Germline RET Research Articles

Is peptide receptor radionuclide therapy still a promising option for medullary thyroid carcinoma?

Medullary thyroid carcinoma (MTC) is a rare cancer that originates from germline RET proto-oncogene mutations in all hereditary forms and from somatic RET mutations in most sporadic cases. Currently, highly selective RET inhibitors have been approved for clinical use in patients with RET mutations with persistent, recurrent or metastatic disease. This therapy has proven efficacy, low toxicity, and a limited impact on patients' quality of life. However, for recurrent or metastatic RET-negative disease, few systemic therapies are available. Multikinase inhibitors are used; however, tumour cells frequently develop resistance mechanisms, or treatment must be discontinued due to the high incidence of side effects. In this context, peptide receptor radionuclide therapy (PRRT) may be a treatment option, but its clinical utility remains under investigation. The aim of this review is to evaluate the evidence of PRRT in MTC and discuss its limitations in the RET inhibitor era.

Unlocking the Potential of Multigene Parallel Sequencing: A Concomitant Germline RET and BRCA1 Mutation in a Hereditary Medullary Thyroid Carcinoma

We report a rare case of a 33-year-old South Asian woman who visited the Molecular Pathology and Genomics Department referred for hereditary germline cancer genetic testing after being diagnosed with high-grade, multifocal medullary carcinoma of the thyroid. Genetic counselling showed an elaborate family history of cancer. Germline cancer testing on 113 genes for pancancer panel by next-generation sequencing showed a pathogenic heterozygous single nucleotide variant in RET gene c.1901G>C p.Cys634Ser (codon10) and an incidental finding of the presence of a pathogenic splice variant in BRCA1 gene c.213-1G>C at the intron 4 of the gene. The patient was further managed with a paradigm of Precision Medicine (PM) based on the 5Ps like participation, psychological support, and prediction of risk assessment, prevention, and personalisation.

6454 Identifying Gaps in Obtaining Germline RET Testing for Patients with Medullary Thyroid Cancer

Abstract Disclosure: A.N. Lim: None. J. Comeaux: None. C. Ricker: None. K.S. Wei: None. T.E. Angell: None. Background: Medullary thyroid carcinoma (MTC) occurs sporadically or from germline pathogenic variants of the RET proto-oncogene in multiple endocrine neoplasia type 2 (MEN2). Current ATA guidelines recommend germline RET testing in all patients with C-cell hyperplasia or MTC. Because disparities may exist in the implementation of this recommendation, we analyzed records of patients with MTC to identify variables associated with germline RET testing. Methods: Patients with MTC were identified from a cohort study of all adult patients undergoing thyroid surgery from 2015-2022 at two affiliated academic centers: a private hospital or a safety-net hospital. Patients were categorized as RET-tested or not RET-tested. Data collection included: patient age, gender, ethnicity, nodule and lymph nodule findings on ultrasound (US), calcitonin and CEA levels, and surgical pathology results. Medical reports were reviewed for reasons that RET testing was or was not obtained. Results: Of 24 MTC patients, 50% were female, mean age ± SD was 50.8 ± 12.3, and 15 (62.5%) had Hispanic ethnicity. RET testing was performed in 14 (58.3%) patients and 3 (21.4%) had a pathogenic variant. RET-tested patients had a median nodule size of 3.45 cm (IQR 2.40-4.53) vs. 2.40 cm (IQR 0.98-3.25) in not-RET tested patients (p<0.05). There were no significant differences between groups in age, gender, ethnicity, preoperative US findings, preoperative calcitonin or CEA levels, or histopathologic status. RET testing was performed in 11/14 (78.6%) patients at the private hospital vs. only 5/10 (50.0%) patients at the safety-net hospital (p=0.20). Considering this, we further investigated the use of RET testing in the initial management of MTC patients. RET testing was performed or planned during initial management in 13/14 (92.9%) patients at the private hospital vs. only 5/10 (50%) patients at the safety-net hospital (p=0.05). At the private hospital, RET testing was requested for apparent sporadic disease (n=11), family history of MTC (n=1), and coexistent pheochromocytoma (n=1). At the safety-net hospital, RET testing was requested for apparent sporadic disease (n=4) and family history of MTC (n=1), but reportedly was not pursued in 5 patients because MTC appeared to be sporadic. Discussion: In this cohort of patients with MTC, larger nodule size was significantly associated with the rate of germline RET testing. Larger MTC tumor size alone may have prompted greater attention to germline testing, but also may have been associated with other findings, which could be further assessed with a larger sample size by multivariable analysis. The disparity in RET testing as part of initial management at the safety-net hospital may be multifactorial, but future analyses should explore provider decision-making, as well as facility and patient variables. Presentation: 6/1/2024

12396 A Case Of Medullary Thyroid Carcinoma Without Germline RET Mutation

Abstract Disclosure: I. Marranzini Rodriguez: None. M. Lemelman: None. L. Canham: None. Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor that originates from the parafollicular C cells of the thyroid gland. MTC accounts for approximately 5% of thyroid cancer in children, and the majority of MTC cases are associated with the autosomal dominant tumor predisposition syndrome Multiple Endocrine Neoplasia 2 (MEN2). Sporadic MTC is uncommon in the pediatric population and associated with somatic mutations of RET or RAS (1). Existing management options for metastatic disease have demonstrated some benefit, however, with systemic side effects. Selpercatinib, a highly selective RET kinase inhibitor, is FDA approved for patients >= 12 years of age. Here we present a case of a 10-year-old patient with metastatic MTC with encouraging results. Clinical Case: A previously healthy 10 year 2-month-old male presented with left-sided neck swelling. Imaging showed a 9.7 cm solid mass spanning nearly the entire left neck, occluding the left internal jugular vein, extending to the upper chest, and resulting in high-grade narrowing of the trachea near the thoracic inlet; the mass involved the left thyroid gland and engulfed the left common carotid. His initial lab evaluation showed an elevated TSH of 10.10 mcU/mL (0.6-5.5 mcU/mL) and Free T4 1.22 ng/dL (0.9-1.67 ng/dL). Tumor markers revealed a calcitonin of 32,264 pg/mL (normal range <= 6.0 pg/mL) and carcinoembryonic antigen (CEA) of 200 ng/ml (normal range 0 – 3.4 ng/mL). He underwent biopsy of the mass which showed medullary thyroid carcinoma (MTC) and genetic evaluation of tumoral tissue showed RET c.2753T>C, p.M918T somatic mutation. Evaluation for pheochromocytoma and hyperparathyroidism, given association of MTC with MEN2, was negative. Genetic testing was negative for germline RET mutations. He was started on selpercatinib, 120 mg every 12 hours. Follow up imaging after 2 months of therapy demonstrated a significant decrease in tumor burden. Approximately 5 months after starting he had a decrease in CEA to 14.8 ng/mL and calcitonin to 69 pg/mL, prior to surgery. Given the risk of locoregional recurrence he underwent total thyroidectomy with lateral neck dissection. However, the tumor was noted to be adherent to the trachea, encasing the left recurrent laryngeal nerve, and left carotid artery preventing full resection. He was started on levothyroxine at 62.5 mcg daily on POD#1 and re-started on selpercatinib approximately 2 weeks post-operatively. Conclusion: We present a case of RET-positive metastatic medullary thyroid carcinoma without germline RET mutation successfully treated with selpercatinib. Long-term follow-up for sustained response and tolerability is needed. Reference: 1. Bauer, Andrew J. “Pediatric Thyroid Cancer: Genetics, Therapeutics and Outcome.” Endocrinology and metabolism clinics of North America vol. 49,4 (2020): 589-611. doi:10.1016/j.ecl.2020.08.00 Presentation: 6/2/2024

12556 Medullary Thyroid Cancer With Persistent Elevation Of Carcinoembryonic Antigen: Case Report

Abstract Disclosure: M.S. Campana: None. Introduction: Medullary thyroid Cancer (MTC) is a rare neuroendocrine tumor that originates from thyroid parafollicular C-cells and represents 5 % of all thyroid cancers. MTC can be sporadic (75%) or hereditary (25%) associated with multiple endocrine neoplasia type 2 syndrome (MEN2). Serum calcitonin (Ctn) and carcinoembryonic antigen (CEA) are its tumor markers. We report a case of persistently elevated CEA levels despite an undetectable Ctn in a patient with MTC after initial thyroid lobectomy. Description of the case: A 42-year-old woman self-identified a neck lump after intentional weight loss. A neck US showed a right lobe thyroid nodule which resulted as suspicious for malignancy (Bethesda V) with subsequent right lobectomy. Pathology reported a 2.6 cm unexpected MTC with negative surgical margins, extrathyroidal extension, angioinvasion, and lymphatic invasion. No cervical lymph nodes (LNs) were removed. Immunohistochemistry was positive for CEA, chromogranin A, synaptophysin, and Ctn. T2 Nx. One month after lobectomy, the Ctn was 10.5 (0-3.0 pg/mL) and CEA 205.2 (0-3.0 ng/mL Non-smoker; 0-5.0 ng/mL smoker). The patient was then referred to our clinic for further management. Laboratories showed normal serum calcium, PTH, and fractionated plasma metanephrine/normetanephrine. A 2-month post-operative Ctn was undetectable, but CEA was elevated at 24.5. Subsequently, we broaden imaging studies to include neck US, CT neck /chest with contrast, and MRI abdomen pelvis with contrast. The only remarkable finding was a 6.7 cm pelvic mass with normal Ca-125. Genetic testing was negative for germline RET, ruling out MEN2. Patient underwent completion left lobectomy with prophylactic bilateral central neck dissection. Pathology showed benign thyroid parenchyma with multinodular hyperplasia and 0/12 LNs. Because of concerning pelvic mass, the patient was referred to OB/GYN. She underwent a laparoscopic bilateral salpingo-oophorectomy. Pathology showed a follicular ovarian cyst, negative for malignancy. A year post-completion total thyroidectomy Ctn remains undetectable, and a CEA is normal at 1.3. Discussion: Because Ctn was already undetectable 1 month after lobectomy with persistent elevated CEA a complete total thyroidectomy with prophylactic bilateral central neck dissection was indicated to achieve operative cure. Ctn is specific to MTC but variable. CEA is more reproducible with less variability; however, it is not specific to MTC and can also be elevated in smokers, benign breast and genitourinary disease, emphysema, cirrhosis, and cancer of colon, rectum, liver, genitourinary, and lung. If residual disease is present, Ctn tends to be proportionally more elevated than CEA. When the opposite occurs, poorly differentiated MTC with possibility of distant metastases vs. a second primary malignancy vs. a distant benign neoplasm known to elevate CEA need to be ruled out. Presentation: 6/2/2024

Thyroid Malignancy and Cutaneous Lichen Amyloidosis: Key Points Amid RET Pathogenic Variants in Medullary Thyroid Cancer/Multiple Endocrine Neoplasia Type 2 (MEN2).

We aimed to provide an updated narrative review with respect to the RET pathogenic variants and their implications at the clinical and molecular level in the diagnosis of medullary thyroid cancer (MTC)/multiple endocrine neoplasia (MEN) type 2, particularly with respect to the presence of cutaneous lichen amyloidosis (CLA). We searched English-language, in extenso original articles with no timeline nor study design restriction that were published on PubMed. A traditional interplay stands for CLA and MTC in MEN2 (not MEN3) confirmation. While the connection has been reported for more than three decades, there is still a large gap in understanding and addressing it. The majority of patients with MEN2A-CLA have RET pathogenic variants at codon 634; hence, it suggests an involvement of this specific cysteine residue in both disorders (most data agree that one-third of C634-positive subjects have CLA, but the ranges are between 9% and 50%). Females seem more prone to MEN2-CLA than males. Non-C634 germline RET pathogenic variants included (at a low level of statistical evidence) the following: RET V804M mutation in exon 14 for MTC-CLA (CLA at upper back); RET S891A mutation in exon 15 binding OSMR variant G513D (familial MTC and CLA comprising the lower legs to thighs, upper back, shoulders, arms, and forearms); and C611Y (CLA at interscapular region), respectively. Typically, CLA is detected at an early age (from childhood until young adulthood) before the actual MTC identification unless RET screening protocols are already applied. The time frame between CLA diagnosis and the identification of RET pathogenic variants was between 5 and 60 years according to one study. The same RET mutation in one family is not necessarily associated with the same CLA presentation. In MTC/MEN2 subjects, the most affected CLA area was the scapular region of the upper back. Alternatively, another hypothesis highlighted the fact that CLA is secondary to long-term prurit/notalgia paresthetica (NP) in MTC/MEN2. OSMR p. G513D may play a role in modifying the evolutionary processes of CLA in subjects co-harboring RET mutations (further studies are necessary to sustain this aspect). Awareness in CLA-positive patients is essential, including the decision of RET testing in selected cases.

Usefulness of extensive germline ret testing in apparently sporadic medullary thyroid cancer

Usefulness of extensive germline ret testing in apparently sporadic medullary thyroid cancer

Spontaneous and Treatment-Related Changes of Serum Calcitonin in Medullary Thyroid Cancer: Long-Term Experience in a Patient With Multiple Endocrine Neoplasia Type 2B.

Medullary thyroid carcinoma (MTC) in MEN2B syndrome is associated with germline RET mutation. Patients harboring de novo mutations are usually diagnosed at more advanced disease stages. We present a young woman with Met918Th mutation diagnosed with stage IV MTC at age 10 years. The disease progressed despite total thyroidectomy and multiple surgical interventions for cervical lymph node recurrences, leading to distant metastases in the fifth year after the initial diagnosis. Subsequently, she underwent five different types of tyrosine kinase inhibitor (TKI) treatments. The 17-year disease course was divided into periods defined by four surgical interventions and sequential treatment intervals with four multikinase (sunitinib, vandetanib, cabozantinib, and lenvatinib) and one RET-selective TKI (selpercatinib). Tumor growth for different phases of spontaneous development and drug treatment intervals was characterized by changes in serial log-transformed calcitonin measurements (n = 114). Three operations (one for calcitonin-producing adrenal pheochromocytoma) were associated with drops in calcitonin levels. All of the nonselective TKIs were stopped due to adverse effects. As reflected by the negative calcitonin doubling rate, the best treatment response was observed with selpercatinib, which was associated with an initial large drop followed by a decreasing calcitonin trajectory over 514 days without any major side effects. This case of MEN2B medullary thyroid cancer with long-term survival presents how the effectiveness of different treatment modalities can be estimated using log-transformed calcitonin levels. Furthermore, our experience supports the view that serial calcitonin measurements may be more sensitive than radiological follow-up in advanced MTC. Our patient also represents a new case of rarely reported calcitonin-producing pheochromocytomas.

Selpercatinib for treating recurrent mixed medullary and follicular cell-derived thyroid carcinoma: a case report

BackgroundMixed medullary and follicular cell-derived thyroid carcinoma (MMFCC) is characterized by the coexistence of follicular and C cell–derived tumour cell populations within the same lesion. Due to its rarity, its etiology and clinical course remain unclear, and treatment for advanced or recurrent cases has not been established.Case presentationWe report a case of MMFCC treated with selpercatinib. The patient was a 69-year-old male presenting with tumors in the right thyroid lobe and in the upper mediastinum. Fine-needle aspiration (FNA) cytology of the right thyroid lobe tumor revealed a medullary carcinoma; germline RET mutations were not detected. After resection of the right thyroid lobe with central node dissection, rapid intraoperative diagnosis of the mediastinal mass confirmed malignancy, leading to total thyroidectomy with excision of the upper mediastinal tumor. Histologically, the tumor in the right thyroid lobe and the pretracheal lymph node revealed a mixture of medullary and follicular carcinoma components, diagnosed as MMFCC. The mediastinal lymph node exhibited only medullary carcinoma components. At 11 months postoperatively, computed tomography scans showed enlargement of the right supraclavicular and upper mediastinal lymph nodes. FNA cytology of the right supraclavicular lymph node suggested the recurrence of medullary thyroid carcinoma. The gene panel testing (The Oncomine Dx Target Test Multi-CDx system®, Thermo Fisher SCIENTIFIC) of metastatic lymph node revealed RET somatic mutation (M918T). Treatment with selpercatinib was initiated, and both the cervical and mediastinal lymph nodes showed a reduction in size.ConclusionsWe report a rare case of selpercatinib use for MMFCC. Since RET mutations may occur frequently in MMFCC, selpercatinib could be effective in treating MMFCC.

Not Only RET but NF1 and Chromosomal Instability Are Seen in Young Patients with Sporadic Medullary Thyroid Carcinoma.

Genetic analysis of sporadic medullary thyroid carcinoma (MTC) has revealed somatic variants in RET, RAS, and occasionally other genes. However, around 20% of patients with sporadic MTC lack a known genetic driver. To uncover potential new somatic or germline drivers, we analyze a distinct cohort of patients with sporadic, very early-onset, and aggressive MTC. Germline and somatic DNA exome sequencing was performed in 19 patients, previously tested negative for germline RET variants. Exome sequencing of 19 germline samples confirmed the absence of RET and identified an NF1 pathogenic variant in 1 patient. Somatic sequencing was successful in 15 tumors revealing RET variants in 80%, predominantly p.Met918Thr, which was associated with disease aggressiveness. In RET-negative tumors, pathogenic variants were found in HRAS and NF1. The NF1 germline and somatic variants were observed in a patient without a prior clinical diagnosis of neurofibromatosis type 1, demonstrating that the loss of heterozygosity of NF1 functions as a potential MTC driver. Somatic copy number alterations analysis revealed chromosomal alterations in 53.3% of tumors, predominantly in RET-positive cases, with losses in chromosomes 9 and 22 being the most prevalent. This study reveals that within a cohort of early-onset nonhereditary MTC, RET remains the major driver gene. In RET-negative tumors, NF1 and RAS are drivers of sporadic MTC. In addition, in young patients without a RET germline mutation, a careful clinical evaluation with a consideration of germline NF1 gene analysis is ideal to exclude Neurofibromatosis type 1 (NF1).

Extent of Surgery for Medullary Thyroid Cancer and Prevalence of Occult Contralateral Foci

Standard treatment for patients with medullary thyroid cancer (MTC) consists of total thyroidectomy with central neck dissection, but the rationale for bilateral surgery in patients with unilateral disease on ultrasonography remains unclear. To determine the presence of occult contralateral disease (lesions not seen on preoperative ultrasonography) in patients with MTC as a rationale for total thyroidectomy. This multi-institutional, retrospective cohort study was conducted from September 1998 to April 2022 in academic medical centers and included patients with MTC who underwent thyroidectomy with preoperative imaging. The primary end point was the prevalence of sonographically occult foci of MTC in the contralateral lobe among patients with sporadic MTC. The cohort comprised 176 patients with a median age at diagnosis of 55 years (range, 2-87 years), 69 (57.6%) of whom were female. Genetic testing was performed in 109 patients (61.9%), 48 (27.5%) of whom carried germline RET variants. Initial surgical management consisted of total thyroidectomy (161 [91.0%]), lobectomy followed by completion thyroidectomy (7 [4.0%]), and lobectomy alone (8 [4.5%]). Central and lateral neck dissections were performed as part of initial therapy for 146 patients (83.1%). In the entire cohort of 176 patients, 46 (26.0%) had contralateral foci disease and 9 (5.1%) had occult contralateral foci that were not identified on preoperative ultrasonography. Among 109 patients who underwent genetic testing, 38 (34.9%) had contralateral disease, 8 (7.3%) of whom had occult contralateral disease not seen on preoperative ultrasonography. Patients with sporadic MTC experienced a 95.7% reduction in the odds of having a focus of MTC in the contralateral lobe compared with patients with a germline RET variant (odds ratio, 0.043; 95% CI, 0.013-0.123). When adjusting for age, sex, tumor size, and lymph node involvement, the odds ratio of having contralateral MTC in patients with sporadic disease was 0.034 (95% CI, 0.007-0.116). Among patients who underwent lobectomy alone with postoperative calcitonin levels, 5 of 12 (41.7%) achieved undetectable calcitonin levels (<2.0 pg/mL; to convert to pmol/L, multiply by 0.292). The results of this cohort study suggest that a staged approach involving initial thyroid lobectomy could be considered in patients with sporadic MTC and no contralateral ultrasonography findings, with no further surgery if calcitonin levels became undetectable. Further work using prospective randomized clinical trials to evaluate lobectomy as a biochemical cure in patients presenting with unilateral disease is warranted.

An audit of medullary thyroid carcinoma from a tertiary care hospital in northwest India.

Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy originating from parafollicular C cells. It accounts for 5%-10% of all thyroid malignancies. An ambispective analysis of pathologically proven MTC presented in a tertiary care hospital in northwest India was performed after considering demography, clinical manifestation, RET mutation status, management, and outcome as denominators. Among 2,735 thyroid malignancy cases who presented to our institute in the last 10 years (2012-2022), 78 (3%) had MTC with a mean age of presentation of 43 ± 11 years; 60% of them were female. The median duration of symptoms was 23 months (IQR 12-36 months). The most common presenting complaint was goiter with lymphadenopathy (80.8%). Among the atypical presentations, one each had ectopic Cushing's syndrome, hypertensive crisis in pregnancy due to pheochromocytoma, synchronous chondrosarcoma, and Von Hippel-Lindau disease spectrum. Median calcitonin and carcinoembryonic antigen (CEA) levels at presentation were 1,274 pg/mL (n = 64) and 149 ng/mL (n = 39), respectively. Twenty-two patients were germline RET mutation-positive, and they presented at a younger age. Majority of the patients presented with stage IV disease. Surgery was the primary modality of therapy. Twenty-nine patients received radiotherapy and 25 patients received tyrosine kinase inhibitors (TKIs). Nine patients received peptide receptor radiotherapy (PRRT) with Lu-177 with neoadjuvant capecitabine. Median progression-free survival (PFS) was 60 months. Patients without structurally and biochemically residual disease and stable disease after the first modality of therapy (Log-rank 11.4; p = 0.004) had a better PFS. Female patients (Log-rank: 9.5; p = 0.002) had a better PFS than male patients. This study showed that MTC comprises 3% of thyroid malignancies with a female preponderance. RET mutation-positive patients had a younger age at presentation. Surgery was the first-line therapy. Radiotherapy, TKI, and PRRT were given as a part of second-line or third-line therapy due to persistent disease and/or disease recurrence. The median PFS was better in female patients and in patients who had no residual lesions and stable disease after the primary modality of therapy.

Familial Clinical Heterogeneity of Medullary Thyroid Cancer with Germline RET S891A Protooncogene Mutation: 7-Year Follow-up with Successful Sorafenib Treatment.

Hereditary forms of Medullary thyroid carcinoma (MTC) are rare. Different phenotypes with the same mutation may be due to differences in the timing of RET activation steps, additional mutations in other regions of the gene, or the co-occurrence of germline and somatic mutations, which is an infrequent possibility. Here, we aim to present the different features and difficulties in the follow-up of three family members with the same germline mutation. A 4-year-old male patient with respiratory distress was diagnosed with MTC and found to have a heterozygous germline mutation C.2671T>G(S891A) in the RET gene (classified as intermediate risk according to ATA). As the tumor was inoperable, treatment with a tyrosine kinase inhibitor (sorafenib) was initiated. Sorafenib has prevented tumor progression for seven years. Whole exome sequencing (WES) did not identify additional mutations. Segregation analysis showed the same mutation in the asymptomatic mother and sister. In our case, thyroid tissues were examined for somatic mutations, and SDHA c.1223C>T (p.S408L) was found. The clinical presentation of rare mutations such as RET p.S891A differed among family members carrying the same germline mutation. Our index case's more severe clinical presentation may be due to an additional somatic mutation. Sorafenib treatment can be an option for advanced MTC and may prevent disease progression.

SAT561 Pathogenic RET V804M Germline Variant Without Clinical Manifestations Of Multiple Endocrine Neoplasia Type 2 In An Elderly Male

Abstract Disclosure: R. Ghosh: None. G. Al-Naqeeb: None. P. Veeraraghavan: None. C. Craig: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Background: Germline pathogenic variants in the RET protooncogene give rise to multiple endocrine neoplasia (MEN) types 2A and 2B. MEN2A is mainly characterized by MTC (∼100%), pheochromocytoma (PHEO; 4% - 88%), and primary hyperparathyroidism (HPTH; 2% - 30%), while MEN2B predominantly manifests with MTC (100%), PHEO (50%), mucocutaneous neuromas, and marfanoid habitus. Both MEN2A and 2B follow an autosomal dominant mode of inheritance. While certain pathogenic RET variants (M918T, A883F, and C634X) have high penetrance and present with aggressive disease, other variants such as V804M are of low penetrance and manifest with clinically mild disease.Clinical case: A 75-year-old male was referred to our center for further evaluation of the finding of an abnormal RET gene that was identified on a peripheral blood whole-exome gene sequencing research panel performed at an outside center. The patient was noted to have a germline RET c.2410 G&amp;gt;A, p.V804M heterozygous pathogenic variant. The patient denied any history of lump in the neck, symptoms of hyper- or hypothyroidism, tremors, headaches, fatigue, facial flushing, palpitations, constipation, diarrhea, anxiety, depression, or history of fragility fractures. Medical history consisted of hypertension, nephrolithiasis, type 2 diabetes mellitus, obstructive sleep apnea, interstitial pulmonary fibrosis, and colonic diverticula and polyps. Family history was significant for leukemia, colon, and breast cancers, but none of the relatives had a history of MTC, PHEO, or MEN2, and his children, while healthy, had not undergone RET germline testing. Physical examination showed no evidence of hypothyroidism or hyperthyroidism. Neck examination showed no evidence of thyromegaly or cervical lymphadenopathy. Laboratory investigations were unremarkable [serum calcitonin: 7.9 pg/ml (NL: &amp;lt;/=14.3), CEA 2.8 mcg/L (NL: 0.8-3.4), thyrotropin (TSH): 1.92 microIU/ml (NL: 0.35-4.94), free thyroxine: 0.9 ng/dl (NL: 0.7-1.5), plasma free normetanephrine: 0.31 nmol/L (NL: &amp;lt;0.9), plasma free metanephrines 0.24 nmol/L (NL: &amp;lt;0.5), parathyroid hormone: 28.2 pg/ml (NL: 15-65), and ionized calcium 1.23 mmol/l (NL: 1.09-1.30)]. Thyroid sonogram was normal. We recommended active annual surveillance with biochemical markers and imaging along with genetic testing of the RET gene in his children. Conclusion: The V804M RET variant has been often associated with MTC or MEN2A phenotypes [1]. However, the variable expression of this variant may lead to a mild clinical phenotype or even absence of MTC/MEN2A manifestations. Hence, active surveillance as opposed to radical surgery like prophylactic thyroidectomy would be more beneficial in patients with no clinical or biochemical evidence of disease. Reference: Pinna et al., 2007, V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype. Thyroid, 17(2), 101-104. Presentation Date: Saturday, June 17, 2023

SAT540 A Case of Simultaneous Medullary Thyroid Cancer (MTC) And Papillary Thyroid Cancer (PTC) In a Patient With Germline RET Mutation

Abstract Disclosure: N. Vaghasia: None. G. Jaiswal: None. Introduction: There are only handful of cases reported of concurrent MTC and PTC in a patient with germline RET proto-oncogene mutation. Case: A 41 year old female with no PMH presented to Endocrine clinic for evaluation of recently diagnosed RET mutation. Patient’s nephew passed away at 5 weeks of age from abnormal organogenesis of heart and brain. Genetic testing showed germline RET mutation. Subsequently her brother and his two children was tested positive for RET mutation. Patient underwent genetic testing which was positive for RET mutation. Patient was found to be heterozygous for p.V804M (c.2410G&amp;gt;A) mutation reported as moderate risk mutation in the RET gene. The result was consistent with an increased risk for RET-related cancers. No family history of MTC, pheochromocytoma or primary hyperparathyroidism was identified. Patient was asymptomatic on presentation and no previous symptoms concerning for any RET mutation related disease. Her physical examination was normal. Patient underwent testing for pheochromocytoma and hyperparathyroidism which was unremarkable. Patient’s calcitonin level was also normal. Patient had US thyroid done to evaluate for nodule and was found to have 1.62 x 0.97 x 1.50 cm mixed solid cystic, hypoechoic, irregular margins and punctate echogenic foci right sided nodule. No abnormal cervical lymph nodes. Patient underwent FNA of the suspicious nodule which was reported as benign based on Bethesda classification. Patient’s calcitonin level was undetectable &amp;lt;0.2 pg/ml (0.0-5.0). Patient underwent total thyroidectomy and on surgical pathology had three papillary microcarcinomas, classic type, 0.4 cm (right lobe), 0.3 cm (left lobe) and 0.1 cm (right lobe). Patient had medullary microcarcinoma 0.2 cm on left lobe. Background thyroid with C-cell hyperplasia. No lymphovascular invasion, no extrathyroidal extension and margins cleared. Discussion: Association of simultaneous MTC-PTC have been reported in few case reports in patient with germline RET mutation. There has been no risk factors or specific patient phenotype identified in previous cases to suggest any association between the two. One important feature in our case is the presence of highly suspicious thyroid nodule which on FNA was benign. This raise an important question on whether the co-existence of MTC and PTC in germline RET mutation decreases sensitivity of FNA. Also it is yet unknown if specific mutation like in our case p.V804M (c.2410G&amp;gt;A) is associated with higher incidence of multi-tumor pathology or not. Finally, our patient had normal calcitonin level despite having MTC which is unusual. Conclusion: Coexistence of MTC and PTC in germline RET mutation is an uncommon association and more information is required to understand common features, risk factors, phenotype and cancer aggressiveness in these patients. At this point it cannot be concluded that the association is a mere coincidence. Presentation Date: Saturday, June 17, 2023

SAT568 A Case Of Medullary Thyroid Cancer Associated With Cutaneous Metastasis: A Rare And Aggressive Presentation

Abstract Disclosure: N. Vaghasia: None. F. Hasan: None. M. Grimes: None. Introduction: Cutaneous metastasis (CM) is an extremely rare site of metastasis in medullary thyroid cancer (MTC). It suggests aggressive malignancy and poor prognosis in most cases. Case: A 26 year old male with no PMH presented to ER with neck discomfort and lump noted few weeks prior to presentation. Neck examination revealed a tender left uninodular goiter. Thyroid US revealed a 7.1 cm solid, hypoechoic, lobular, taller than wide left thyroid nodule with macrocalcification and two abnormal appearing level 2 and 3 left cervical lymph nodes. FNA of all three lesions were positive for MTC. CT neck and PET scan suggested locally advanced tumor surrounding carotid artery and esophagus plus metastatic lesion in the pelvis. Interestingly, serum calcitonin was only modestly elevated at 28.9 pg/ml (0.0-8.4), while serum CEA was high at 8.7 ng/mL (0-3.0). Genetic testing for germline RET mutation was negative. Patient underwent a total thyroidectomy with central and left lateral neck dissection and pelvic mass resection with pathology revealing MTC, stage T4b N1b M1. Molecular testing was negative for RET mutation. Patient underwent EBRT of the neck for residual disease after surgery. Patient was started on Cabozantinib therapy. Seven months after initial presentation, he had new skin lesions, one on scalp and two on left lateral chest wall described as 1-2 cm cystic papular lesion, reddish-yellow in color and tender to palpation. Excision of all three lesions were positive for MTC confirming CM. Patient’s most recent PET scan suggested residual disease in the neck and new metastatic lesion in the right humerus. Patient’s serum calcitonin level remained within the reference range after surgery despite residual disease. Discussion: MTC with CM is extremely rare with fewer than 10 reported cases. Most of them are associated with high mortality with death within one year from diagnosis. Most of the cases had skin lesions in upper body with scalp being the most common site. Not much is known about the molecular profiling of MTC with CM. Our case is similar to previously reported cases in terms of disease aggressiveness and skin lesions involving the scalp and upper chest. Two unique features about our case are: first, the modest elevation of calcitonin preoperatively despite large tumor burden and normal calcitonin after surgery despite having residual disease and new distant metastasis. Second, molecular profiling of our patient was negative for germline mutations in association with MTC. This may suggest the presence of an unknown mutation or pathway leading to this unusual manifestation in MTC. Conclusion: In a patient with known MTC, skin lesions especially on scalp should raise suspicion for metastatic and aggressive MTC. With minimally elevated calcitonin and negative RET mutation our case raise one important question - Is a normal calcitonin and negative RET oncogene associated with an aggressive form of MTC? Presentation: Saturday, June 17, 2023

Pathogenic Insights into DNA Mismatch Repair (MMR) Genes-Proteins and Microsatellite Instability: Focus on Adrenocortical Carcinoma and Beyond.

DNA damage repair pathways, including mismatch repair (MMR) genes, are prone to carcinoma development in certain patients. The assessment of the MMR system is widely recognized as part of strategies concerning solid tumors (defective MMR cancers), especially MMR proteins (through immunohistochemistry), and molecular assays for microsatellite instability (MSI). We aim to highlight the status of MMR genes-proteins (including MSI) in the relationship with ACC (adrenocortical carcinoma) according to current knowledge. This is a narrative review. We included PubMed-accessed, full-length English papers published between January 2012 and March 2023. We searched studies on ACC patients for whom MMR status was assessed, respectively subjects harboring MMR germline mutations, namely Lynch syndrome (LS), who were diagnosed with ACC. MMR system assessments in ACCs involve a low level of statistical evidence. Generally, there are two main types of endocrine insights: 1. the role of MMR status as a prognostic marker in different endocrine malignancies (including ACC)-which is the topic of the present work, and 2. establishing the indication of immune checkpoint inhibitors (ICPIs) in selective, mostly highly aggressive, non-responsive to standard care forms upon MMR evaluation (which belongs to the larger chapter of immunotherapy in ACCs). Our one-decade, sample-case study (which, to our knowledge, it is the most comprehensive of its kind) identified 11 original articles (from 1 patient to 634 subjects per study diagnosed with either ACC or LS). We identified four studies published in 2013 and 2020 and two in 2021, three cohorts and two retrospective studies (the publication from 2013 includes a retrospective and a cohort distinct section). Among these four studies, patients already confirmed to have LS (N = 643, respective 135) were found to be associated with ACC (N = 3, respective 2), resulting in a prevalence of 0.0046%, with a respective of 1.4% being confirmed (despite not having a large amount of similar data outside these two studies). Studies on ACC patients (N = 364, respective 36 pediatric individuals, and 94 subjects with ACC) showed that 13.7% had different MMR gene anomalies, with a respective of 8.57% (non-germline mutations), while 3.2% had MMR germline mutations (N = 3/94 cases). Two case series included one family, with a respective four persons with LS, and each article introduced one case with LS-ACC. Another five case reports (between 2018 and 2021) revealed an additional five subjects (one case per paper) diagnosed with LS and ACC (female to male ratio of 4 to 1; aged between 44 and 68). Interesting genetic testing involved children with TP53-positive ACC and further MMR anomalies or an MSH2 gene-positive subject with LS with a concurrent germline RET mutation. The first report of LS-ACC referred for PD-1 blockade was published in 2018. Nevertheless, the use of ICPI in ACCs (as similarly seen in metastatic pheochromocytoma) is still limited. Pan-cancer and multi-omics analysis in adults with ACC, in order to classify the candidates for immunotherapy, had heterogeneous results, and integrating an MMR system in this larger and challenging picture is still an open issue. Whether individuals diagnosed with LS should undergo surveillance for ACC has not yet been proven. An assessment of tumor-related MMR/MSI status in ACC might be helpful. Further algorithms for diagnostics and therapy, also taking into consideration innovative biomarkers as MMR-MSI, are necessary.

Abstract #1399269: Never Too Old for Genetics: An Unusually Late Presentation of Medullary Thyroid Cancer in MEN2A

Virtually all germline RET pathogenic variant carriers develop medullary thyroid carcinoma (MTC). If possible, thyroidectomy should be performed prophylactically, before developing MTC. We describe a patient with pheochromocytoma found to have a germline RET p.Cys634Ser pathogenic variant at age sixty years who would be categorized as high risk based on genotype classification described by the American Thyroid Association and would have warranted prophylactic thyroidectomy at a young age. A 60-year-old man with history of hypothyroidism and osteopenia was found to have an adrenal mass during evaluation for kidney stones. It measured 4.1 x 3.2 x 3.8 cm on CT scan of abdomen and pelvis. MRI with and without gadolinium revealed a 4 cm left adrenal mass with T2 enhancement. Diagnosis of pheochromocytoma was confirmed with elevated levels of plasma free metanephrine and normetanephrine. The adrenal nodule showed avid uptake on PET CT Gallium-68 DOTATATE scan. No uptake was noted on the contralateral adrenal gland or in the neck. Patient underwent left adrenalectomy. Surgical pathology confirmed pheochromocytoma. Patient also had evidence of primary hyperparathyroidism (pHPT). Germline genetic analysis revealed a RET c.1900T >A(p.Cys634Ser) pathogenic variant confirming the diagnosis of multiple endocrine neoplasia type 2A (MEN2A). Calcitonin level was noted to be mildly elevated at 27.8 pg/ml. Subsequently, patient underwent total thyroidectomy, subtotal parathyroidectomy and bilateral central neck dissection. Surgical pathology revealed multifocal MTC, diffuse C-cell hyperplasia, and a foci of papillary thyroid microcarcinoma. Immunohistochemistry for calcitonin revealed diffuse C-cell hyperplasia. Patient was doing well on postoperative follow up and calcitonin level downtrended to < 2 pg/ml. Nearly all patients with MEN2A have either C-cell hyperplasia (CCH) or MTC, approximately 50% have a pheochromocytoma and 20-30% have pHPT. Age-related penetrance of CCH and hMTC is mutation dependent. Peak incidence in index patients is in the third decade of life in MEN2A. Our patient presented in the sixth decade of life. We decided to pursue genetic testing. The DOTATE scan did not show uptake in the neck and the calcitonin was only mildly elevated. However, as there is known complete penetrance of MTC in patients with MEN2A syndrome, patient underwent total thyroidectomy with central neck dissection with results of surgical pathology confirming presence of MTC. This case highlights the importance of considering genetic syndromes even in patients who present at older ages and challenges the classic genotype-phenotype correlation of the RET p.Cys634Ser pathogenic variant and MTC.

Update on C-Cell Neuroendocrine Neoplasm: Prognostic and Predictive Histopathologic and Molecular Features of Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is a C-cell-derived epithelial neuroendocrine neoplasm. With the exception of rare examples, most are well-differentiated epithelial neuroendocrine neoplasms (also known as neuroendocrine tumors in the taxonomy of the International Agency for Research on Cancer [IARC] of the World Health Organization [WHO]). This review provides an overview and recent evidence-based data on the molecular genetics, disease risk stratification based on clinicopathologic variables including molecular profiling and histopathologic variables, and targeted molecular therapies in patients with advanced MTC. While MTC is not the only neuroendocrine neoplasm in the thyroid gland, other neuroendocrine neoplasms in the thyroid include intrathyroidal thymic neuroendocrine neoplasms, intrathyroidal parathyroid neoplasms, and primary thyroid paragangliomas as well as metastatic neuroendocrine neoplasms. Therefore, the first responsibility of a pathologist is to distinguish MTC from other mimics using appropriate biomarkers. The second responsibility includes meticulous assessment of the status of angioinvasion (defined as tumor cells invading through a vessel wall and forming tumor-fibrin complexes, or intravascular tumor cells admixed with fibrin/thrombus), tumor necrosis, proliferative rate (mitotic count and Ki67 labeling index), and tumorgrade (low- or high-grade) along with the tumor stage and the resection margins. Given the morphologic and proliferative heterogeneity in these neoplasms, an exhaustive sampling is strongly recommended. Routine molecular testing for pathogenic germline RET variants is typically performed in all patients with a diagnosis of MTC; however, multifocal C-cell hyperplasia in association with at least a single focus of MTC and/or multifocal C-cell neoplasia are morphological harbingers of germline RET alterations. It is of interest to assess the status of pathogenic molecular alterations involving genes other than RET like theMET variants in MTC families with no pathogenic germline RET variants. Furthermore, the status of somatic RET alterations should be determined in all advanced/progressive or metastatic diseases, especially when selective RET inhibitor therapy (e.g., selpercatinib or pralsetinib) is considered. While the role of routine SSTR2/5 immunohistochemistry remains to be further clarified, evidence suggests that patients with somatostatin receptor (SSTR)-avid metastatic disease may also benefit from the option of 177Lu-DOTATATE peptide radionuclide receptor therapy. Finally, the authors of this review make a call to support the nomenclature change of MTC to C-cell neuroendocrine neoplasm to align this entity with the IARC/WHO taxonomy since MTCs represent epithelial neuroendocrine neoplasms of endoderm-derived C-cells.

Genetics and genomics in healthcare: The future is now.

Genetics and genomics in healthcare: The future is now.