressive cases. TERT promoter mutations are molecular events frequently associated with high-risk thyroid tumors with poor outcomes and may identify cases at risk of dissemination. In various internati...

Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular may progress from a low/intermediate to a high‐grade disease. The aim of this work was to understand the molecular mechanisms underlying metastatic progression as wel...

Context BRAFV600E and TERT promoter mutations in papillary thyroid carcinoma (PTC) have a synergistic effect on prognosis. This effect is believed to arise from MAPK activation triggered by BRAFV600E, leading to the upregulation of ETS transcription factors that bind to the mutant TERT promoter. Objective To explore the role of ETS factors in rela...

Pheochromocytoma and abdominal paraganglioma (PPGL) are rare catecholamine-producing, keratin-negative, non-epithelial neuroendocrine neoplasms characterized by a unique association with syndromic diseases caused by constitutional mutations in a wide range of susceptibility genes. While PPGLs are recognized for their malignant potential, the risk o...

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...

Background Adrenocortical carcinoma (ACC) is one of the most lethal endocrine malignancies and there is a lack of clinically useful markers for prognosis and patient stratification. Therefore our aim was to identify clinical and genetic markers that predict outcome in patients with ACC. Methods Clinical and genetic data from a total of 162 patient...

Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) (together abbreviated PPGL) frequently present with an underlying genetic event in a PPGL driver gene, and additional susceptibility genes are anticipated. Here we re-analysed whole-exome sequencing data for PCC patients and identified two patients with rare missense variants in the calcium...

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-i...

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-DO...

While morphological assessment remains the primary cornerstone in tumor diagnostics, immunohistochemical (IHC) analyses hold immense value in surgical pathology. This is particularly true in endocrine pathology, which encompasses a multitude of tumors from various organs, often presenting with several morphological mimics. In many cases, IHC proves...

The parathyroid cell is a vital regulator of extracellular calcium levels, operating through the secretion of parathyroid hormone (PTH). Despite its importance, the regulation of PTH secretion remains complex and not fully understood, representing a unique interplay between extracellular and intracellular calcium, and hormone secretion. One signifi...

Anaplastic and poorly differentiated thyroid cancer (ATC, PDTC) are rare and highly aggressive tumors that historically have been associated with a short life expectancy and low chance of cure. Molecular pathology and the introduction of highly effective targeted drugs have revolutionized the possibilities of management of patients with ATC and PDT...

Follicular thyroid carcinoma (FTC) is recognized by its ability to invade the tumor capsule and blood vessels, although the exact molecular signals orchestrating this phenotype remain elusive. In this study, the spatial transcriptional landscape of an FTC is detailed with comparisons between the invasive front and histologically indolent central co...

Background Mutations in micro-RNA (miRNA) regulators DICER1 and DGCR8 have recently been uncovered, revealing a potential novel mechanism driving thyroid tumor development. However, the true frequency of these hotspot mutations in follicular-patterned thyroid tumors (FTs) and their relation to established driver gene events remains elusive. Method...

Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular, show frequent progression from a low/intermediate to a high-grade disease. To understand the molecular mechanisms underlying this phenomenon, we performed multi-omic...

Background: Thyroid nodules are prevalent among the general population, thus imposing substantial demands upon healthcare providers to establish effective management paradigms when investigating these lesions. A pivotal component in the diagnostic process involves the cytomorphologic evaluation of fine needle aspiration (FNA) specimens extracted f...

Simple Summary Lung carcinoids are divided into typical and atypical. Most tumors are slow-growing yet have malignant potential, which is more common in patients harboring atypical carcinoids. A large proportion of these patients are diagnosed incidentally on chest X-ray or CT scan. Cough, dyspnea, or recurrent pneumonia are common presenting sympt...

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

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. C...

Telomerase reverse transcriptase (TERT) gene aberrancies correlate to adverse prognosis in follicular thyroid carcinoma (FTC). As loss of 5-hydroxymethylcytosine (5hmC) has been associated with TERT promoter mutations in papillary thyroid carcinoma, this study sought to analyze the levels of 5hmC in a cohort of follicular thyroid tumors with availa...

Purpose Patients with persistent or recurrent papillary and poorly differentiated thyroid cancer can be effectively treated with radioiodine, if the tumour tissue is iodine-avid. However, iodine-avidity status is often unknown at the time of initial radioiodine treatment, limiting any adaptive approach. This study aimed to clarify the relationship...

Background Successful radioiodine treatment of differentiated thyroid cancer requires iodine avidity: that is, the concentration and retention of iodine in cancer tissue. Several parameters have previously been linked with lower iodine avidity. However, a comprehensive analysis of which factors best predict iodine avidity status, and the magnitude...

Adrenal cysts are rare lesions representing approximately 1–2% of adrenal incidentalomas. The majority of these rare lesions are benign. Rarely, phaeochromocytomas and adrenal malignant masses can present as cystic lesions and can occasionally be difcult to disting uish from benign cysts. Histologically, adrenal cysts are subdivided into pseudocyst...

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 adrenohepati...

While most benign lesions of the adrenal glands represent either an adrenocortical adenoma or a myelolipoma, the advent and frequent use of high-resolution radiological investigations have led to relatively increased incidental discovery of rare adrenal lesions, specifically benign adrenal cysts, adrenal ganglioneuromas, adrenal schwannomas, adrena...

Background The spectrum of neuroendocrine neoplasia (NEN) of the head and neck region is wide-ranging and diverse, including a variety of diagnoses stretching from benign and low-malignant tumor forms to highly proliferative, poor prognosis neuroendocrine carcinoma (NEC). Moreover, there are several non-neuroendocrine differential diagnoses to keep...

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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 p...

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 ACTH-independent hypercortisolism and increased estradiol secretion responsible for gynecomastia and hypogonadism. B...

Purpose TERT promoter mutations and TERT gene expression correlate to adverse prognosis in follicular thyroid carcinoma (FTC), identifying cases at risk of poor outcome. As loss of 5-hydroxymethylcytosine (5hmC) immunoreactivity has been associated with TERT promoter mutations in papillary thyroid carcinoma, this study sought to analyze the levels...

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 p...

The clinical significance of thyroglobulin (Tg) expression in papillary thyroid cancer (PTC) has not been systematically explored in relation to the Ki-67 index, lymph node ratio (LNR), or other conventional prognostic predictors. In this retrospective study of 327 patients with PTC, we investigated the immunohistochemical expression of Tg in both...

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 neoplast...

Context and Objectives Urinary bladder paraganglioma (UBPGL) is rare. We aimed to characterize the presentation and outcomes of patients diagnosed with UBPGL. Methods We conducted a multi-center study of consecutive patients with pathologically-confirmed UBPGL evaluated between 1971 and 2021. Outcomes included repeat bladder surgery, metastases, a...

The 5th edition of the Classification of Endocrine and Neuroendocrine Tumors has been released by the World Health Organization (WHO). This timely publication integrates several changes to the nomenclature of non-neoplastic and neoplastic thyroid diseases, as well as novel concepts that are essential for patient management. The heterogeneous group...

Introduction:Pheochromocytoma and abdominal paraganglioma (PPGL) are rare neuroendocrine tumors originating from chromaffin cells. Even though only 10-15% of the tumors metastasize, all PPGL are considered potentially malignant. Topoisomerase 2A (TOP2A) is a protein involved in cell proliferation and was recently found to be over-expressed in metas...

The parathyroid cell is a critical physiological regulator of extracellular Ca ²⁺ levels via secretion of parathyroid hormone (PTH). Regulation of PTH secretion is complex, not fully understood and represents a unique feature between extracellular Ca ²⁺ , intracellular Ca ²⁺ , and hormone secretion. One major problem in parathyroid research is the...

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...

Adrenal incidentalomas are commonly detected via routine radiological procedures, and any sign of grossly invasive properties may alert the clinical team to suspect malignancy. Adreno-hepatic fusion (AHF) is a developmental disorder in which the parenchyma of the right adrenal gland is partly or wholly fused with the liver. The development of an ad...

Context and Objectives Urinary bladder paraganglioma (UBPGL) is rare. We aimed to characterize the presentation and outcomes of patients diagnosed with UBPGL. Methods We conducted a multi-center study of consecutive patients with pathologically-confirmed UBPGL evaluated between 1971 and 2021. Outcomes included repeat bladder surgery, metastases, a...

Mitochondria are the main consumers of oxygen within the cell. How mitochondria sense oxygen levels remains unknown. Here we show an oxygen-sensitive regulation of TFAM, an activator of mitochondrial transcription and replication, whose alteration is linked to tumours arising in the von Hippel–Lindau syndrome. TFAM is hydroxylated by EGLN3 and subs...

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 pinp...

Adrenocortical carcinoma (ACC) is one of the deadliest endocrine malignancies and telomere maintenance by activated telomerase is critically required for ACC development and progression. Because telomerase reverse transcriptase (TERT) and regulator of telomere elongation helicase 1 (RTEL1) play key roles in telomere homeostasis, we determined their...

Simple Summary While most neuroendocrine neoplasms are indolent and slow-growing tumors, subsets of cases will spread beyond the tissue of origin. Given the rather slow progress, some lesions are incidentally discovered as metastatic deposits rather than primary masses. In these cases, a biopsy is often taken to allow the pathologist to identify th...

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,...

This review summarizes the changes in the 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors that relate to the thyroid gland. The new classification has divided thyroid tumors into several new categories that allow for a clearer understanding of the cell of origin, pathologic features (cytopathology and histopathology), m...

Promoter mutations of the telomerase reverse transcriptase (TERT) gene occur frequently in thyroid carcinoma (TC), including papillary (PTC) and anaplastic subtypes (ATC). Given that the ETS family transcription factors GABPA and GABPB1 activate the mutant TERT promoter and induce TERT expression for telomerase activation, GABPB1 has been proposed...

The new WHO classification of adrenal cortical proliferations reflects translational advances in the fields of endocrine pathology, oncology and molecular biology. By adopting a question–answer framework, this review highlights advances in knowledge of histological features, ancillary studies, and associated genetic findings that increase the under...

The 2022 WHO classification reflects increases in the knowledge of the underlying pathogenesis of parathyroid disease. In addition to the classic characteristic features of parathyroid neoplasms, subtleties in histologic features which may indicate an underlying genetic abnormality reflect increased understanding of the clinical manifestations, his...

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 PPG...

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 meta...

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...

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) abnorm...

The cover image is based on the Short Report Macrofollicular variant follicular thyroid tumors are DICER1 mutated and exhibit distinct histological features by C Christofer Juhlin et al., https://doi.org/10.1111/his.14416

Merkel cell carcinoma is an aggressive skin malignancy, mostly caused by Merkel cell polyomavirus (MCPyV). MCPyV T-antigens can induce mature microRNA expressions through the DnaJ domain, but its underlying mechanism is still unknown. Here, we report that the T-antigens induce protein expression and mRNA stability of DICER1, a key factor in microRN...

Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. Here we study single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland....

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 ex...

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...

Parathyroid adenoma is a tumor composed of increased parenchymal tissue, often built-up by chief cells, transitional cells or oncocytic cells arranged in acinar or solid formations. Occasionally, rare histological patterns are reported, including cystic or trabecular arrangements. We present a 47 year-old male patient with primary hyperparathyroidi...

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 m...

Papillary thyroid cancer (PTC) and poorly differentiated thyroid cancer (PDTC) are treated with radioiodine to reduce recurrence and to treat the spread of disease. Adequate iodine accumulation in cancer tissue, iodine avidity, is important for treatment effect. This study investigated which clinical and histological tumour characteristics correlat...

Background The genomic and transcriptomic landscape of widely invasive follicular thyroid carcinomas (wiFTCs) and Hürthle cell carcinoma (HCC) are poorly characterized and subsets of these tumors lack information on genetic driver events. The aim of this study was to bridge this gap. Methods We performed whole-genome and RNA sequencing and subsequ...

Rarely, salivary gland tumors such as mucoepidermoid carcinoma, mammary analogue secretory carcinoma and mucinous carcinoma arise as primary tumors from ectopic or metaplastic salivary gland tissue adjacent to or within the thyroid gland. We report for the first time a case of primary salivary acinic cell carcinoma (AcCC) adjacent to the thyroid gl...

Benign thyroid lesions such as multinodular goiter and adenomatoid nodules are well-circumscribed lesions displaying a macrofollicular growth pattern and lack of nuclear atypia. The highly unusual macrofollicular variant of follicular thyroid carcinoma (MV-FTC) mirrors these attributes and is thereby misclassified by cytological examination of fine...

Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although few pathologists outside of endocrine tertiary centers will ever diagnose such a lesion, the tumors are well known through the medical community—possible due to a combination of the...

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 therefor...