Rao, Sarika

Abstract Context The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. Objective To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. Design and Setting We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance collaborative research group. Patients Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. Intervention Performance (or not) of cytoreductive surgery of the primary tumor. Main outcome and measures A propensity score match was done using age and the number of organs with metastasis (≤2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. Results Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65). Conclusion Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.

Abstract Background: Isolated pituitary stalk thickening (PST) from neuroinfundibulitis is a rare entity that requires thorough evaluation of secondary causes and understanding of treatment options. Clinical Case: A 55-year-old male presented with progressive polyuria and polydipsia over several months. He had no significant head injuries, headache, weight loss, fatigue or inability to exercise. His serum sodium level was 148 (135 - 145 mmol/L) with a serum osmolality 310 (275-305 mOsm/kg), and urine osmolality was 246 (40-1200 mOsm/kg) suggestive of partial diabetes insipidus (DI). A 24-hour urine collection had a volume of 9.2 liters. He had a normal hemoglobin A1c. Hormonal work-up was unremarkable with normal range his prolactin, IGF-1, and a.m. cortisol (19 mcg/dl). He was already on levothyroxine with normal thyroid function tests and negative thyroid antibodies. Water deprivation testing confirmed a diagnosis of central DI and he was started on desmopressin. Magnetic resonance imaging (MRI) of the pituitary demonstrated diffuse PST with T2 hyperintensity and loss of normal T1 hyperintensity (“bright spot”) of the posterior pituitary. Repeat imaging 3 months later showed progressive thickening. He underwent full body positron emission tomography-computerized tomography (PET-CT) which demonstrated increased metabolism of the pituitary stalk, but no other suspicious uptake in other areas. Chest X-ray, tuberculin screen, angiotensin converting enzyme, and calcium were all normal. Patient underwent transsphenoidal stalk biopsy. Pathology demonstrated fibrosis and chronic inflammation without malignancy but otherwise was nondiagnostic. Based on these findings, he was presumed to have neuroinfundibulitis and is being actively followed with MRIs and labs. Conclusion: Isolated PST is exceedingly rare, especially in adults. The differential diagnosis includes neoplastic (germinomas, lymphoma, metastatic disease), autoimmune, and infiltrative disease (sarcoidosis, histiocytosis). One review of 38 adult patients with central DI and PST showed that almost half had neuroinfundibulitis. Of those, 4 were treated with corticosteroids and 7 were not. All patients showed reduction or resolution of PST on subsequent MRIs indicating that resolution of thickening can be spontaneous without steroid use, and can be followed by MRI and with hormone replacement for deficiencies (1). Because of the rarity of isolated neuroinfundibulitis, it is important that neoplastic and systemic diseases be ruled out in all patients with PST, as in the case of our patient. 1.Devuyst F, Kazakou P, Baleriaux D, Alexopoulou O, Burniat A, Salenave S, et al. Central diabetes insipidus and pituitary stalk thickening in adults: distinction of neoplastic from non-neoplastic lesions. European Journal of Endocrinology. 2020;183(1):95-105.

Abstract Introduction: Postmenopausal hyperandrogenism is a rare condition that causes hirsutism, virilization, and clitoromegaly that should be carefully evaluated in order to avoid overlooking an androgen secreting tumor (1). Case: A 48 year old African American female with a prior history of polycystic ovarian syndrome (PCOS) presented for evaluation of hirsutism. Of note, she also underwent menopause at age 41 after receiving chemotherapy for a history of multiple myeloma, and she has been on steroids since the time of her diagnosis. On exam, she had thick, dark hair growth on her chin, upper lip, and chest, as well as male-patterned baldness, acne, easy bruising, proximal muscle weakness, deep voice, and elevated blood pressure. Prior to endocrinology evaluation, she was started on spironolactone 25 mg BID. Lab work up included dehydroepiandrosterone sulfate (DHEAS) 73 mcg/dL (27-240 mcg/dL), 17-hydroxyprogesterone 74 ng/dL (31-455 ng/dL), androstenedione 271 ng/dL (30-200 ng/dL), total testosterone 763 ng/dL (8-60 ng/dL), bioavailable testosterone 244 ng/dL (0.8-10 ng/dL), hemoglobin A1c 4.3%, follicle stimulating hormone 30 IU/L, luteinizing hormone 23.9 IU/L, insulin 11 mcIU/mL (2.6-24.9 mcIU/mL), glucose 71, insulin-like growth factor 1 236 ng/mL (44-227 ng/mL) with subsequent normal glucose suppression test. While transvaginal ultrasound did not note any abnormal findings, a computed tomography of the abdomen/pelvis showed a new hyperdense focus in the left ovary as well as a tiny right adrenal nodule, most likely an adenoma. Follow up magnetic resonance imaging confirmed a 1.6 cm enhancing solid left ovarian mass; it also confirmed a right adrenal adenoma and left adrenal thickening versus a tiny adenoma. Urine metanephrines and catecholamines were normal. Patient had total hysterectomy and bilateral oophorectomy; pathology showed a steroid cell tumor. Conclusion: Postmenopausal hyperandrogenism has several causes: insulin resistance, PCOS, non-classic congenital adrenal hyperplasia, medications, and tumors of the ovaries or adrenals. Severe hyperandrogenemia should raise the suspicion of an ovarian or adrenal neoplasm, necessitating prompt imaging (1). Certain imaging may not reveal smaller masses, and additional imaging or ovarian/adrenal vein sampling may be needed. Typically, an elevated DHEAS with a high testosterone suggests an adrenal source, while androstenedione can be elevated in both glands. Once identified, the involved gland is surgically resected. This patient was found to have a steroid cell tumor, which has malignant potential. They make up less than 0.1% of all ovarian tumors (2). Initial treatment is surgical resection and may necessitate chemotherapy if malignant. 1) Markopoulos MC, Kassi E, Alexandraki KI, Mastorakos G, Kaltsas G. Hyperandrogenism after menopause. Eur J Endocrinol. 2015 Feb;172(2):R79-91. doi: 10.1530/EJE-14-0468. Epub 2014 Sep 15. PMID: 25225480.2) Hayes, Mary C. M.D.; Scully, Robert E. M.D. Ovarian Steroid Cell Tumors (Not Otherwise Specified), The American Journal of Surgical Pathology: November 1987 - Volume 11 - Issue 11 - p 835-845

AbstractBackgroundIndeterminate thyroid nodules are diagnosed in up to 30% of fine‐needle aspirations and the risk of malignancy in these cases are highly variable. Consequently, managing these nodules has been a challenge. While a diagnostic thyroidectomy would help clarify the pathology, there is the risk of developing surgical‐related complications for a procedure that may not have been necessary and associated high costs. Genomic testing of indeterminate thyroid nodules may help better guide management.MethodsWe present an unbiased comprehensive review of available molecular testing for classifying indeterminate thyroid nodules, as well as their strengths and limitations, with the objective to allow practitioners to choose the best testing modality for their patients.ResultsMolecular testing of these nodules provided a platform to help distinguish benign versus malignant nodules, providing more confidence to rule in or rule out the likelihood of thyroid cancer in indeterminate nodules.ConclusionGenomic testing has evolved to more comprehensive panels to better stratify indeterminate nodules, including Hürthle cell neoplasms and noninvasive follicular neoplasm with papillary‐like nuclear features. Understanding the methodology of each available test improves patient care and reduces unnecessary costs.

Abstract 17 year old female presented for evaluation of galactorrhea of 3 months duration. Patient was diagnosed with papillary thyroid cancer and underwent total thyroidectomy in 2011. She was prescribed Synthroid 175 mcg but was not compliant with taking her medicine. In April 2019 she developed bilateral galactorrhea for which she was evaluated at an outside facility and was found to have a prolactin 143.7ng/mL (n 7.2-63) and TSH 996 mIU/L (n 0.5 -4.0). Pituitary MRI revealed pituitary macroadenoma measuring 1.5 x 1.4 x 1.2 cm with slight elevation of the optic chiasm and infundibulum. She was advised to restart Synthroid and was referred for the neurosurgery team at our facility for surgical resection of pituitary macroadenoma. Over the same period of time, she gained 25 lbs, developed headaches, excessive fatigue, constipation, hair loss, lower extremity swelling, and puffiness of her face. Her menstrual cycles were regular but this was only after she was placed on norelgestromin/ ethinyl estradiol transdermal patch. She denied visual changes. By the time she was seen at our clinic in June 2019, she was taking Synthroid daily for 1 month. TSH decreased to 1.0 mIU/L and prolactin improved to 68 ng/mL. IGF-1 was low at 98 ng/mL (n 149-509). ACTH, morning cortisol, and 24 hour urine free cortisol were within reference range. Visual field testing showed no visual defects. We advised patient to continue taking Synthroid and to follow up in 1 month. On the follow up visit in July 2019, TSH was 0.2 mIU/L, prolactin was 52 ng/mL and IGF-1 was 105 ng/mL. Pituitary MRI showed pituitary hyperplasia that has decreased compared to previous MRI, now measuring around 1 cm at the largest dimension without contact with the optic chiasm and the Infundibulum was at midline. Galactorrhea and headaches resolved and fatigue significantly improved.

Abstract Purpose: Pheochromocytomas and paragangliomas (PPGL) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown. Experimental Design: We performed exome or transcriptome sequencing of 43 samples from 41 patients. A validation set of 136 PPGLs was used for amplicon-specific resequencing. In addition, a subset of these tumors was subjected to microarray-based transcription, protein expression, and histone methylation analysis by Western blotting or immunohistochemistry. In vitro analysis of mutants was performed in cell lines. Results: We detected mutations in chromatin-remodeling genes, including histone-methyltransferases, histone-demethylases, and histones in 11 samples from 8 patients (20%). In particular, we characterized a new cancer syndrome involving PPGLs and giant cell tumors of bone (GCT) caused by a postzygotic G34W mutation of the histone 3.3 gene, H3F3A. Furthermore, mutations in kinase genes were detected in samples from 15 patients (37%). Among those, a novel germline kinase domain mutation of MERTK detected in a patient with PPGL and medullary thyroid carcinoma was found to activate signaling downstream of this receptor. Recurrent germline and somatic mutations were also detected in MET, including a familial case and sporadic PPGLs. Importantly, in each of these three genes, mutations were also detected in the validation group. In addition, a somatic oncogenic hotspot FGFR1 mutation was found in a sporadic tumor. Conclusions: This study implicates chromatin-remodeling and kinase variants as frequent genetic events in PPGLs, many of which have no other known germline driver mutation. MERTK, MET, and H3F3A emerge as novel PPGL susceptibility genes. Clin Cancer Res; 22(9); 2301–10. ©2015 AACR.