8787 A Case of Indolent Medullary Thyroid Cancer with Sporadic HRAS Mutation and Prolonged Stability

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

Medullary thyroid cancer (MTC) has a historic recurrence rate up to 50%, and surgery remains the only cure. This study aims to assess factors related to recurrence and metastatic spread in MTC. Retrospective chart review was performed from 1990 to 2023 at a single specialized tertiary care referral center. Descriptive analysis and regression models were used for analysis. Sixty-eight patients with MTC, who underwent surgery, were included and the main outcome measure was recurrence. Mean age at diagnosis was 54.9 years (42.2-64.1), 65% (n = 44) females. Lymph node and distant metastases were found in 24% (n = 16) and 4% (n = 3), respectively. RET mutations were present in 52% (n = 35): MTC risk levels were highest 6%, high 7%, and moderate 39%. Mean tumor size was 1.9 cm (1.2-3.2) and mean preoperative calcitonin was 504.4 pg/mL (133.2-1833.8). Total thyroidectomy (TT) was performed in 10 patients, TT + central neck dissection (CND) in 28, and TT + CND + lateral neck dissection (LND) in 25. On final pathology, 40% had positive central nodes and 25% had positive lateral nodes. Recurrence was 22%, median follow-up 4.7 years (1.2-28.0). Male gender (hazard ratio [HR] 5.81, P = .021), positive lateral neck nodes (HR 8.10, P = .011), and high/highest MTC risk level RET mutations (HR 8.66, P = .004) were significantly associated with recurrence. Preoperative calcitonin >2175 pg/mL was a strong predictor for distant metastasis (area under the curve [AUC] 0.893) and a good predictor for lateral neck disease (AUC 0.706). Extent of surgery was not significantly associated with recurrence (P = .634). One of 4 patients undergoing surgery for MTC will recur. Risk factors associated with recurrence are male gender, lateral lymph node metastasis, and high/highest MTC risk level mutations, but not necessarily surgery type. Preoperative calcitonin >2175 pg/mL is suggestive of advanced disease and should prompt further evaluation.

Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

ObjectiveThe co-existence of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) is rare. The study analyzed the clinicopathological findings and prognosis of concomitant PTC in MTC patients.MethodsClinicopathological data and follow-up outcomes of 25 patients with concurrent medullary and papillary thyroid carcinoma (combination group) between January 2009 and May 2024 were collected and analyzed retrospectively. We compared clinicopathologic characteristics and follow-up outcomes between patients with concurrent MTC and PTC (combination group) and those with MTC alone (MTC group).ResultsThe 25 patients with concurrent MTC and PTC comprised 19 females and 6 males. There were no statistically significant differences between the combination group and the MTC group in terms of age, gender, or pathological features such as the diameter of MTC lesions, multifocality, extra-thyroidal extension (ETE), number of lymph node (LN) resected, the number of LN metastasis, the maximum diameter of LN metastasis, and TNM staging. The recurrence rate was similar between the two groups. Univariate analysis showed that the max tumor diameter, capsule invasion, extracapsular invasion and recurrent nerve invasion were associated with the risk of biochemical/structural abnormalities in MTC group. Multivariate analysis showed that only the max tumor diameter and capsule invasion were significant independent prognostic factors for biochemical/structural abnormalities.ConclusionThe result of this comparative study between patients with MTC and PTC co-existence and those with MTC alone showed similar invasiveness and prognosis.

6000 Background: Cabo extends progression-free survival (PFS) in patients (pts) with progressive, metastatic MTC (Schöffski, J Clin Oncol 30, 2012). Mutations in the RET oncogene are associated with most hereditary cases and ~half of sporadic cases of MTC. RAS gene mutations have recently been identified in subsets of RET wild type (wt) cases. Therefore, we investigated the association of RET (a prospectively defined endpoint) and RAS mutations (a post hoc analysis) with efficacy outcomes in the phase 3 study of cabo in MTC. Methods: Pts enrolled into the double-blind, placebo-controlled phase III trial were evaluated for the presence of somatic and germline RET mutations using Sanger and next generation methods. A subset of pts determined to be RET wt (44 pts) or RET unknown (41 pts) were then evaluated for tumor-associated mutations in KRAS, NRAS, and HRAS in codons 12, 13, and 61 by next generation sequencing. Impact of RET and RAS gene mutation status was evaluated with respect to PFS and tumor response rate (RR) according to RECIST. Results: RET status was determined in 65% of the study pts (215/330), of which 79% harbored an activating mutation, and 21% were RET wt. All RET mutational subgroups (RET mutated, RET wt, and RET unknown) showed hazard ratios indicating PFS benefit from cabo treatment, and demonstrated RRs between 22% and 32%. However pts harboring a RET mutation had longer median PFS on cabo (60 wks) than pts with wt RET (25 wks, PFS difference p=0.0001). Also, pts with the poor prognosis mutation RET M918T showed a longer median PFS on cabo treatment (61 wks) than pts with any other RET mutation (36 wks, PFS difference p=0.009). Patients with hereditary MTC had similar PFS to those with sporadic disease, and the presence of the common RET polymorphism G691S had no effect on either PFS or RR. Sixteen of 85 tested pts (5% of total study pts) with wt or unknown RET status were found to harbor a RAS gene mutation. The RAS-mutated pts showed a similar RR (31%) and PFS (47 wks) as RET mutated pts (32% and 60 wks). Conclusions: While hazard ratios indicate PFS improvement for all RET subgroups on cabo, the extent of benefit may depend in part on RET genotype. Cabo treatment benefit is also seen in pts harboring a RAS mutation. Clinical trial information: NCT00704730.

Medullary thyroid cancer (MTC) accounts for around 5-10% of all thyroid cancers. Though usually sporadic, 1 in 4 cases are of genetic origin, with germinal mutations in the RET proto-oncogene in familial forms and somatic mutations both in RET and in the RAS family genes in sporadic ones.This study aimed to characterize a rare H-RAS sequence variant -M72I- in a patient with sporadic MTC, focusing on its functional significance.Mutation analysis was performed for the RET, N-RAS, K-RAS and H-RAS genes by direct sequencing. Western blot analysis was done on 4 thyroid tissues from 1 patient carrying the M72I mutation in H-RAS, 1 with the Q61R mutation in H-RAS, 1 with no RET, H-RAS, K-RAS or N-RAS gene mutations, and 1 normal thyroid, using different antibodies against Erk1/2, phospho-Erk1/2 (Thr202/Tyr204), Akt and phospho-Akt (Ser473). Large-scale molecular dynamics simulations were completed for H-RAS wt and H-RAS M72I.Western blot analysis demonstrated that both MAPK and PI3K/Akt pathways were activated in the MTC patient carrying the M72I variant. In silico results showed conformational changes in H-RAS that could influence its activation by Sos and phosphate binding. Results of molecular dynamics were consistent with Western blot experiments.The M72I mutation may contribute effectively to proliferation and survival signaling throughout the MAPK and PI3K/Akt pathways. This work underscores the importance of studying genetic alterations that may lead to carcinogenesis.

Medullary thyroid cancer (MTC) is a relatively rare thyroid malignancy, constituting a small percentage of all thyroid cancer cases. Even more rare is the occurrence of mixed MTC and papillary thyroid cancer (PTC), found in a very small fraction of MTC cases. These cancers originate from different cell types with distinct developmental origins. The coexistence of MTC and PTC in the same patient raises questions about whether this occurrence is merely coincidental or if there is an underlying genetic link. We present the case of a woman with metastatic mixed MTC and PTC.A 61-year-old woman with a history of Hashimoto's disease was found to have bilateral thyroid nodules; the largest (1.7 cm) was in the right lobe. This nodule met fine needle aspiration (FNA) biopsy criteria and was found to have a follicular neoplasm of undetermined significance. The patient elected to pursue total thyroidectomy instead of lobectomy given the presence of bilateral nodules. Postoperative pathology showed mixed medullary carcinoma (pT3b) and follicular variant papillary thyroid microcarcinoma (pT1a) involving the right lobe with positive anterior and posterior margins and lymphovascular invasion. Preoperative calcitonin was not checked. However, post-thyroidectomy calcitonin was 1599 pg/mL. She underwent central and right lateral neck dissection which showed 27 out of 35 lymph nodes were positive for malignancy. Postoperative calcitonin dropped to 38.7 pg/mL. She then established care in our endocrine clinic. Screening for pheochromocytoma and primary hyperparathyroidism was normal. She underwent external beam radiation of the neck. A year after her initial surgery, her neck ultrasound and computed tomography (CT) studies show no signs of local or distant anatomic recurrence. Her thyroglobulin level remains undetectable, carcinoembryonic antigen (CEA) within normal range, and calcitonin stable at about 20 pg/mL. She is on levothyroxine 100 mcg daily with thyroid-stimulating hormone (TSH) at a suppression goal of <0.1 mIU/L. Mixed PTC and MTC is poorly studied due to its rarity. The origin of these mixed tumors is unclear, but some suggest that they arise from neoplastic changes of remnant multipotent cells in the thyroid. While patients with PTC often have a favorable prognosis following surgical therapy, MTC has a more aggressive course. We suggest monitoring patients like ours for both MTC and PTC, as if present in isolation. Our case highlights the clinical aspects of this condition and our current knowledge of its pathophysiology.

Medullary thyroid carcinoma (MTC) is characterized by proto-oncogene RET mutations in almost all hereditary cases as well as in more than 40% of sporadic cases. Recently, a high prevalence of RAS mutations was reported in sporadic MTC, suggesting an alternative genetic event in sporadic MTC tumorigenesis. This study aimed to extend this observation by screening somatic mutational status of RET, BRAF, and the three RAS proto-oncogenes in a large series of patients with MTC. Direct sequencing of RET (exons 8, 10, 11, 13, 14, 15, 16), BRAF (exons 11 and 15), and KRAS, HRAS, and NRAS genes (exons 2, 3, and 4) was performed on DNA prepared from 50 MTC samples, including 30 sporadic cases. Activating RET mutations were detected in the 20 hereditary cases (germline mutations) and in 14 sporadic cases (somatic mutations). Among the 16 sporadic MTC without any RET mutation, eight H-RAS mutations and five K-RAS mutations were found. Interestingly, nine RAS mutations correspond to mutation hot spots in exons 2 and 3, but the other four mutations were detected in exon 4. The RET and RAS mutations were mutually exclusive. No RAS gene mutation was found in hereditary MTC, and no BRAF or NRAS mutation was observed in any of the 50 samples. Our study confirms that RAS mutations are frequent events in sporadic MTC. Moreover, we showed that RAS mutation analysis should not be limited to the classical mutational hot spots of RAS genes and should include analysis of exon 4.

Medullary thyroid carcinoma (MTC) represents 4–10 % of all thyroid carcinomas; MTCs arise from the parafollicular cells (C cells). Around 20–25 % of MTCs are part of inherited multiple endocrine neoplasia type 2 (MEN2) syndromes, while the rest are sporadic. Most are MEN2 syndromes that are divided in MEN2A and MEN2B. MEN2A represents 95 % of all MEN2 cases and is subdivided in 4 variants: classical MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung’s disease (HD), and familial medullary thyroid carcinoma (FMTC). Codon 634 in exon 11 is found mutated in 80–93 % of MEN2A patients. MEN2B are 5 % of all patients with MEN2 syndromes. MEN2B is characterized by the presence of MTC, pheochromocytoma, ganglioneuromatosis of the intestine and oral mucosa, neuromas of the tongue, marfanoid habitus, and medullated corneal nerve fibers. The mutation M918T in exon 16 is found in 95–100 % of MEN2B cases. Two thirds of sporadic MTCs have somatic mutations in RET: M918T in exon 16, the most common mutation; 8–68 % of the RET mutation-negative cases have somatic mutations in HRAS and KRAS. RET germline mutations should be offered to all patients with C-cell hyperplasia, familial MTC, and apparently sporadic MTC. These molecular studies are very helpful in characterizing these tumors.

SummaryWe report a rare case of concurrent medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC) with intermixed disease in several of the lymph node (LN) metastases in a patient who was subsequently diagnosed with clear cell renal cell carcinoma (RCC). A 56 year old female presented with dysphagia and was found to have a left thyroid nodule and left superior cervical LN with suspicious sonographic features. Fine needle aspiration biopsy (FNAB) demonstrated PTC in the left thyroid nodule and MTC in the left cervical LN. Histopathology demonstrated multifocal PTC with 3/21 LNs positive for metastatic PTC. One LN in the left lateral neck dissection exhibited features of both MTC and PTC within the same node. In the right lobe, a 0.3 cm focus of MTC with extra-thyroidal extension was noted. Given persistent calcitonin elevation, a follow-up ultrasound displayed an abnormal left level 4 LN. FNAB showed features of both PTC and MTC on the cytopathology itself. The patient underwent repeat central and left radical neck dissection with 3/6 LNs positive for PTC in the central neck and 2/6 LNs positive for intermixed PTC and MTC in the left neck. There was no evidence of distant metastases on computed tomography and whole body scintigraphy, however a 1.9 x 2.5 cm enhancing mass within the right inter-polar kidney was discovered. This lesion was highly suspicious for RCC. Surgical pathology revealed a 2.5 cm clear cell RCC, Fuhrman grade 2/4, with negative surgical margins. She continues to be observed with stable imaging of her triple malignancies.Learning points:Mixed medullary-papillary thyroid neoplasm is characterized by the presence of morphological and immunohistochemical features of both medullary and papillary thyroid cancers within the same lesion. Simultaneous occurrence of these carcinomas has been previously reported, but a mixed disease within the same lymph node is an infrequent phenomenon.Prognosis of mixed medullary-papillary thyroid carcinomas is determined by the medullary component. Therefore, when PTC and MTC occur concurrently, the priority should be given to the management of MTC, which involves total thyroidectomy and central lymph node dissection.Patients with thyroid cancer, predominantly PTC, have shown higher than expected rates of RCC. To our knowledge, this is the first report describing the combination of MTC, PTC, and RCC in a single patient.

Preoperative serum inflammation-based scores in medullary thyroid cancer

Preoperative serum inflammation-based scores in medullary thyroid cancer

Abnormal expression of non-coding micro RNA (miRNA) has been described in medullary thyroid carcinoma (MTC). Expression of genes encoding factors involved in miRNA biogenesis results often deregulated in human cancer and correlates with aggressive clinical behavior. In this study, expression of four genes involved in miRNA biogenesis (DICER, DROSHA, DCGR8, and XPO5) was investigated in 54 specimens of MTC. Among them, 33 and 13 harbored RET and RAS mutations, respectively. DICER, DGCR8, and XPO5 mRNA levels were significantly overexpressed in MTC harboring RET mutations, in particular, in the presence of RET634 mutation. When MTCs with RET and RAS mutations were compared, only DGCR8 displayed a significant difference, while MTCs with RAS mutations did not show significant differences with respect to non-mutated tumors. We then attempted to correlate expression of miRNA biogenesis genes with tumor aggressiveness. According to the TNM status, MTCs were divided in two groups and compared (N0 M0 vs. N1 and/or M1): for all four genes no significant difference was detected. Cell line experiments, in which expression of a RET mutation is silenced by siRNA, suggest the existence of a causal relationship between RET mutation and overexpression of DICER, DGCR8, and XPO5 genes. These findings demonstrate that RET- but not RAS-driven tumorigenic alterations include abnormalities in the expression of some important genes involved in miRNA biogenesis that could represent new potential markers for targeted therapies in the treatment of RET-mutated MTCs aimed to restore the normal miRNA expression profile.

Dear Editor, It is well known that medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) have different histogeneses, the former being of neuroectodermal and the latter of endodermal origin. The simultaneous occurrence of these two tumors is a rare phenomenon, observed either as a mixed tumor (dual differentiation) or as a concurrent/collision tumor (spatially different tumors with well-defined components) [1]. We describe a case of concurrent MTC and PTC in a patient with a RET proto-oncogene germline mutation. A 63-year-old male, with type 2 DM, stage III chronic kidney disease (CKD), and hypertension, without prior history of head and neck radiation or family history of endocrine disease, was evaluated for an asymptomatic goiter. Thyroid ultrasound revealed a 0.6× 0.9×1.2 cm solid hypoechoic nodule with microcalcification in the right superior thyroid lobe. Fine needle aspiration biopsy (FNAB) was suspicious for medullary neoplasm. Calcitonin was high (175 pg/ml) and carcinoembryogenic antigen (CEA) was normal (3.3 ng/ml). Urine catecholamines and metanephrines were normal. He underwent total thyroidectomy and central lymph node dissection. There was a 0.5×0.7×1.5 cm MTC in the right lobe with capsular invasion without extra-thyroidal extension or perineural invasion. 1/5 level VI lymph nodes was positive for metastatic disease. The tumor cells were positive for calcitonin, CEA, and thyroid transcription factor-1 (TTF-1) and negative for thyroglobulin. C-cell hyperplasia was present (Fig. 1). A spatially distinct 0.4-cm second tumor was identified in the right lobe, focally invading the perithyroid fibroadipose tissue suggestive of extrathyroidal extension. The tumor cells were positive for cytokeratin-19 (CK19) and galectin and negative for calcitonin, consistent with micro-PTC (Fig. 2). Baseline and stimulated thyroglobulin were undetectable. Whole body scan showed two small foci of faint activity in the thyroid bed. RET proto-oncogene germline genetic testing was positive for Y791F (Tyr791Phe) in exon 13. This mutation is associated with low penetrance and less aggressive MTC. Somatic BRAF was not identified in either PTC or MTC tumors (Fig. 3a, b). The PTC tissue was negative for RET/PTC1 and RET/PTC3 rearrangements. CT scan of the chest, neck, and abdomen revealed multiple normal appearing cervical and mediastinal lymph nodes. A left adrenal adenoma measuring 1.9 cm was noted. Salivary cortisol, plasma aldosterone, and plasma renin activity were normal which suggested a non-functioning adrenal adenoma. Secondary hyperparathyroidism was attributed to vitamin D deficiency and CKD and was treated with vitamin D and calcium. Stage III MTC (pT1bN1aM0) and an * Robert J. Anderson Robert.Anderson4@va.gov

Background: Medullary thyroid carcinoma (MTC) is a rare thyroid cancer with a disproportionate high mortality and can be sporadic or familial. Surgery is the only potentially curative treatment. Our aim was to access demographic, clinical and pathological characteristics of MTC patients associated with biochemical failure after surgery. Methods: Retrospective observational study of patients with MTC diagnosed between 1984 and 2018 and followed-up in our institution. Results: We evaluated 76 individuals with MTC, 27.6% with hereditary MTC, 69.7% female, median of age 49 years-old (IQR 33.50-60.00). The median of preoperative calcitonin levels was 1121 pg/mL (IQR 445-4383), being ≥500 pg/mL in 72.3%. Preoperative calcitonin levels, when performed, had a sensitivity of 97.9%. According to TNM staging (AJCC 8th ed.), 35.9% were in stage I, 15.6% in stage II, 1.6% in stage III and 46.9% in stage IV. One patient had poor functional status, contraindicating surgery. A total of 75 patients were submitted to thyroidectomy (or completion thyroidectomy when indicated) with lymph node dissection at our institution (n=50) or an outside one (n=25). Biochemical cure (BC) was achieved in 48 (64%) patients after surgery; of these, 7 (14.58%) relapsed. BC was 95.7% in stage II, 100% in stages II/III and 24.1% in stage IV (p<0.001). Biochemical failure occurred in 36% of patients, all of them with preoperative calcitonin levels ≥500 pg/mL (p<0.001). There were no significant differences in sex, age, presence of germline RET mutation and results of fine-needle aspiration cytology between groups. Regarding histological features, patients with biochemical failure had higher tumor size (2.5 cm vs. 1.9 cm, p=0.025), multifocality (66.7% vs. 37.5%, p=0.024), vascular invasion (76.5% vs. 43.8%, p=0.028), perineural invasion (23.4 % vs. 0%, p=0.024), capsular invasion (82.4% vs. 12.1%, p<0.001), extrathyroidal extension (57.9% vs. 7.9%, p<0.001), surgical margin positivity (57.9% vs. 7.9%, p<0.001) and lymph node positivity (100% vs. 33.3%, p<0.001). Preoperative calcitonin levels (OR per increments of 500 pg/mL=1.183; p=0.012), tumor size in cm (OR=2.093; p=0.003), multifocality (OR=2.769; p=0.049), vascular invasion (OR=4.250; p=0.024), capsular invasion (OR=27.000; p<0.001), extrathyroidal extension (OR=85.000; p<0.001), surgical margins positivity (OR=17.455; p=0.001) and lymph nodes positivity (OR=62.500; p<0.001) were predictors of biochemical failure. The 5-year survival rate was higher in the BC group (91.7% vs. 74.1%; p=0.049). Conclusions: Several tumor histological characteristics were the best predictors for biochemical failure and preoperative calcitonin level was the only significant predictor performed before surgery. Demographic data, RET mutation and cytology were not associated with BC. These findings highlight that early detection is important to achieve BC in MTC.