bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACTH-Producing Thymic Carcinoid: A Rare Cause of Cushing’s Syndrome
Authors: Rodriguez Lisette Patricia , Kozlow Wende Michele 
Published: May 2021

Abstract
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 &lt; 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 (&lt; 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 (&lt; 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

Abstract
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&gt;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

Abstract
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

Abstract
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 [&lt;65] and normetanephrine (NMN) 3500 pg/ml [&lt;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 [&lt;65]; NMT 198 pg/ml [&lt;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

Abstract
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 (&lt;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 &lt; 2 pg/ml, CEA 2.3 U/ml (&lt;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 (&lt;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

Abstract
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

Abstract
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

Abstract
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.