Critically evaluated key points on hereditary medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) accounts for only 3% of all thyroid carcinomas: 75% as sporadic MTC (sMTC) and 25% as hereditary MTC (hMTC) in the context of multiple endocrine neoplasia type 2 (MEN2). Early diagnosis is possible by determining the tumour marker calcitonin (Ctn) when clarifying nodular goitre and by detecting the mutation in the proto-oncogene RET in the MEN2 families. If the Ctn level is only slightly elevated, up to 30 pg/ml in women and up to 60 pg/ml in men, follow-up checks are advisable. At higher levels, surgery should be considered; at a level of > 100 pg/ml, surgery is always advisable. The treatment of choice is total thyroidectomy, possibly with central lymphadenectomy. In the early stage, cure is possible with adequate surgery; in the late stage, treatment with tyrosine kinase inhibitors is an option. RET A mutation analysis should be performed on all patients with MTC. During follow-up, a biochemical distinction is made between: healed (Ctn not measurably low), biochemically incomplete (Ctn increased without tumour detection) and structural tumour detection (metastases on imaging). After MTC surgery, the following results should be available for classification in follow-up care: (i) histology, Ctn immunohistology if necessary, (ii) classification according to the pTNM scheme, (iii) the result of the RET analysis for categorisation into the hereditary or sporadic variant and (iiii) the postoperative Ctn value. Tumour progression is determined by assessing the Ctn doubling time and the RECIST criteria on imaging. In most cases, "active surveillance" is possible. In the case of progression and symptoms, the following applies: local (palliative surgery, radiotherapy) before systemic (tyrosine kinase inhibitors).

Risk factor analysis and nomogram development and verification for medullary carcinoma of the colon using SEER database.

Medullary Carcinoma of the Colon (MCC) is a rare histological subtype of colon cancer, and there is currently no recognized optimal treatment plan for it, with its prognosis remaining unclear. The aim of this study is to analyze the independent prognostic factors for MCC patients and develop and validate nomograms to predict overall survival (OS). A total of 760 patients newly diagnosed with MCC from 2004 to 2020 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. All patients were randomly allocated to a training group and a validation group in a 7:3 ratio. Univariate and multivariable Cox regression analyses were conducted to identify prognostic factors and construct nomograms. The nomogram prediction model was evaluated and validated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The study found that elderly women are more susceptible to MCC, and the ascending colon and cecum are the most common sites of involvement. MCC is poorly differentiated, with stages II and III being the most common. Surgery is the primary treatment for MCC. The prognosis for patients with stage IV MCC is poor, with a median survival time of only 10 months. Independent prognostic factors for MCC include age, N stage, M stage, surgery, chemotherapy, and tumor size. Among them, age < 75 years and completion of chemotherapy were protective factors for colon medullary carcinoma, while N2 (HR = 2.18, 95%CI 1.40-3.38), M1 (HR = 3.31, 95%CI 2.01-5.46), no surgery (HR = 27.94, 95%CI 3.69-211.75), and tumor diameter > 7 cm (HR = 1.66, 95%CI 1.20-2.30) were risk factors for colon medullary carcinoma. The results of ROC, AUC, calibration curves, and DCA demonstrate that the nomogram prediction model exhibits good predictive performance. We have updated the demographic characteristics of colon medullary carcinoma and identified age, N staging, M staging, surgery, chemotherapy and tumor size as independent prognostic factors for colon medullary carcinoma. Additionally, we have established nomograms for prognostic prediction. These nomograms can provide personalized predictions and serve as valuable references for clinical decision-making.

Renal Medullary Carcinoma: The Zebra Amongst the Horses.

A 13-year old Latino male presented with recurrent gross hematuria, 5cm right-sided poorly defined heterogeneous mass, enlarged retrocaval lymph nodes, and 1.2 cm paratracheal lymph node. Given the need for multiple blood transfusions, robot-assisted radical nephrectomy with lymph node dissection was performed. Pathology revealed pT3a high-grade tumor, clear margins, and positive lymph node. Additionally, with multiple sickled RBCs and loss of staining of SMARCB1 in tumor specimen, and hemoglobin electrophoresis suggesting sickle cell trait, diagnosis of metastatic renal medullary carcinoma was confirmed. The patient was enrolled into COG AREN 03B2 trial, and has completed 10 cycles of carboplatin/gemcitabine/bortezomib alternating with cisplatin/gemcitabine/paclitaxel, with no evidence of recurrent disease 9 months post-surgery.

[Precision medicine in endocrinology exemplified by medullary thyroid cancer]. / Präzisionsmedizin in der Endokrinologie am Beispiel des medullären Schilddrüsenkarzinoms.

Medullary thyroid cancer (MTC) is a prime example for precision medicine in endocrinology and underlines the immediate benefits of basic, translational and healthcare research for patients with a rare disease in clinical . A mutation in the rearranged during transfection (RET) proto-oncogene that codes for a transmembrane receptor protein tyrosine kinase, leads to constitutive activation of the kinase, which is the decisive pathomechanism for the disease. The MTC occurs in a sporadic (somatic RET mutation) or hereditary form (RET germline mutation, multiple endocrine neoplasia types 2 and 3). For germline mutation carriers the timing of preventive thyroidectomy depends on the RET genotype. For advanced metastasized RET-mutant MTC, selective RET kinase inhibitors are available, which are currently considered to be game changers in the treatment. Based on the specific tumor marker calcitonin, MTC can be identified at an early stage during the differential diagnosis of thyroid nodules. The preoperative calcitonin level even enables statements on the degree of dissemination of the disease and on the probability of a cure through surgery. A new development is the consideration of desmoplasia as a histopathological biomarker for the metastatic potential of a MTC, which could possibly modify the operative approach as well as the future MTC nomenclature. Furthermore, the postoperative calcitonin level and the calcitonin doubling time are highly valid prognostic markers for tumor burden and biological aggressiveness of MTC and therefore decisive for patient follow-up. Biochemical, molecular and histological markers enable a risk-adapted surgical treatment and together with new targeted systemic treatments have contributed to a paradigm shift in the diagnostics, prognosis and treatment of MTC in recent years. Endocrine precision medicine for MTC therefore enabled a change from the previous purely symptom-oriented to a modern preventive and individualized treatment.

Renal Medullary Carcinoma: A Surveillance, Epidemiology, and End Results (SEER) Analysis.

INTRODUCTION: Renal medullary carcinoma (RMC) is an aggressive and rare renal malignancy that predominantly affects Black patients but is also found in individuals of other ethnicities. To date, only a few hundred cases have been reported in the urologic literature. Due to this extreme rarity, the exact pathophysiology and optimal treatment have yet to be well described. This study aims to determine the predictors of mortality and overall survival outcomes in patients with RMC. METHODS: We utilized the Surveillance, Epidemiology, and End Results Program (SEER) database 18 registries to retrieve demographic and clinical information on patients with RMC between 1996 and 2018. A multivariate analysis was performed to determine predictors of mortality in the study population. Kaplan-Meier survival curves were then created to display the differences in overall survival of Black versus non-Black patients diagnosed with renal medullary carcinoma during the study period. RESULTS: We identified 100 patients diagnosed with renal medullary carcinoma using the SEER Database in the study period. The mean age was 28.0 ± 12.0 (95% confidence interval [CI] 25.7-30.4). Among the patients, 76% were male and 24% were female. Most RMC patients were Black (83%) with only 17% identifying as White. The mean survival in months was 13.8 ± 3.0 (95% CI 7.9-19.7). The majority (70%) of patients in this study presented with distant, metastatic disease at the time of diagnosis. Black patients with RMC were less likely to receive surgery and five times more likely to die in comparison to their White counterparts OR = 5.4 (95% CI 1.09-26.9, P = 0.04). Not only did Black patients have a lower survival rate at 12 mo compared to White patients, but they also continued to experience a sharp decline in survival to 10.2% at 24 mo (P < 0.05) and 7.6% at 48 mo (P < 0.05) following diagnosis of renal medullary carcinoma. CONCLUSIONS: These data confirm that RMC is a rare disease that disproportionately affects Black patients. The prognosis appears to be substantially worse for Black subjects diagnosed with this cancer than non-Black patients. The worse outcomes seen in Black subjects are of an unclear etiology and are yet to be investigated.

Calcium-stimulated calcitonin test for the diagnosis of medullary thyroid cancer: results of a multicenter study and comparison between different assays.

BACKGROUND: A basal serum calcitonin (Ct) increase >100 pg/mL in patients with a thyroid nodule is consistent with the diagnosis of medullary thyroid cancer (MTC). In cases where the CT test have a slight to moderate increase, the calcium gluconate stimulation test is helpful to increase diagnostic accuracy. However, reliable cut-offs for calcium-stimulated Ct are still lacking. The aim of this study was to evaluate the sex-specific calcium-stimulated Ct cutoffs for the diagnosis of MTC in a multicenter series. A comparison between different Ct assays has been also performed. METHODS: 90 subjects undergone calcium-stimulated Ct for a suspected MTC in 5 Endocrine Units between 2010-2021 were retrospectively analyzed. Serum Ct concentrations were assessed by immunoradiometric (IRMA) or chemiluminescence (CLIA) assays. RESULTS: MTC was diagnosed in 37 (41.1%) and excluded in 53 (58.9%) patients. The best calcium-stimulated Ct cut-off to identify MTC was 611 pg/mL in males (AUC =0.90, 95% CI (0.76;1) and 445 pg/mL in females (AUC=0.79, 95% CI (0.66;0.91). Logistic regression analysis showed that both basal (OR 1.01, P=0.003) and peak Ct after stimulation (OR 1.07, P=0.007) were significantly associated with MTC, together with sex (OR=0.06, P<0.001). The "Ct assay" variable was also considered in the logistic regression model, but it was not significantly associated with MTC (OR=0.93, P=0.919). CONCLUSIONS: This study indicates that calcium test could be helpful to identify patients with early-stage MTC and those without MTC. A Ct value of 611 pg/mL in males and 445 pg/mL in females are proposed as the optimal Ct cut-offs at the stimulation test.

Diagnostic challenges of renal medullary carcinoma and the role for cytologic assessment: Case report and literature review.

BACKGROUND: Renal medullary carcinoma (RMC) is a diagnostically challenging, aggressive primary renal malignancy associated with abysmal survival. Delays in diagnosis contribute to most patients having diffusely metastatic disease at the time of initial presentation. METHODS: We present the case of a 13-year-old African American male with sickle cell trait who presented with a renal mass and hematuria. Evaluation included imaging, fluid cultures, and cytologic assessment. RESULTS: Patient was diagnosed with RMC based on cytologic assessment of sub-centimeter fluid collections aspirated from the left kidney at the time of cortical biopsy for suspected renal mass. The additional fluid aspiration in conjunction with renal biopsy was an atypical but crucial step in early diagnosis. CONCLUSION: Cytomorphologic evaluation of fluid biospecimens is not currently part of the standard work-up for patients with renal masses but, when available, can provide crucial information that reduces time to diagnosis. Prompt symptom recognition and treatment initiation may improve patient outcomes.

A Comparison of Outcomes in Medullary Thyroid Carcinoma Patients With and Without a Preoperative Diagnosis: A Multicenter Retrospective Cohort Study.

Background: Cytological limitations pose a challenge to preoperative diagnosis of medullary thyroid carcinoma (MTC) and therefore, a significant subset of patients is only diagnosed postoperatively. The objective of this study was to investigate the impact of knowledge of a preoperative MTC diagnosis on disease management and outcomes. Methods: Multicenter, retrospective, cohort study of MTC patients treated in Israel from January 2000 to June 2021. We compared cohorts of patients according to the presence or absence of a preoperative MTC diagnosis. Results: Ninety-four patients with histologically confirmed MTC were included (mean age 56.2 ± 14.3 years, 43% males). Fifty-three patients (56%) had a preoperative MTC diagnosis (preop-Dx group), and 41 (44%) were confirmed only postoperatively (no-Dx group). The extent of surgical resection, including completion procedures, was as follows: total thyroidectomy in 83% versus 100% (p = 0.002), central lymph node dissection (LND) in 46% versus 98% (p < 0.001), ipsilateral lateral LND in 36% versus 79% (p < 0.001), and contralateral lateral LND in 17% versus 28% (NS), in the no-Dx versus the preop-Dx group, respectively. Pathology confirmed a smaller median tumor size of 16 ± 17.4 mm versus 23 ± 14.0 mm (p = 0.09), a higher proportion of micro-MTC (size ≤10 mm) 32% versus 15% (p = 0.03), and a higher rate of co-occurrence of follicular cell-derived carcinoma 24% versus 4% (p = 0.003), in the no-Dx compared to the preop-Dx group, respectively. The rates of extrathyroidal and extranodal tumor extension were not significantly different between the groups. At the last follow-up, the biochemical cure was attained in 55% [CI 0.38-0.71] compared to 64% [CI 0.50-0.77] of the no-Dx and the preop-Dx group, respectively (p = 0.41). After the exclusion of patients with micro-MTC, biochemical cure was more commonly achieved in the preop-Dx group (33% [CI 0.14-0.52] vs. 62% [CI 0.46-0.77], p = 0.04). Preop-Dx patients had improved overall survival compared to the no-Dx group (log-rank p = 0.04) over a median follow-up of 82 months (interquartile range [IQR] 30-153). Conclusions: Preoperatively, the diagnosis of MTC is often missed. An accurate preoperative diagnosis of MTC may enable guideline-concordant surgical treatment and ultimately contribute to an overall survival benefit in MTC patients.

[Hereditary medullary thyroid cancer]. / Hereditäres medulläres Schilddrüsenkarzinom.

Parafollicular C cells progress via C cell hyperplasia to medullary thyroid cancer (MTC), which can be present even in the first years of life in multiple endocrine neoplasia (MEN) type 2A and 2B patients. Basal calcitonin and carcinoembryonic antigen (CEA) are useful tumor markers for the diagnosis and monitoring. The prognosis depends on the stage when the disease is diagnosed and there is a good genotype-phenotype correlation with the RET proto-oncogene, which can be used for estimation of the risk. The risk-stratified prophylactic thyroidectomy plays a decisive role in the prognosis of known gene mutation carriers.

Oncologic outcomes of calcitonin-negative medullary thyroid carcinoma.

Objective: Calcitonin (Ct)-negative medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor. This study aimed to clarify its incidence, clinicopathologic characteristics, management, and treatment outcome. Methods: We retrospectively analyzed data of patients with primary MTC. Patients were divided into two groups according to the preoperative serum Ct level (Ct-negative and Ct-positive). The demographic, pathologic, and molecular characteristics, and treatment outcomes were compared between the two groups. In the Ct-negative group, we analyzed the association between the operation type and treatment outcome. Results: Of the total 312 patients, 24 were diagnosed with Ct-negative MTC. The rate of lymph node metastasis was significantly higher in the Ct-positive than in the Ct-negative group (47.9% vs. 0%, p<0.001). The proportion of patients with Ki-67 ≤10% was significantly higher in the Ct-negative than in the Ct-positive group (87.5% vs. 38.2%, p<0.001). Excellent response was achieved by 91.7% and 34.7% of patients in the Ct-negative and Ct-positive groups, respectively (p<0.001). In the Ct-negative group, excellent response was achieved by all female patients, but only 50% of male patients. Conclusions: Ct-negative MTC is rare and unlikely to develop lymph node metastasis. Unilateral lobectomy tends to provide a satisfactory chance of excellent response; however, this requires further validation.

How New Developments Impact Diagnosis in Existing Renal Neoplasms.

In recent years, several emerging diagnostic entities have been described in renal cell carcinoma (RCC). However, our understanding of well-known and established entities has also grown. Clear cell papillary RCC is now relabeled as a tumor rather than carcinoma in view of its nonaggressive behavior. Renal tumors with a predominantly infiltrative pattern are very important for recognition, as most of these have aggressive behavior, including fumarate hydratase-deficient RCC, SMARCB1-deficient medullary carcinoma, collecting duct carcinoma, urothelial carcinoma, and metastases from other cancers.

Management of medullary carcinoma of the thyroid: a review.

Medullary thyroid carcinoma (MTC) is an uncommon malignancy of neuroendocrine origin derived from the parafollicular C cells. Although infrequent, the interest in this cancer exceeds its incidence owing to its distinctive features and its characteristic association with other endocrine tumors. Although the majority of MTCs are sporadic, hereditary varieties occur in isolation or as a part of multiple endocrine neoplasia type 2 syndrome (MEN 2). Currently, complete surgical resection of the tumor and nodal metastases with a curative intent remains the mainstay of therapy. The role of adjuvant therapy is limited, although radiotherapy and newer targeted therapies are routinely used for metastatic disease. The lack of consensus in the available guidance regarding the most appropriate diagnostic, therapeutic and follow-up strategies has caused substantial variability in clinical practice. Therefore, this review summarizes the latest available evidence and guidelines on the management of MTC with an emphasis on diagnosis, surgical treatment and follow-up.

The dilemma of routine testing for calcitonin thyroid nodule's patients to detect or exclude medullary carcinoma: one single negative test should be valuable as rule-out strategy to avoid further calcitonin measurements over time.

PURPOSE: While calcitonin (CT) measurement is recognized as the most accurate tool to diagnose medullary thyroid carcinoma (MTC), its routine use in patients with thyroid nodule (TN) is not universally accepted. The present study raised the question whether a TN patient with an initial normal CT can have suspicious CT levels (i.e., at least >20 pg/ml) later during his follow-up. METHODS: The historical database of our institution was searched to select TN patients undergone multiple CT tests, having an initial normal CT, and clinically followed up for years. The event of a CT above 20 pg/ml (mild-to-moderate suspicion) and 100 pg/ml (high suspicion) was searched in the follow-up of the included patients. RESULTS: According to the study design, the study sample encompassed 170 patients (131 female, 39 male) with initial CT value ≤10 pg/ml. On the first CT test, patients were 54.8 years and median CT was 2.1 pg/ml in both females and males. Over a period of 14.5 years and a median clinical follow-up of patients of 53.0 (23.9-102.5) months, MTC could be excluded by histology or cytology in 109 (64%) and clinically in the remaining ones. On the follow-up over time, no patients had CT >20 pg/ml and only two cases had CT just above 10 pg/ml. CONCLUSION: According to the present results, one single CT testing with normal value could be reasonably used as a rule-out strategy in patients with TN to avoid further CT measurements.

Diagnostic Utility of Procalcitonin for Sporadic Medullary Thyroid Carcinoma in Patients with Nodular Disease and Mild or Moderate Hypercalcitoninemia.

Many authors recommend the measurement of serum calcitonin (Ctn) to screen for sporadic medullary thyroid carcinoma (MTC) in patients with thyroid nodules. In this situation, procalcitonin (pro-Ctn) would have greater utility in patients with hypercalcitoninemia<100 pg/ml. The aim of this study was to evaluate the utility of pro-Ctn in patients with thyroid nodules and without a suspicion of familial MTC or type 2 multiple endocrine neoplasia who had mild or moderate hypercalcitoninemia without an apparent cause. Consecutive patients with nodular thyroid disease assessed routinely by Ctn measurement were selected. Sixty patients with basal Ctn>10 pg/ml but<100 pg/ml were included. Nine patients (15%) had MTC, with cytology being diagnostic in only four. Among the 51 patients without MTC, pro-Ctn was<0.1 ng/ml in 46 (90.2%). All patients with MTC had pro-Ctn>0.1 ng/ml. Basal Ctn was>24.6 pg/ml in all patients with MTC and in 42 patients (82.3%) without MTC. It is noteworthy that among patients with basal Ctn>24.6 pg/ml (n=18) pro-Ctn>0.1 ng/ml identified all patients with MTC and 64.2% of subjects with these pro-Ctn concentrations had this tumor. In conclusion, we did not find superiority of pro-Ctn over Ctn for the diagnosis of sporadic MTC in patients with nodular disease and mild or moderate hypercalcitoninemia. However, in the case of patients with hypercalcitoninemia in the gray zone, pro-Ctn has an excellent negative predictive value while the data regarding its positive predictive value are not uniform.

Colorectal medullary carcinoma: heterogeneous presentations of a rare clinico-pathological entity. Report of two cases.

Colorectal medullary carcinoma (CMC) is a rare subset of minimally differentiated carcinomas. CMC tend to be right-sided and present at an advanced stage. Despite this, distant metastases are rare at presentation. The liver and the regional lymph nodes represent the most common sites of metastases. Most of the time, CMCs exhibit mismatch repair deficiency and a strong association with high-level microsatellite instability. There is no conspicuous data regarding treatment strategies and short-term outcomes. CMC is supposed to be related to better prognosis compared to poorly-differentiated and undifferentiated colonic adenocarcinomas, but reports are controversial.This lesion, with heterogeneous presentations and unclear prognostic significance, may be unfamiliar to histopathologists and can lead to diagnostic uncertainty and overtreatments.Our aim is to renew the attention to this rare histological subtype through the report of two cases.

Molecular targets of tyrosine kinase inhibitors in thyroid cancer.

Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in ∼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %-50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis. Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAFV600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor. Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.

The value of routine measurement of serum calcitonin on insufficient, indeterminate, and suspicious thyroid nodule cytology.

Routine calcitonin measurement in patients with nodular thyroid disease is rather controversial. The aim of this study was to evaluate the contribution of serum calcitonin measurement in the diagnostic evaluation of thyroid nodules with insufficient, indeterminate, or suspicious cytology. Out of 1668 patients who underwent thyroidectomy with the diagnosis of nodular thyroid disease and were screened, 873 patients with insufficient, indeterminate, or suspicious fine needle aspiration biopsy results were included in the study. From the total number of patients in this study, 10 (1.1%) were diagnosed as medullary thyroid cancer (MTC) using histopathology. The calcitonin level was detected to be above the assay-specific cut-off in 23 (2.6%) patients ranging between 6.5 - 4450 pg/mL. While hypercalcitoninemia was detected in all 10 MTC patients, a false positive elevation of serum calcitonin was detected in 13 patients (1.5%). Of the MTC group, 7 patients had cytology results that were suspicious for malignancy (Bethesda V), one patient's cytology showed atypia of undetermined significance (Bethesda III) and two patient's cytology results were suspicious for follicular neoplasm (Bethesda IV). Among the cases with non-diagnostic cytology (Bethesda I), none of the patients were diagnosed with MTC. In conclusion, routine serum calcitonin measurement can be performed in selected cases rather than in all nodular thyroid patients. While it is reasonable to perform routine calcitonin measurement in patients with Bethesda IV and Bethesda V, this measurement was not useful in Bethesda I patients. In Bethesda III patients, patient-based decisions can be made according to their calcitonin measurement.

Calcitonin and complementary biomarkers in the diagnosis of hereditary medullary thyroid carcinoma in children and adolescents.

OBJECTIVES: Medullary thyroid carcinoma (MTC) is a rare malignancy that is effectively curable by surgery. Unlike in adults, hereditary MTC has a predominant role in children. A fast and safe diagnosis is important to assure the good prognosis for the patients. A major cornerstone is the assessment of biomarkers, but the interpretation must respect their pre-, post- and analytical features. Especially calcitonin (Ctn) is a challenging biomarker in daily laboratory diagnostics. However, Ctn is of particular relevance for the diagnostic in MTC. The American Thyroid Association recommends thyroidectomy if the upper reference range of Ctn is exceeded. Interestingly, age-dependent reference ranges for children and adolescents have become available only recently for Ctn assays. With this review, we aim to highlight the importance of a timely diagnosis of MTC in children and adolescents. CONTENT: Recent developments in pediatric biochemical diagnostics of MTC were summarized. This includes guidance on interpretation of RET, Ctn, procalcitonin, carcinoembryonic antigen, carbohydrate antigen 19-9, and chromogranin A. SUMMARY: Currently, Ctn is the most investigated biomarker in the diagnosis of MTC in children and adolescents. Other biomarkers as PCT suggest complementary evidence about pediatric MTC but their interpretation based largely on adult's data. A successful treatment of MTC requires, besides results of biomarkers, information about medical history, RET gene analysis and recent guideline knowledge. OUTLOOK: More research is required to validate complementary biomarkers of Ctn in children. Additionally, the effect of different confounder on pediatric Ctn levels has to be further clarified.

Haplotype-resolved germline and somatic alterations in renal medullary carcinomas.

BACKGROUND: Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited. METHODS: We used linked-read genome sequencing to reconstruct germline and somatic haplotypes in 15 unrelated patients with RMC registered on the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 or from our prior study. We performed fine-mapping of the HBB locus and assessed the germline for cancer predisposition genes. Subsequently, we assessed the tumor samples for mutations outside of SMARCB1 and integrated RNA sequencing to interrogate the structural variants at the SMARCB1 locus. RESULTS: We find that the haplotype of the sickle cell mutation in patients with RMC originated from three geographical regions in Africa. In addition, fine-mapping of the HBB locus identified the sickle cell mutation as the sole candidate variant. We further identify that the SMARCB1 structural variants are characterized by blunt or 1-bp homology events. CONCLUSIONS: Our findings suggest that RMC does not arise from a single founder population and that the HbS allele is a strong candidate germline allele which confers risk for RMC. Furthermore, we find that the SVs that disrupt SMARCB1 function are likely repaired by non-homologous end-joining. These findings highlight how haplotype-based analyses using linked-read genome sequencing can be applied to identify potential risk variants in small and rare disease cohorts and provide nucleotide resolution to structural variants.