bluuebunny/crossref_metadata_2025 huggingface dataset:
Reverse T3 Level and T3 to Reverse T3 Ratio in Dried Blood Spot Samples at Birth May Facilitate Early Diagnosis of MCT8 Deficiency
Authors: Iwayama Hideyuki , Kakita Hiroki , Iwasa Masumi , Adachi Shinsuke , Takano Kyoko , Kikuchi Masahiro , Fujisawa Yasuko , Osaka Hitoshi , Yamada Yasumasa , Okumura Akihisa , Refetoff Samuel
Published: May 2021

Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X- chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transporter across cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as inability of standard biomarkers of neonatal screening to make an early diagnosis. Here, we report for the first time the ability to identify MCT8 deficiency at birth using dried blood spot (DBS) samples.

Methods: We measured T3, T4, and reverse T3 (rT3) levels in DBS samples obtained at birth in healthy neonates (n = 42) and neonates with genetically confirmed diagnosis of MCT8 deficiency (n = 6). T3, rT3 and T4 levels were measured in 8 mm diameter DBS samples using liquid chromatography-tandem mass spectrometry.

Results: Mean ± SD level of T3 tended to be higher in the MCT8 group than that in healthy neonates (0.941 ± 0.183 ng/mL vs. 0.742 ± 0.195 ng/mL, p = 0.0525). More importantly rT3 level in the MCT8 group was significantly lower than that in healthy neonates (0.317 ± 0.065 ng/mL vs. 0.768 ± 0.196 ng/mL, p < 0.0001) and the T3/rT3 ratio in the MCT8 group was significantly higher (3.04 ± 0.67 vs. 1.01 ± 0.34, p < 0.0001) with no overlap of values. T4 was lower in the MCT8 group than in healthy babies (93.4 ± 22.4 ng/mL vs. 156.7 ± 35.9 ng/mL, p < 0.0005) and the T3/T4 ratio of the MCT8 deficient group was higher (0.0105 ± 0.0029 vs. 0.0051 ± 0.0010, p< 0.0001).

Conclusion: rT3 and T3/rT3 ratio measured in the DBS obtained from neonates can serve as biomarkers for diagnosis of MCT8 deficiency at birth.
Thyroid Function in 3000 Cases of Patients With Atrial Fibrillation Treated With Catheter Ablation
Authors: Yamada Sayaka , Nakajima Yasuyo , Nishikido Ayaka , Akuzawa Masako , Sakamaki Koji , Toki Akiko , Ishida Emi , Shimomura Yonosuke , Kobayashi Isao , Ando Yoshitaka , Maruhashi Michiyo , Naito Shigeto , Yamada Masanobu
Published: May 2021

Objective: Thyroid hormones have various effects on cardiac and circulatory systems, leading to arrhythmias and heart failure. In Europe and the United States, it has been reported that elevated thyroid hormones within the normal range have been reported to be associated with a risk of atrial fibrillation, however, there was no report on Japanese cases, a country that differs in iodine intake and ethnicity from the West. Therefore, we evaluated the abnormality of thyroid function in a large number of cases of atrial fibrillation (AF) who received catheter ablation (RFCA) in Japan. Methods: We evaluated 2,937 cases of atrial fibrillation (2,084 males, mean age 64.1±10.7 years and 853 females, 69.0±8.5 years) who underwent RFCA at the Gunma Prefectural Cardiovascular Center between 2012 and 2018. As a control we used a total of 15,660 participants for health check-up (9,176 males, mean age 49.7±9.8 years and 6,484 females, 48.9±10.3 years) from 2006 to 2013, and we evaluated thyroid function after adjusting for gender-specific age. Results: The prevalence of overt hyperthyroidism was significantly higher in the RFCA-treated male group (0.43%) than in the control group (0.07%), even after adjusting for age (p<0.01). Similarly, the prevalence of subclinical hyperthyroidism was also significantly higher in the RFCA-treated male group (3.12%) than in the control group (0.94%) after adjusting for age (p<0.01). On the other hand, subclinical hypothyroidism was significantly lower in the RFCA-treated group after adjusting for age (2.97% in the RFCA-treated group and 3.93% in the control group, p<0.01). Females showed the same results as males. Conclusions: In an iodine rich country Japan, not only overt hyperthyroidism but also subclinical hyperthyroidism is an obvious risk factor for severe atrial fibrillation in Japan. Intriguingly, subclinical hypothyroidism might contribute to the prevention of atrial fibrillation, suggesting that slightly higher serum TSH levels might be better for elderlies.
Urinary Steroid Metabolome Signature is Associated With Cognitive Function in Older Adults
Authors: Singh Sumitabh , Ebbehoj Andreas , Stricker Nikki , Mielke Michelle , Bostwick J Michael , Rivard Ann L , Singh Ravinder J , Grebe Stefan Karl Gunther , Thomas Melinda , Khosla Sundeep , Rocca Walter A , Bancos Irina
Published: May 2021

Background: Elevated urine cortisol (<1% of urinary steroid metabolome) was reported to predict future development of dementia. Our objective was to determine the association of urine steroid metabolome and its diurnal variation with cognitive function in men and women. Methods: Cross-sectional study of community-dwelling adults ≥ 50 years. Participants with adrenal disorders, end-stage renal or liver disease, on exogenous steroids or drugs affecting steroid metabolism were excluded. All participants completed day and night separate urine collection. A series of seven IPad-based tests using the National Institute of Health Toolbox Cognition Battery were administered to evaluate five key domains; performance was reported using fully corrected T-scores for age, sex, education, and race with a national normative mean of 50. T-scores were generated for the two summary measures: 1) fluid cognition (includes executive function, episodic memory, working memory, and processing speed), and 2) total composite (composite of fluid and language score). Urine samples were analyzed with the liquid-chromatography, high-resolution, accurate-mass mass spectrometry for 25 urine steroid metabolites. Results: Of 109 participants, 56 (51%) were women, and age and educational status were similar in men and women. On cognitive assessment, men and women had similar median composite cognition (T-score of 53 vs 54, p=0.74) and fluid cognition (T-score of 53 vs 51, p-value 0.96). Urine steroid metabolome analysis demonstrated 21/25 steroids were higher in men vs women. In both women and men, the ratio of total cortisol metabolites/total androgen metabolites (TCM/TAM) was associated with lower fluid cognition (women: ρ= -0.34, p=0.01, men: ρ= -0.43, p=0.001) and composite cognition (women: ρ= -0.27, p=0.04, men: ρ= -0.39, p=0.004). Higher ratio of day to night TCM were associated with a better fluid cognition in men (ρ= 0.35, p=0.01), but not in women (ρ= -0.11, p=0.41). Steroid ratios suggesting a relative enzymatic deficiency of 5α-Reductase type 2 was associated with lower fluid cognition in women (ρ= -0.29, p=0.03). In men, the fluid composite score was associated with a relative deficiency in 21-Hydroxylase (ρ= 0.42, p=0.002), 3β-Hydroxysteroid dehydrogenase (ρ= 0.43, p=0.001), and P450oxidoreductase (ρ= -0.35, p=0.01). Conclusion: We showed that a higher glucocorticoid to androgen ratio and a flattened circadian steroid variation were associated with lower global and fluid cognition score. Steroid ratios reflecting steroidogenesis enzymatic activity demonstrated sex differences in relation to cognition. Additional studies should examine whether the steroid fingerprint associated with lower cognition is predictive of a future dementia onset.
“The Way to a Man’s Heart” - Adrenocortical Carcinoma With Vascular Invasion Into the Right Atrium and Ventricle
Authors: Aftab Hassaan B , Newton Kaye-Anne L , Kantorovich Vitaly
Published: May 2021

Background: Adrenocortical carcinoma (ACC) is a rare aggressive malignant neoplasm which may present with intravascular extension into the inferior vena cava (IVC) and rarely into the right atrium (RA). Clinical Case: 62-year-old male with no prior known significant medical history presented to ED with 2-day history of mild hematuria with 3-week history of headache. Vital signs were normal other than blood pressure of 198/88 while physical exam was unremarkable. Headache subsided and blood pressure improved to 130/60 range after IV labetalol administration. CT abdomen and pelvis with contrast revealed a large right suprarenal mass extending into the right hepatic vein, IVC, and RA. The right adrenal gland was not visualized while the left adrenal gland and bilateral kidneys were normal. MRI chest, heart and abdomen with contrast showed heterogeneously enhancing lobulated right adrenal mass measuring 11.4 x 11 x 14 cm (AP, transverse, CC, respectively) with extensive tumor thrombus invading the right hepatic vein, IVC, RA and notably protruding into the right ventricle (RV) through the tricuspid valve during diastole. Technitium-99m MDP whole body scan did not show any uptake suspicious for metastases. Pre-op lab assessment showed mildly abnormal 1 mg dexamethasone suppression test but no evidence of ACTH suppression, elevated catecholamines or excess adrenal steroidogenesis. He underwent combined cardiothoracic and abdominal surgery on cardiopulmonary bypass with resection of adrenal mass, removal of thrombus from IVC, RA, RV and patch angioplasty of IVC with bovine pericardium. Pathology report was consistent with ACC (AJCC stage III). On 1 month postoperative follow-up, patient is clinically doing well with plans to start mitotane with addition of etoposide/doxorubicin/cisplatin (EDP) chemotherapy. Conclusion: ACC is a rare, highly aggressive malignancy which may produce extensive intravascular invasion. It may rarely extend to the RA and even rarer into the RV; with 42 and 1 reported cases, respectively. No study has conclusively found that vascular extension of ACC is a poor prognostic factor, hence surgical management is the primary strategy including cases with RA/RV involvement. There is lack of data and consensus regarding adjuvant or palliative medical therapy. However, in phase II trials combination of EDP chemotherapy and mitotane have shown response rates ranging from 11% to 54%. Reference: Alghulayqah, Abdulaziz, et al. “Long-term recurrence-free survival of adrenocortical cancer extending into the inferior vena cava and right atrium: Case report and literature review.” Medicine 96.18 (2017).
A Case of Improvement of Insulinoma Symptoms in Pregnancy
Authors: Syed Shumail , George Andrea
Published: May 2021

Background: Insulinomas are rare tumors with an incidence of approximately 4 cases per million person per year. Only 39 cases of pancreatic neuroendocrine tumors have been reported in pregnancy. We report a case of pregnancy protecting the mother from manifesting the symptoms of insulinoma. Clinical Case: This case describes a 25-year old female who initially noticed symptoms of generalized weakness and oral tingling sensation in Fall 2018. She became pregnant in March 2019. She noticed an immediate reduction of the intensity of her symptoms during pregnancy. Her pregnancy was uneventful, and she delivered a healthy newborn in November 2019. Two months postpartum, she had worsening symptoms including syncopal episodes, confusion, difficulty ambulating and visual changes that improved with PO intake specifically carbohydrate intake. She was evaluated in March 2020 and labs showed the following: venous glucose 32 mg/dL, C-peptide 1.7 nmol/L, BOHB 0.4 mmol/L, Insulin 6.1 microU/ml, Proinsulin 25.8 pmol/L, IGF-2 354 ng/mL, negative insulin antibodies and negative oral hypoglycemic agent screen. TSH was unremarkable and AM cortisol was 16.1 mcg/dL. She was started on diazoxide twice a day. She underwent MRI of abdomen, which was negative followed by an EUS which was also negative. She had run out of her diazoxide and became severely symptomatic resulting in an ER visit where she was found to be hypoglycemic. Further evaluation was done with a Triple Phase spiral CT which showed a 1 cm arterial enhancing focal lesion within the pancreatic neck compatible with insulinoma. This was further evaluated with EUS FNA which confirmed the diagnosis of insulinoma on pathology. Her chromogranin A was 46.5 ng/mL. She is scheduled for surgical removal of the lesion. Conclusion: Pregnancy leads to an increased insulin resistance through hormonal changes with increased expression of placental growth hormone, human placental lactogen and the placental variant of corticotrophin-releasing hormone (via ACTH and cortisol production), TNF-alpha and leptin. These changes that increase the insulin resistance act as a protective mechanism against the detrimental effects of an insulinoma. Pregnancy most likely also delayed the diagnosis of the insulinoma in this patient. Further research is warranted to evaluate the effects of an insulinoma on the mother and fetus. References: 1) Lowy AJ, Chisholm DJ. Insulinoma masked by pregnancy. Intern Med J. 2001 Mar;31(2):128-9. doi: 10.1046/j.1445-5994.2001.00017.x. PMID: 11480477.
A Mass in Disguise: A Rare Case of High-Attenuation Adrenal Myelolipoma
Authors: Kim Yoon Kook , Malek Rana
Published: May 2021

Background: Adrenal incidentalomas are common, and imaging studies play a large role in reaching the diagnosis in many cases. Adrenal myelolipomas are classically diagnosed by CT as a hypodense well circumscribed heterogenous mass with low attenuation. Clinical Case: A 51-year-old man with history of resistant hypertension presented with neck pain after a motor vehicle crash. After a cervical X-ray revealed an odontoid fracture, a whole body CT was obtained. The CT incidentally identified a massive heterogeneous left adrenal mass measuring 22.3 × 15.5 × 20.6 cm, with multiple attenuation measurements ranging from 20 to 53 Hounsfield units (HU). The patient’s physical examination and hormonal assessment were both unrevealing, with normal catecholamine, androgen, and an unremarkable renin aldosterone ratio. Inpatient urinary cortisol levels were elevated, however a repeat urinary cortisol as an outpatient weeks after repair of the odontoid fracture showed normal levels, suggesting physiologic stress response. Positron emission tomography showed a metabolically inactive adrenal mass without metastatic diseases. The patient eventually underwent a left adrenalectomy, and pathology revealed a myelolipoma measuring 24.2 × 20.5 × 8.3 cm. Imaging characteristics for adrenal incidentalomas are considered useful diagnostic information according to most clinical guidelines. Lesions with high HU are typically pheochromocytomas, adrenocortical carcinoma, metastatic disease, or lipid poor adenomas. Myelolipomas are identified on CT by their characteristically low HU (often -30). In this case of a massive myelolipoma with high HU, the unique imaging characteristics posed a diagnostic challenge. The patient’s history of resistant hypertension combined with the high HU led to the patient undergoing extensive testing for a functional mass or cancer. Conclusion: This is a rare case of a massive myelolipoma with low attenuation. The role of imaging studies in the diagnosis of adrenal incidentalomas is not definitive, and detailed exam along with hormonal assessment may be warranted in atypical cases. Providers should consider myelolipoma in the differential diagnosis of a large adrenal mass with a negative hormonal evaluation even in the setting of high HU.
A Rare Case of Chronic Diarrhea in a Pediatric Patient
Authors: Srivastava Priya S , Yen Kevin , Lindquist Robert , Rangaswami Arun , Ozgediz Doruk , Nakakura Erik , Lodish Maya Beth
Published: May 2021

Background: VIPoma, also known as Watery Diarrhea-Hypokalemia- achlorhydria (WDHA) Syndrome is a rare manifestation of multiple endocrine neoplasia syndrome type 1 (MEN1). Vasoactive intestinal peptide, part of the secretin-glucagon family, may be overexcreted in tumors associated with MEN1 and results in diarrhea that persists while fasting, resulting in massive secretion of water and electrolytes. First-line treatment is surgical resection.

Clinical Case: We present a 13-year-old male with a past medical history of chronic diarrhea for four years who was transferred from an outside hospital for severe diarrhea and associated electrolyte derangements, including hypokalemia of <1.0 mmol/L (3.5-5.0 mmol/L), sodium of 120 (135-145 mmol/L), and chloride of 84 mmol/L (101-110 mmol/L). Family history was significant for pancreatic, breast, thyroid, stomach, parathyroid, and uterine cancer, as well as hyperparathyroidism and nephrolithiasis. The patient had been admitted to the hospital before for a similar episode of acute on chronic diarrhea but was treated for infectious diarrhea during that admission. CT enterography was obtained during this hospitalization and it revealed multiple solid and heterogeneous appearing pancreatic masses in the head and tail of the pancreas. Work-up was significant for pancreatic polypeptide of 1,523 pg/mL (92-752 pg/mL) and vasoactive intestinal peptide of 1,105 pg/mL (<75 pg/mL). Pancreatic biopsy revealed a grade 2 pancreatic neuroendocrine tumor. Genetic testing revealed a known pathogenic mutation in the menin gene p.R526 (c. 1579>T, pArg527). A pylorus-preserving total pancreatectomy, duodenectomy, cholecystectomy, and splenectomy was performed and surgical pathology revealed a well-differentiated grade 1 neuroendocrine tumor in the head of the pancreas and a well-differentiated grade 2 neuroendocrine tumor in the tail of the pancreas. Since the surgery, the patient currently has no signs of other neuroendocrine tumors associated with MEN1 but continues to follow-up for regular screening for other tumors associated with MEN1.

Clinical Lessons: 1. VIPoma, also known as Watery Diarrhea- Hypokalemia- Achlorhydria Syndrome, is characterized by secretory diarrhea that persists while fasting. 2. VIPoma should be considered in patients with a history of chronic diarrhea and a significant family history of neuroendocrine tumors.
A Rare Presentation of Multiple Endocrine Neoplasia Type 1
Authors: Pradeep Pallavi , Eisenberg Yuval
Published: May 2021

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal dominant inherited syndrome caused by mutations in the MEN1 tumor suppressor gene with a reported incidence of 2 in 100,000.

Clinical Case: A 26-year-old Caucasian female was seen for surveillance screening given positive familial mutation in the MEN1 gene. She had a significant family history of pathogenic MEN1 in her son, brother, father and paternal aunt. On presentation, she denied any history of headache, nipple discharge, kidney stones, fractures, heart burn, abdominal pain, diarrhea, hypoglycemia, flushing, lightheadedness. She was on hormonal IUD for contraception and had not had menstrual cycles for the last 6 months. Vital signs and physical examination were unremarkable. Her initial evaluation included a normal calcium of 9.8mg/dL (RR:8.6-10.6mg/dL), PTH of 70pg/ml (RR:12-88pg/ml), 25OH-vitamin-D of 11ng/ml (RR:20-80ng/ml). She had normal gastrin, chromogranin A, glucagon, and vasoactive intestinal peptide levels. Prolactin was 17.6ng/ml (RR:3.3-26.7 ng/ml). MRI pituitary showed a 6mm lesion representing a Rathke’s cleft cyst, not compressing surrounding structures.

Two months following the initial encounter, she presented with abdominal pain, nausea, vomiting. She was found to have an obstructing renal stone requiring stent placement. Calcium was 10.1mg/dl. She was also noted to have an incidental pancreatic tail mass of 4.2cm on CT abdomen. She underwent laparoscopic robotic distal spleno-pancreatectomy. Surgical pathology showed a well differentiated 3.5cm neuroendocrine tumor with negative margins, which stained positively for insulin. She had not reported symptoms of weight gain or any episodes suspicious for sympathoadrenal activation or neuroglycopenia, and was again confirmed after surgery.

Patient was re-admitted to the hospital for right-sided flank pain and was found to have a new 6mm obstructing calculus with moderate hydronephrosis of the right kidney. Corrected calcium level was found to be mildly elevated at 11.1mg/dL. Repeat PTH was stable at 81pg/ml, and urinary calcium was elevated at 447.3mg/24h (RR:50-250mg/24h). Subsequently, she underwent 3.5 gland parathyroidectomy and thymectomy. On POD20, PTH was 29pg/ml and calcium was 8.6mg/dl.

Conclusion: This case highlights a rare presentation of MEN1 with an asymptomatic insulinoma and nephrolithiasis, despite having normal calcium and PTH levels initially. Primary hyperparathyroidism is the most common presentation of MEN1, seen in up to 90% of patients. The second most common finding in MEN1 patients, reported in 70% of the cases, are entero-pancreatic tumors, the most common being gastrinoma. Insulinoma, which is less common and is seen in only 10-30% patients, needs documentation of Whipple’s triad. Interestingly, our patient never had any history of hypoglycemia.
ACTH-Producing Thymic Carcinoid: A Rare Cause of Cushing’s Syndrome
Authors: Rodriguez Lisette Patricia , Kozlow Wende Michele
Published: May 2021

Background: Thymic carcinoids are rare neoplasms that account for less than 5% of all thymic tumors. Approximately 25% of these tumors will result in Cushing’s syndrome due to ectopic ACTH secretion. These tumors can also be associated with MEN1 syndrome. This is a case report of a patient with history of macroprolactinoma now presenting with Cushing’s syndrome due to ectopic ACTH production from a thymic carcinoid tumor.

Clinical Case: This is a 57 year old male with history of pituitary macroprolactinoma diagnosed in 2011, now status post transsphenoidal resection and external beam radiation therapy, with persistent hyperprolactinemia on cabergoline, who presented to our clinic for a routine follow up visit. Patient had already developed secondary hypogonadism and secondary hypothyroidism as a consequence of treatment for the macroprolactinoma. He complained of worsening fatigue and weight gain ongoing for several months. Laboratory studies revealed an hemoglobin A1c of 8.3% (nl < 5.7%), TSH 0.24 MIU/L (0.4-4.5 MIU/L), free T4 1.2 ng/dL (0.8-1.8 ng/dL), 8 AM cortisol 31.4 mcg/dL (4-22 mcg/dL), ACTH 185 pg/mL (6-50 pg/dL), prolactin 29.6 ng/mL (2-18 ng/mL), IGF-1 88 ng/mL (50-317 ng/mL). Follow up labs confirmed cushings syndrome: cortisol AM-DST 36.4 mcg/dL (< 2 mcg/dL), free urinary cortisol 291.9 mcg/24h (2-50 mcg/24h). Pituitary MRI showed empty sella turcica. Cortisol after an 8 mg DST 32.5 mcg/dL (< 5 mcg/dL). CT chest, abdomen and pelvis revealed an heterogeneously enhancing solid anterior mediastinal mass measuring 4.9 x 3.1 x 4.3 cm. Whole body OctreoScan showed a markedly hyperintense large mass adjacent to the right heart border measuring 47 x 32 mm. He was referred to cardiothoracic surgery and underwent a right video-assisted thoracic surgery with resection of the anterior mediastinal mass. Pathology revealed a thymic well-differentiated neuroendocrine tumor with strong cytoplasmic staining for ACTH. It was also positive for OSCAR, Cam5.2, synaptophysin, CD56, and S100. Ki67 stain was positive in fewer than 1% of tumor cells. Final diagnosis was carcinoid tumor.

Conclusion: Cushing’s syndrome secondary to ectopic ACTH secretion from a thymic carcinoid is rare. The presence of two MEN1-associated tumors in this patient, macroprolactinoma and thymic carcinoid, is highly suggestive of a clinical diagnosis of MEN 1.
An Unusual Presentation of Parathyroid and Micro Papillary Thyroid Carcinoma
Authors: Griffith Mindy , DeRosairo Anne , Rodriguez Martha Bilbatua
Published: May 2021

Background: Parathyroid carcinoma is a rare endocrine malignancy, that usually presents with parathyroid hormone elevations five to ten times higher than normal. It is rarely diagnosed in cases with a normal or mildly elevated PTH. Clinical Case: 68 yo female with history of Hypertension, Spontaneous Vocal Cord Paralysis, Multinodular Goiter, Breast cancer s/p right radical mastectomy/chemotherapy, and Osteoporosis who presented to outpatient Endocrine clinic for hypercalcemia. Medications include Coreg 12.5 mg BID. Patient was asymptomatic. Labs showed BUN 21 mg/dL [8 mg/dL - 27 mg/dL], Creatinine 0.82 mg/dL [0.57 mg/dL - 1 mg/dL], eGFR 74 ml/min/1.73 m2 [nl>59 ml/min/1.73 m2], Calcium 10.8 mg/dL [8.7 mg/dL - 10.3 mg/dL], Phosphorus 3 mg/dL [3 mg/dL - 4.3 mg/dL], Magnesium 2.2 mg/dL [1.6 mg/dL - 2.3 mg/dL], PTH 77 pg/mL [15 pg/mL - 65 pg/mL], Albumin 4.2 g/dL [3.8 g/dL - 4.8 g/dL], Vitamin D 1,25 Dihydroxy 47.2 pg/mL [19.9 pg/mL - 79.3 pg/mL], Vitamin D 25-OH 18.2 ng/mL Low [30 ng/mL - 100 ng/mL], TSH 1.599 uIU/mL (.450-5.330 uIU/mL), Hgb 13.4 g /dL (12.0 -16.0 g/dL). Most recent FNA in 2019 of a dominant thyroid nodule was benign. Bone Density Scan June 2020 showed a T score of -3.4 in the lumbar spine and -3.1 in the left hip. Sestamibi Scan showed a right inferior parathyroid adenoma. Following ENT consultation, patient underwent surgical exploration. Pathology showed parathyroid tissue with extensive fibrosis, consistent with Parathyroid Carcinoma (1.8 x 1 x .7cm), probable positive margins, nodular growth pattern with individual nodules separated by fibrous bands, capsular invasion, focally, into adjacent adipose tissue invading through the thyroid capsule, positive for perineural invasion and PTH. Ki67 approximately six percent. Right thyroid lobe excision should a micro focus of papillary thyroid carcinoma (.2 x .2 cm), capsulated, negative margins, pT1a. Conclusion: This case demonstrated an unusual presentation of Parathyroid carcinoma causing a mild elevation of PTH level that in pathology after excision unexpectedly revealed a right parathyroid carcinoma along with micro papillary thyroid carcinoma.
Development of Delayed Paraneoplastic ACTH Syndrome in Small Cell Lung Carcinoma
Authors: Azmath Misbah , Tannenbaum Susan , Taxel Pamela
Published: May 2021

Background: Paraneoplastic/ectopic ACTH syndrome (EAS) is a rare but well-recognized syndrome in small cell lung carcinoma (SCLC), occurring in 1-5% of cases (1) and most often at diagnosis. We present a patient with SCLC who developed paraneoplastic ACTH syndrome 9 months after initiation of treatment. Case: A 73 year old female with long history of smoking and COPD (on home O2) and SCLC seen during hospitalization with severe muscle cramps, generalized weakness, hypertension and hypokalemia. Eleven months prior, she was diagnosed with SCLC after presenting with left superior mediastinum, supraclavicular and neck lymphadenopathy. She received 4 cycles of chemotherapy and immune checkpoint inhibitor (ICI) therapy (atezolizumab) was also initiated and continued throughout. Good response to therapy occurred until nine months post initiation, when relapse in same regions was identified on repeat PETCT. Physical examination revealed new onset resistant hypertension up to 240/120mmHg, and extensive bilateral lower extremity edema. Labs showed hypokalemia of 2.3 mmol/l and metabolic alkalosis with serum bicarbonate 43 mmol/l. Further investigations showed a random cortisol of 97.1 ug/dl with repeat of 175.9 ug/dl the following AM. ACTH was 374.1pg/ml. TSH was 0.25 uU/ml with low normal T4 and T3. Pituitary MRI showed no evidence of hypophysitis or enlargement. Repeat biopsy of cervical lymph node was unchanged from initial biopsy with two notable differences: morphology showed a “more organized, trabecular pattern” and MIB-1 staining had declined from 70-80% to 20%, and tumor cells stained positive for ACTH. She did not respond to octreotide, but did respond to ketoconazole (hypokalemia, edema improved and cortisol levels decreased to 24.2 ug/dl). However, hepatotoxicity occurred and thus it was discontinued with rapid rise of cortisol. As she was not a candidate for bilateral adrenalectomy, we started metyrapone with lowering of cortisol levels within 4 doses. However, new cavitary lesions on chest CT developed with concern for disseminated fungal infection. Patient elected for hospice and passed away the following day. Conclusion: We present an unusual case of paraneoplastic ACTH syndrome that developed after immunotherapy in SCLC. In summary, the relapse of SCLC while on immune therapy was associated pathologically by differentiation into a neuroendocrine tumor type and biochemically by a considerable ACTH production. We conclude that ACTH production with subsequent severe hypercortisolism causing immunosuppression may be a novel mechanism by which SCLC can evade immunotherapy.

Reference: (1) Nagy-Mignotte H, Shestaeva O, Moro-Sibilot D et al. Prognostic impact of paraneoplastic cushing’s syndrome in small-cell lung cancer. J Thorac Oncol. 2014 Apr,9.
Double Trouble: A Challenging Case of Synchronous Catecholamine-Secreting Neck Paraganglioma and Pheochromocytoma
Authors: Oleinikov Kira , Grozinsky-Glasberg Simona , Gross David J , Kuzmina Natasha , Pizov Reuven , Mazeh Haggi , Kaganov Yevgeny , Weinberger Jeffrey M , Hirshoren Nir
Published: May 2021

Background: Sympathetic paragangliomas (PGL) are regarded as catecholamine-secreting, extra-adrenal counterparts of pheochromocytomas (PCC). Hormone producing head and neck PGL (HNPGL) are exceedingly rare, as most HNPGL are biochemically silent parasympathetic tumors. Here, we present a case of synchronous sympathetic cervical PGL and PCC. Clinical Case: A 47-year-old male was referred to the Neuroendocrine Tumor Unit clinic after a failed attempt at PGL removal at another center. The patient had a 10-year history of hypertension and a family history of his mother’s sudden death. Prior to referral, he presented with a palpable 6 cm right neck mass - an uneventful core-needle biopsy pathology revealed PGL. Subsequent workup showed profoundly elevated plasma metanephrine (MN) 3000 pg/ml [<65] and normetanephrine (NMN) 3500 pg/ml [<196]. Following a week of 2 mg/d doxazosin therapy, an attempt to operate on the patient for PGL was aborted after the skin incision over the mass due to an intraoperative hypertensive crisis. Upon arrival to our unit, reassessment disclosed a sustained stage 3 hypertension that required a four antihypertensive drug regimen with doxazosin dose titration up to 16 mg/d. MRI showed a 6 cm well-defined mass that displaced the common carotid artery and internal jugular vein (IJV) anteromedially, consistent with a PGL of sympathetic chain origin. MRA identified no tumor feeding vessels that could be suitable for embolization. Ga68 DOTATATE PET/CT showed a single focus of radiotracer uptake in the right neck PGL; however, the CT did image a 1.3 cm right adrenal mass with radiographic features suggestive of PCC. The patient underwent surgery for the PGL, using vigilant intraoperative hemodynamic and upper cranial nerve monitoring. An extreme hypertensive episode (systolic BP 340 mmHg) early on during the tumor’s dissection was resolved once the venous connection between the PGL and the IJV was divided. Pathology revealed a 6 cm PGL with free surgical margins. Postoperatively, hormone levels dropped significantly (MN 98 pg/ml [<65]; NMT 198 pg/ml [<196]). Subsequently, right adrenalectomy was performed, confirming the diagnosis of a 1.6 cm PCC. At the last follow-up, the patient’s hypertension was controlled on 5 mg/d amlodipine. Plasma MN and NMN levels were normal. Genetic analysis for PGL/PCC-associated genes revealed no germline mutation. Conclusion: This case highlights the importance of preoperative workup and perioperative management of large PGL. Head and neck PGL resection may be challenging depending on tumor size and location. Early division of the venous outflow from the PGL into the IJV plays a crucial role in intraoperative hemodynamic control. A multidisciplinary team at experienced centers must be involved in every aspect of the patient’s care to achieve optimal results.
Occurrence of Hepatocellular Carcinoma in a 40-Year-Old Male With MEN2A Syndrome
Authors: Kontoghiorghes Christopher P , Lovre Dragana , Galagan Robert
Published: May 2021

Background: Multiple Endocrine Neoplasia Type 2A (MEN 2A) is a genetic syndrome in which the patient is susceptible to the development of: 1. medullary thyroid carcinoma, 2. pheochromocytoma, and 3. parathyroid adenomas or hyperplasia. Our objective is to report the first occurrence of hepatocellular carcinoma in a young adult male with MEN 2A syndrome without prior liver disease.

Clinical Case: A 40-year-old male was screened positive for the C634R point mutation of the RET Proto-Oncogene after his sister with MEN 2A syndrome had tested positive. The patient had no history of alcohol or drug abuse. His family history was remarkable for the deaths of his mother and maternal grandmother from unknown malignancies at the ages of 35 and 45 respectively. His physical exam revealed a BP of 135/85mm Hg, BMI 26 kg/m2 and palpable bilateral thyroid nodules. Lab tests included a calcitonin of 131 pg/ml, (0.0-8.4 pg/ml), calcium 11.4 mg/dL (8.4-10.3 mg/dL), parathyroid hormone (PTH) 1765 pg/ml (12-65 pg/ml), ALK PHOS 1856 U/L (20-120 U/L), ALT 16 U/L (<39 U/L), Albumin 4.1gm/dl (3.4-5.0gm/dl), plasma normetanephrine 0.95 nmol/L (0.00- 0.89 nmol L) and urine metanephrines 291 pg/d (62-207 pg/d). A CT scan demonstrated hyperdense 12 mm right and 5 mm left adrenal nodules, both confirmed MIBG positive. Neck ultrasound showed bilateral thyroid nodules, the largest measuring 1.1 x 0.8 x 1.1 cm in the right lobe and a 3.5 x 2.2 x 2.1 cm heterogeneous mass posterior to the right thyroid lobe. The patient was prepped with doxazosin and underwent a laparoscopic right adrenalectomy then 2 months later a total thyroidectomy with neck lymph node dissection, resection of the right parathyroid tumor mass and bilateral inferior parathyroid glands. Surgical pathology confirmed the right adrenal pheochromocytoma, multifocal bilateral medullary thyroid cancer with 1 of 70 neck lymph nodes positive and a single large parathyroid adenoma. He received levothyroxine to maintain euthyroidism. Within 6 months of his surgery, calcitonin was < 2 pg/ml, CEA 2.3 U/ml (<5.0 U/ml) and ALK PHOS 44 U/L. Urine metanephrines remained mildly elevated 291 pg/d (62-207 pg/d). Serial abdominal CT imaging revealed no change of the left adrenal mass but three new bi-lobar 1-2 cm enhancing liver lesions. CT guided needle biopsies of the liver masses revealed hepatocellular cancer without evidence of cirrhosis. The patient underwent successful thermal ablation of all 3 liver lesions. Laboratory evaluation was negative for Hepatitis A, B and C. His alpha fetal protein level has remained stable in the range of 4.7 to 5.8 ng/ml (<15ng/ml).

Conclusions: This is the first reported case of hepatocellular carcinoma in a patient with MEN 2A syndrome who had no predisposing liver disease, raising suspicion that his germline RET mutation contributed to his liver cancer.
Serendipity and the Second Malignancy: Clear Cell Renal Carcinoma Workup Revealing a Paraaortic Paraganglioma With Post-Operative Vasoplegia
Authors: Thomas Robert Lee , Ekanayake Preethika Subashini , Pettus Jeremy , Mimoto Mizuho
Published: May 2021

Pheochromocytoma and paraganglioma (PPGL) are neuroendocrine tumors requiring careful pre- and post-operative management to dampen fluctuations in catecholamines. These lesions are not typically biopsied due to risk of catecholamine-induced hemodynamic instability. This case illustrates the importance of considering PPGL in patients without typical symptoms, and highlights challenges with post-operative blood pressure management following use of phenoxybenzamine.

A 52 year old man presented with a 40 lb weight loss. PET/CT revealed a right renal mass, enlarged retroperitoneal lymph nodes, and increased uptake in retroperitoneal and paraaortic lesions. Paraaortic lymph node biopsy was consistent with paraganglioma.

This finding was unexpected as the patient did not report palpitations, paroxysmal hypertension, or diaphoresis. He had no family history of neuroendocrine tumors. Fortunately, he had no adverse effects during biopsy despite subsequent testing showing elevated plasma metanephrines (271 pg/mL, normal ≤ 57 pg/mL) and normetanephrines (770 pg/mL, normal ≤ 148 pg/mL). I-123 MIBG scan revealed an enlarged left paraaortic mass with increased activity consistent with paraganglioma. He started preoperative alpha blockade with phenoxybenzamine 14 days prior to surgery. Propranolol was added 10 days later to provide combined sympathetic blockade.

The patient underwent partial right nephrectomy and resection of the paraaortic mass. Pathology showed renal cell carcinoma (RCC) and paraganglioma, respectively. On post-operative day 1, maintenance fluids were discontinued and he developed palpitations and tachycardia to 140 beats per minute, with blood pressure in the 130s/80s. RCC associated pulmonary embolism, beta-blocker withdrawal, and vasoplegia due to phenoxybenzamine use and paraganglioma resection were considered. The patient was treated with 4 additional liters of normal saline over the next two days to address post-operative vasoplegia, and his tachycardia resolved. Genetic testing for neuroendocrine tumor syndromes including Von Hippel-Lindau (VHL) is ongoing.

Clinical Lessons: 1. PPGL should be considered in patients with newly identified intraabdominal masses, even in patients without typical symptoms of catecholamine excess to avoid high risk biopsy. 2. Paraganglioma resection is associated with vasoplegia due to post-operative reduction in circulating catecholamines. 3. The covalent, irreversible alpha antagonist phenoxybenzamine accumulates in adipose tissue, and clinical effects can last up to 7 days after discontinuation. Hypotension can be avoided with aggressive fluid resuscitation. Beta antagonists should be used with caution as they may precipitate hypotension. 4. For patients presenting with paraganglioma and renal cell cancer, genetic syndromes including VHL or RAPTAS etiologies should be considered.
Androgen Activity in the Primary and Metastatic Prostate Cancer Microenvironments Influences Disease Progression and Patient Outcomes
Authors: Leach Damien , Buxton Alison , de Almeida Gilberto Serrano , Buchanan Grant , Bevan Charlotte Lynne
Published: May 2021

Background: Cancers do not exist in isolation, surrounding tumours are supportive cells, which create the microenvironment in which cancer cells reside. In the prostate cancer (PCa), androgen receptor (AR) signalling in the surrounding fibroblasts is strikingly distinct from that within PCa cells, and has specific functions to produce, maintain, and modulate the extracellular matrix (ECM) which surrounds and interacts with PCa cells. The supportive cells of metastatic sites differ from those in the primary site and produce different types of cellular microenvironments. Since the advent of second generation anti-androgen therapy there has been an increase in the presence of liver metastasis. This project investigates how AR and anti-androgen therapy affect the prostate liver microenvironment and the subsequent effects on cancer. Results: Analysis of microenvironment of primary and metastatic sites indicates transcriptional responses distinct from that seen in PCa cells. This is exemplified by proliferation responses to androgen and anti-androgens in microenvironment cells being the reverse to that seen in Pca cells. Dichotomising microdissected PCa patient material of matched cancer and stromal tissue, based on stromal AR level shows distinct transcriptional profiles in the matched cancer cells. From previous studies, we know AR status in cancer adjacent fibroblasts (CAFs) of the primary tumor inversely associates with patient outcomes. Analysis of single cell CAFs and microdissected stromal samples points to a potential sub population of CAFs with this AR status. Conditioned media from liver and prostate fibroblast cells suggests that inactivation of AR signalling produces proliferative paracrine signals that can affect cancer cell growth. AR in primary site fibroblast and liver stellate cells regulates secretome and ECM production in the primary and metastatic site. Prostates and livers from enzalutamide treated mice showed changes in collagen fibres compared to control mice, as visualised by picro-direct-red staining. We cultured PCa cells within 3D-ECM microenvironments created in vitro from prostate fibroblasts or liver cells. The different 3D-ECM were able to produce changes in PCa cells, including gene transcription, intracellular signalling pathways, and proliferation and apoptotic responses. These data suggest that the responses of primary and metastatic microenvironments to androgens and anti-androgens can influence phosphorylation of intracellular pathways leading to alterations in gene transcription. Furthermore, the transcriptional responses of cancer cells in vitro to changes in microenvironmental AR signalling can be used to predict patient outcomes. Conclusions: Our data suggests that anti-AR therapy produces organ microenvironment-specific signals that influence the response of prostate cancer to treatments and affects patient outcomes.
Clinicopathologic Characteristics of Thyroid Nodules Positive for PTEN Mutations on Preoperative Molecular Testing
Authors: Quaytman Jacob , Nikiforov Yuri E , Nikiforova Marina , Morariu Elena
Published: May 2021

Somatic and germline mutations of PTEN tumor suppressor gene are associated with follicular-pattern thyroid tumors and PTEN Hamartoma Tumor Syndrome (PHTS). The incidence of cancer in thyroid nodules positive for PTEN mutations on fine-needle aspiration (FNA) is not well defined. The aim of this study was to characterize diagnostic and phenotypic features of thyroid nodules with preoperatively detected PTEN mutations and their impact on management. Thyroid nodules with PTEN mutations on ThyroSeq v3 GC testing of FNA and core needle biopsy specimens from November 2017 to July 2020 were identified from the ThyroSeq Molecular Database. Demographic and clinicopathologic data were obtained through retrospective chart review. We identified 49 PTEN mutation-positive nodules from 48 patients. Patients were 57 years old on average (range 14-88) and 80% female. Cytology was predominantly indeterminate (73% atypia of undermined significance, 18% follicular neoplasm). There were 18 (29%) frameshift, 6 (10%) splice site, and 39 (62%) single nucleotide variant PTEN mutations. Fourteen (29%) nodules had two PTEN mutations, 5 (10%) had copy number alterations, and single cases had concurrent BRAF K601N, EZH1, and NRAS mutations. Surveillance was pursued for 27 (56%) and surgery for 21 (44%) patients (16 lobectomies, 5 total thyroidectomies). There were 14 follicular adenomas (FA), 4 oncocytic FA’s, 1 oncocytic hyperplastic nodule, and 1 encapsulated follicular variant papillary thyroid carcinoma (EFVPTC). The EFVPTC had two low-frequency PTEN mutations, PTEN locus loss, an NRAS mutation, and was a low-risk tumor with capsular but no angiolymphatic invasion. Four (8.3%) patients had confirmed or suspected PHTS, all with multiple nodules. Two had surgery finding no malignancies (2 FA). One PHTS patient had a prior thyroidectomy for a MET mutation-positive nodule that was follicular carcinoma. On US, the mean nodule size of patients who had surgery was larger than the surveillance group (3.2 cm vs. 2.3 cm, p=0.02) but there was no difference in TI-RADS level (p=0.54). There was no difference in mean nodule size (3.5 cm vs. 2.6 cm, p=0.35) or TI-RADS level (p=0.81) between PHTS and non-PHTS patients. Among surveillance patients, follow-up US was done at 1 year in 13/19 (68%) and 2 years in 3/6 (50%) of eligible cases. Only 1/19 (5%) underwent repeat FNA for increased nodule size. No thyroid malignancy was found with a mean of 1.75 years of follow-up (range 1.00-2.78). The EFVPTC patient had no recurrence after 1.05 years of follow-up. In summary, thyroid nodules with isolated somatic PTEN mutations are primarily benign and can be safely followed with serial imaging. Nodules with multiple PTEN mutations were only associated with malignancy when accompanied by an additional NRAS mutation. About 8% of patients with PTEN mutations may be PHTS patients who may be at greater risk for malignancy.
Estradiol Augments the Production and Actions of Polymorphonuclear Cells to Promote Lymphangioleiomyomatosis (LAM) Progression
Authors: Minor Briaunna M N , Hammes Stephen R
Published: May 2021

Affecting almost exclusively women, lymphangioleiomyomatosis (LAM) is a rare lung disease characterized by slowly growing, estrogen-sensitive metastatic smooth muscle cell-like adenomas that result in cystic lung changes and loss of pulmonary function. LAM tumors are caused by mutations in either TSC1 or TSC2 genes that induces defective inhibition of the mTORC1 pathway, leading to increased mTORC1 activity and augmented cell proliferation. We have previously reported that estrogen ablation in our uterine-specific Tsc2 knockout mouse, which grows tumors with characteristic LAM features and lung colonization potential, effects notable regression of tumors. Thus, estrogen is required for to maintain heightened mTORC1 activity and LAM-like tumor progression. Interestingly, the observed estrogen sensitivity in vivo is more markedly pronounced than that of our estrogen receptor-positive TSC2-null cells when stimulated with estradiol in vitro, suggesting that estradiol may act elsewhere—in mTORC1 independent manner—in vivo to promote LAM progression. Flow cytometry revealed large numbers of Ly-6Cint Ly-6Ghigh myeloid cells—polymorphonuclear cells or PMNs—in the blood and myometrial tumors of our uterine-specific Tsc2-null mice. Accordingly, we found that Tsc2-null tumors required PMNs for normal disease progression, as Gr-1 (Ly-6C/Ly-6G) depletion or inhibition of PMN recruitment reduced tumor growth. Therefore, we hypothesized that, in addition to direct effects of estrogen on tumor cells, estrogen might also stimulate tumor growth by promoting PMN production in the bone marrow and actions in the tumor microenvironment. Using bone marrow cultures, we found that estradiol is indeed a potent inducer of PMN production. This effect occurs equally in both male and female bone marrow. Employing both pharmacologic agents and bone marrow from ERα; knockout mice, we showed that ERα; is necessary for promoting a PMN fate for myeloid progenitors. Additionally, we have evidence implicating estrogen in the pro-tumorigenic function of PMNs co-cultured with TSC2-null cell lines. Overall, these data suggest that estradiol maybe facilitating crosstalk in LAM tumors, directly stimulating tumor cells while also promoting the production and actions of PMNs, which in turn promote tumor growth.