Diffuse Hyperplasia Research Articles

MON-362 Undiagnosed Non-classic Congenital Adrenal Hyperplasia as a Driving Force for Persistent Hyperandrogenemia in Prostate Cancer

Background Non-classic congenital adrenal hyperplasia (CAH) is a common condition and can lead to adrenal hyperandrogenemia. Clinical case We present a case of an 82-year-old man with prostate adenocarcinoma (Gleason 4+3=7) diagnosed 5 years prior to presentation. During surveillance, he was found to have lymphadenopathy, extra-capsular extension, and rising prostate specific antigen (PSA) (from 4.5 to 14.2 ng/ml, n< 4). Stereotactic radiation therapy and androgen deprivation therapy (ADT) with Gonadotropin-releasing hormone (GnRH) analog leuprolide (22.5 mg every 3 months) were initiated. Post-treatment labs showed inadequate testosterone suppression (total testosterone [TT], 87 ng/dl; target,<5.0). Therefore, bicalutamide (50 mg daily), an androgen receptor inhibitor, was added. Subsequently, PSA declined to 0.29 ng/ml and TT remained at 88.4 ng/dl. Prostate cancer remained stable and Leuprolide was discontinued. Three months prior to presentation, F18-Fluciclovine PET/CT revealed skeletal metastases and incidental bilateral adrenal enlargement. PSA increased to 10.86 ng/dl and TT to 218 ng/dl. ADT was resumed with the GnRH analog degarelix (240 mg monthly). Subsequently, PSA remained elevated (10.6 ng/dl) with TT only partly suppressed (90 ng/dl). Further work-up revealed 17-hydroxyprogesterone 4910 ng/dl (n<220), DHEAS 312 mcg/dl (n<166), corticotropic hormone 39 pg/mL (n,7.2-63), cortisol 5.6 mcg/dl (n,5-23), plasma normetanephrine 1.1 nmol/l (n<0.9), plasma metanephrine 0.39 nmol/l (n<0.5), aldosterone 4.0 ng/dl (n<21), and TT 119 ng/dl. An adrenal CT showed diffuse bilateral adrenal hyperplasia, with a 5.6-cm right adrenal gland and 6.7-cm left adrenal gland. The patient shared that he underwent precocious puberty, was shorter than predicted based on the sex adjusted mid-parental height, and never fathered children. In light of his history, he was diagnosed with non-classic CAH due to partial 21-hydroxylase deficiency (21-OHD), causing inadequate testosterone suppression and progression of prostate cancer despite ADT and androgen receptor blocker. Following the diagnosis, the patient was treated with abiraterone (1000 mg daily), a CYP17A1 inhibitor, and prednisone (2.5 mg twice daily), to suppress adrenal androgen production. TT became undetectable (< 5 ng/dl) and PSA declined from 12.93 to 1.27 ng/ml. Conclusion: Non-classic CAH is a common autosomal recessive disorder and presents in late childhood as premature pubarche and accelerated bone age. The prevalence of non-classic CAH is 0.1%-1% among Caucasians and even higher among Ashkenazi Jews and Hispanics. Treatment in men is generally not required unless there is oligospermia in those desiring fertility. Adrenal hyperandrogenemia can be treated with systemic steroids. Non-classic 21-OHD CAH should be considered in men with prostate cancer with inadequate testosterone suppression after ADT.

MON-319 A Young Woman with Familial Isolated Primary Hyperparathyroidism Due to Parathyroid Adenoma and Atrophic Gastritis

Background: High levels of gastrin and parathyroid hormone (PTH) can coexist outside the multiple endocrine neoplasia (MEN) kindred syndromes. There is significant non-causal association between chronic autoimmune atrophic gastritis (CAAG) and primary hyperparathyroidism (PHPT). Prevalence of PHPT is increased in patients with CAAG (8.4 vs 1–3%, general population).1,2 These studies excluded people with familial PHPT, MEN1 syndrome, those on proton pump inhibitors, H. pylori infection and renal failure. Some studies show an association between gastric carcinoid type 1 tumor (GC-1) and PHPT.3 No data is available on association between hypergastrinemia, gastritis and familial isolated HPT (FIHPT) Case: A 37-year-old female with hypothyroidism due to Hashimoto’s thyroiditis and premature ovarian insufficiency was incidentally found to have hypercalcemia with total calcium of 10.8 mg/dL (8.9–10.4), ionized calcium 1.4 mg/dL (1.14–1.33), 24 hour urine calcium of 0.252 g/d (0.032–0.368), urine creatinine 0.56 g/24hr (0.78–2.31), urine volume 1650 mL. 25 OH Vitamin D was low at 17 pg/ml. She also had elevated chromogranin A level at 541 ng/mL (0–95), gastrin level of 1522 pg/mL (0–100) and Vitamin B12 level of 299 pg/mL (> 201 acceptable), negative intrinsic factor and antiovarian antibody. There is a strong family history of primary hyperparathyroidism in mother and sister and hypercalcemia in brother and niece (unknown workup). Parathyroid scan showed ectopic parathyroid adenoma, with mild focal uptake a few centimeters inferior to the lower pole of the right thyroid gland. Bone density scan showed osteopenia at L1- L4 lumbar spine with T score -2.1 and BMD of 0.924 g/cm2. Genetic test was negative for CASR, CDC73, CDKN1B, MEN1, RET amplified by long-range PCR and sequenced by Pacific Biosciences SMRT. Upper GI endoscopy with gastric biopsy showed severe chronic atrophic gastritis with extensive intestinal metaplasia associated with diffuse neuroendocrine cell hyperplasia within the crypts. She was diagnosed with familial isolated primary hyperparathyroidism with chronic atrophic gastritis. Conclusion: As far as we know, there are no reported cases documenting chronic atrophic gastritis occurring with familial isolated primary hyperparathyroidism. This case highlights that in patients with FIHPT, hypergastrinemia and gastritis can occur independent of MEN -1 syndrome.

SAT-068 A Precise Prevalence Of Genotypes And Histological Subtypes Of Consecutive JapanesePA CasesUndergoing Surgery From 2012 To 2017

Recent advances of molecular analysis and the development of specific monoclonal antibody against aldosterone synthase (CYP11B2) have indeed established the histological subtypes based on the localization of aldosterone overexcess and revealed the association between genotype and clinicopathological phenotype. In particular, several kinds of aldosterone-driver gene somatic mutation have been reported, including KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1. Among them, KCNJ5 somatic mutation was most frequently detected in aldosterone-producing adenoma although the prevalence of PA genotypes was markedly different among ethnic groups. The precise prevalence of genotype and histological subtypes in Japanese PA patients in large cohort has virtually remained unknown. Therefore, in this study, consecutive 125 unilateral PA cases entirely composed of Japanese patients who underwent surgery from 2012 to 2017 were histologically and genetically evaluated in order to clarify the precise prevalence of genotypes and histological subtypes among Japanese PA patients. 125 cases were precisely classified as follows based on detailed histopathological examination; single APA (84.0%), multiple (more than two) APAs (1.6%), APA + NFA (non-functional adenoma) (5.6%), MN (multiple adrenocortical micronodules) (5.6%), MN+NFA (2.4%) and DH (diffuse hyperplasia of the zona glomerulosa) (0.8%). Adrenal glands harboring single APA were further examined for genotyping. Among them, 67% harbored KCNJ5 mutated (G151R: 39.6%, L168R: 26.4%, T158A: 1.1%) and 33% harbored wild type. 5.4% of single APA clinically combined with Subclinical Cushing's syndrome, all harbored KCNJ5 mutated APAs. The results of our large-scaled analysis did firstly reveal the precise prevalence of histological subtypes and genotypes among Japanese PA patients who underwent surgery. Approximately 10% of unilateral resected PA cases histologically harbored non-neoplastic subtypes such as MN and DH. In addition to those non-neoplatic subtypes, 15% of unilateral resected PA cases other than single APA definitely required CYP11B2 immunohistochemistry in order to precisely detect the responsible lesions for aldosterone overexcess, distinguishing from the non-functional adrenocortical lesions or/and detecting more than two responsible lesions.

MONITORING OF PATHOLOGICAL LESIONS IN NON-GRAVID OVINE UTERUS

A total of 108 non-gravid ovine uteri were collected from slaughtered ewes at Mosul slaughter house and private butcheries to monitor and identify the uterine pathological lesions. The uteri were grossly examined for observation of gross pathological lesions. Tissues samples were collected for histopathological studies. The incidence of different pathological lesions was calculated. Diffuse or nodular endometrial hyperplasia, endometrial degeneration and desquamation and endometrial coagulative necrosis at ratios 36.11%, 20.37% and 16.66% respectively. Endometritis and subendometrial fibrosis were noticed in 7.40% and 3.70% of the examined samples. Also vascular hyperemia and vascular wall thickening were observed in 12.96% and 5.55% of total examined samples. It is concluded that most of the detected lesions in nongravid uteri appears to be related with previous infections or pregnancies.Key words: Nongraviduteri; lesions; ewes

Frequency of Thyroid Lesions on Fine Needle Aspiration Cytology in Different Age Groups: A Teaching Hospital-Based Study

Background: Thyroid Fine Needle Aspiration Cytology (FNAC) was introduced in Scandinavian countries in 1950s and became popular in the United States in 1970s and then worldwide in the 1980s. Subjects and Methods: A total of 129 patients with thyroid nodules were enrolled after fulfilling these inclusion & exclusion criteria and were sent for FNAC. Total of 129 patients presented with thyroid swelling were assessed clinically, along with laboratory investigations like thyroid function tests, ultrasonography and by FNAC study. Results: Nodular goiter was the commonest-34 (26.3%), colloid goiter- 13 (10.1%), nodular goiter with cystic change- 11(8.5%), thyroid cyst- 10(7.75%), nodular goitre with hyperplasia- 3 (2.3%). Hashimoto’s thyroiditis accounted for 45(34.9%), papillary carcinoma and papillary carcinoma with Hashimoto’s thyroiditis- 6(4.6%), diffuse hyperplasia- 2(1.55%), lymphocytic thyroiditis- 2(1.55%), follicular neoplasm- 1(0.77%). Conclusion: The wide range of lesions, both benign and malignant, can be diagnosed by FNAC thus restricting surgery to cases only requiring further histopathological evaluation. Nodular goiter (26.3%) is the foremost commonest cause of thyroid enlargement followed by Hashimoto’s thyroiditis.

Relationship between parathyroid gland scintigraphy and its histopathology, oxyphil cell content and volume: a retrospective study.

Mechanisms that are responsible for positive 99mTc-MIBI uptake in parathyroid glands are not clearly understood, some authors suggest there is a correlation between 99mTc MIBI accumulation and oxyphil cell content or parathyroid gland volume. The aim of our work was to assess the relationship between the pathological structure of parathyroids, their volume, oxyphil cell content and parathyroid 99mTc-MIBI retention. A total of 62 hyperfunctioning parathyroid glands in 46 patients were retrospectively analyzed. Preoperative 99mTc-MIBI scintigraphy was performed according to the double-phase and subtraction protocol. After surgery all glands were evaluated histologically, oxyphil cell content was assessed and volume of each excised gland was calculated. Scintigraphy was positive in 41 of 62 parathyroid glands (66%). The median volume of positive glands was larger than that of negative glands (1.33 ml vs 0.7 ml, p = 0.015). Of the parathyroid lesions, there were 14 (22.6%) cases of nodular hyperplasia, 23 (37.1%) cases of diffuse hyperplasia, and 25 (40.3%) cases of adenomas. A high (≥ 25%) oxyphil cell content was found in 16 glands (25.8%) and a low ( < 25%) oxyphil cell content in 46 (74.2%) glands. Histopathology of parathyroid glands was related to the scintigraphy result (p = 0.002), but not to the 99mTc-MIBI uptake pattern (p = 0.868). The overall result of scintigraphy was not related to the oxyphil cell content (p = 0.797). 99mTc-MIBI uptake pattern wasn't related to the oxyphil cell content (p = 0.833). In general, parathyroid lesions with low oxyphil cell content were larger than parathyroid glands with high oxyphil cell content (1.33 ml vs 0.5 ml, respectively; p = 0.01). The median volume of parathyroids containing a high number of oxyphil cells and having a prolonged 99mTc-MIBI retention was larger than those without prolonged 99mTc-MIBI retention (1.62 ml vs 0.3 ml, respectively; p = 0.008). The median volume of parathyroids with low oxyphil cells content and showing prolonged 99mTc-MIBI retention was larger than those without prolonged 99mTc-MIBI retention (1.95 ml vs 1.07 ml, respectively; p = 0.014). Our findings suggest that a positive scintigraphy result depends on parathyroid histopathology and gland volume and does not depend on the presence of oxyphil cells. Prolonged 99mTc-retention is not related to the parathyroid gland histopathology and the presence of oxyphil cells but to the gland volume.

Distinct differences in the mechanisms of mucosal damage and γ-H2AX formation in the rat urinary bladder treated with o-toluidine and o-anisidine.

Although aromatic amines are widely used as raw materials for dyes, some of them have been concerned about carcinogenicity in the urinary bladder. We examined early changes in histopathology and the formation of γ-H2AX, a biomarker of DNA damage, in the urinary bladder of rats to investigate the mechanisms of mucosal damage induced by monocyclic aromatic amines. 6-week-old male F344 rats were administered 0.4% or 0.8% o-toluidine, 0.3% or 1.0% o-anisidine, 0.4% 2,4-xylidine, 0.2% p-toluidine, or 0.6% aniline in the diet for 4 weeks. Animals were sequentially killed from day 2 to after 2 weeks of recovery, and histopathological and immunohistochemical analyses were performed. In the 0.8% o-toluidine group, there was sequential progression of bladder lesions, characterized by edematous changes and intramucosal hemorrhage at day 2 and formation of granulation tissue with mononuclear cell infiltration at week 1, followed by diffuse hyperplasia at weeks 2 and 4. In the 1.0% o-anisidine group, simple hyperplasia only with slight inflammation was detected from week 1. Whereas γ-H2AX-positive bladder epithelial cells in the 1.0% o-anisidine group were significantly increased in a time-dependent manner, transient increases in γ-H2AX-positive cells were detected at day 2 and week 1 in the 0.8% o-toluidine group. No apparent bladder lesions or increases in γ-H2AX formation were observed in any other groups. These results revealed different mechanisms of bladder mucosal damage associated with o-toluidine and o-anisidine. Moreover, immunohistochemical analysis for γ-H2AX suggested that both compounds may induce DNA damage in epithelial cells, mainly basal cells, of the bladder mucosa.

Parathyroidectomy in dialysis patients: Indications, methods, and consequences.

Secondary hyperparathyroidism, characterized by increased PTH synthesis and secretion, is often seen in advanced stages of chronic kidney disease. Excessive proliferation of parathyroid cells leads to the development of diffuse hyperplasia that subsequently progresses to nodular histology. Refractory hyperparathyroidism occurs when parathyroid glands fail to respond to medical therapy. Parathyroidectomy (PTX), surgical resection of parathyroid glands, is usually performed in cases of persistent serum levels of PTH above 1000pg/mL associated with hypercalcemia or when hyperparathyroidism is refractory to conservative therapy. Parathyroidectomy can be carried out using different procedures: subtotal PTX or total PTX with or without parathyroid autotransplantation. Parathyroid surgery may have undesirable consequences due to PTH oversuppression, such as the development of adynamic bone disease; hungry bone syndrome is quite common after this surgery. However, PTX improves survival and parameters of mineral metabolism. Parathyroidectomy needs to be considered in those patients with severe hyperparathyroidism with a poor response to pharmacological treatment and with distinct undesirable effects of PTH on bone and mineral metabolism parameters.

Hexavalent chromium (Contaminants).

The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of hexavalent chromium, hereinafter referred to as Cr (VI), related to the amendment of the standards for beverages established by the Ministry of Health, Labour and Welfare. Major toxicities induced by Cr (VI) were damages to small intestine and anemia in experimental animals. The finding observed at the lowest LOAEL was diffuse hyperplasia of mucosal epithelium in the duodenum in mice. Regarding to carcinogenicity, Cr (VI)-treatment by drinking water significantly increased incidences of tumors in the small intestine in mice and in the oral mucosa and tongue in rats. Therefore, FSCJ considered that Cr (VI) is carcinogenic. Cr (VI) showed positive results in many genotoxic studies in vitro, and in vivo after parenteral administration, whereas no clear positive results were obtained after the oral administration. These data indicate the genotoxic properties of Cr (VI), though genotoxicity by the oral administration including drinking water remains unclear. The mechanism of small intestinal tumors in mice is considered as follows: Continuous damage to mucosal epithelium in the small intestine by long-term exposure to Cr (VI) induces the hyperplasia in the crypt of small intestine, which would lead to the formation of tumor. In the in vivo gene mutation assays using transgenic rats and mice, no significant increases in mutant frequencies of the transgenes were observed in the carcinogenic target tissues, after exposure to Cr (VI) in drinking water for either 28 (rats) or 90 days (mice)1),2). On the basis of these results, FSCJ judged that the carcinogenic mechanism of Cr (VI) intakes through drinking water was hardly attributable to the genotoxicity. FSCJ considered that the quantitative risk assessment of Cr (VI) through drinking water was difficult to conduct based on the results from epidemiological studies of non-occupational and occupational exposures in human population. Consequently, specifying a tolerable daily intake (TDI), based on the results of animal studies with oral exposure to Cr (VI) through drinking water, is rather feasible. FSCJ specified the TDI of Cr (VI) as 1.1 μg/kg bw/day after applying the uncertainty factor of 100 to BMDL10 of 0.11 mg/kg bw/day, which was ascribed on the diffuse epithelial hyperplasia in the duodenum in male mice observed in the two-year oral exposure study. Since chromium in food is regarded to be present as trivalent chromium3), FSCJ estimated daily intake of Cr (VI) from consumption of mineral water and tap water. The estimation gave the mean and high intakes as ca. 0.04 μg/kg bw/day and 0.290 μg/kg bw/day, respectively. Since both of these two values were lower than the TDI, 1.1 μg/kg bw/day, FSCJ concluded the risk of health effects from Cr (VI) at the current exposure through the consumption of mineral water and tap water to be extremely low.

Cushing syndrome secondary to late onset adrenal hyperplasia: presentation and challenges of management

Cushing’s syndrome is a clinical disorder caused by overproduction of cortisol. Adrenal adenoma is the cause in 5% of cases of Cushing syndrome. ACTH-independent Cushing’s syndrome in 90% is caused by unilateral adrenal tumors. Of these, adenomas are the cause in 80% of the cases, while the others are adrenocortical carcinoma. Rare causes of Cushing’s syndrome include adrenal hyperplasia. Overproduction of cortisol results in weakened protein structures leading to protuberant abdomen and poor wound healing, glucose is converted to fat and deposited in the abdomen, supraclavicular fossa and cheeks. Other presentations are diabetes, hypertension, osteoporosis, fractures, impaired immune function, glucose intolerance, and psychosis. We report a 21-year-old female who presented with clinical symptoms of newly diagnosed hypertension and diabetes mellitus which after poor response to treatment she was evaluated and diagnosed to have Cushing syndrome. She subsequently had left adrenalectomy and did very well with resolution of patients’ symptoms. The histology came out to be diffuse adrenal hyperplasia.

Magnetic Resonance Imaging Features of Normal Thyroid Parenchyma and Incidental Diffuse Thyroid Disease: A Single-Center Study.

Background: No previous studies have investigated the feasibility of magnetic resonance imaging (MRI) diagnosis for detecting incidental diffuse thyroid disease (DTD). This study investigated MRI features of normal thyroid parenchyma and incidental DTD.Methods: From January 2008 to December 2017, 387 patients underwent neck MRI in our hospital due to tumor/nodal staging (n = 137), lymphadenopathy (n = 122), inflammatory neck lesion (n = 85), congenital neck lesion (n = 12), and patient request (n = 31). Among them, 375 patients were excluded because of a lack of appropriate histopathological data on the thyroid parenchyma.Results: Among the patients included, 10 had normal thyroid parenchyma, 1 had Hashimoto thyroiditis, and 1 had diffuse hyperplasia. The common MRI features of normal thyroid parenchyma include iso-/slightly high and homogeneous signal intensity on T1/T2-weighted images, normal anteroposterior diameter of the thyroid gland, smooth margin, and homogeneously increased enhancement as compared to adjacent muscle. Hashimoto thyroiditis exhibited high and inhomogeneous signal intensity on T2-weighted images, while diffuse hyperplasia revealed an increased anteroposterior diameter and lobulated margin of the thyroid gland, and inhomogeneous enhancement.Conclusions: MRI may be helpful for detection of incidental DTD.

A case series of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

A case series of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

Long-term performance of an external stent for saphenous vein grafts: the VEST IV trial

BackgroundExternally stenting saphenous vein grafts reduces intimal hyperplasia, improves lumen uniformity and reduces oscillatory shear stress 1 year following surgery. The present study is the first to present the longer-term (4.5 years) performance and biomechanical effects of externally stented saphenous vein grafts.MethodsThirty patients previously implanted with the VEST external stent in the randomized, within-patient-controlled VEST I study were followed up for adverse events; 21 of these were available to undergo coronary angiography and intravascular ultrasound.ResultsTwenty-one stented and 29 nonstented saphenous vein grafts were evaluated by angiography and ultrasound at 4.5 ± 0.3 years. Vein graft failure rates were comparable between stented and nonstented grafts (30 and 23% respectively; p = 0.42). All failures were apparent at 1 year except for one additional nonstented failure at 4.5 years. In patent vein grafts, Fitzgibbon perfect patency remained significantly higher in the stented versus nonstented vein grafts (81 and 48% respectively, p = 0.002), while intimal hyperplasia area (4.27 mm2 ± 1.27 mm2 and 5.23 mm2 ± 1.83 mm2 respectively, p < 0.001) and thickness (0.36 mm ± 0.09 mm and 0.42 mm ± 0.11 mm respectively, p < 0.001) were significantly reduced. Intimal hyperplasia proliferation correlated with lumen uniformity and with the distance between the stent and the lumen (p = 0.04 and p < 0.001 respectively).ConclusionsExternal stenting mitigates saphenous vein graft remodeling and significantly reduces diffuse intimal hyperplasia and the development of lumen irregularities 4.5 years after coronary artery bypass surgery. Close conformity of the stent to the vessel wall appears to be an important factor.Trial registrationNCT01415245. Registered 11 August 2011.

Diagnostic accuracy of computed tomography for differentiating diffuse thyroid disease from normal thyroid parenchyma: A multicenter study.

This study aimed to assess the diagnostic performance of computed tomography (CT) for differentiating diffuse thyroid disease (DTD) from normal thyroid parenchyma (NTP) using multicenter data. Between January 2016 and June 2016, 229 patients underwent preoperative neck CT and subsequent thyroid surgery at five participating institutions. The neck CT images of each patient were retrospectively reviewed and classified into the following four categories: no DTD, indeterminate, suspicious for DTD, and DTD. The results of the CT image evaluations were compared with the histopathological results to determine the diagnostic accuracy of CT at each institution. According to the histopathological results, there were NTP (n = 151), Hashimoto thyroiditis (n = 24), non-Hashimoto lymphocytic thyroiditis (n = 47), and diffuse hyperplasia (n = 7). The CT categories of the 229 patients were “no DTD” in 89 patients, “indeterminate” in 40 patients, “suspicious for DTD” in 42 patients, and “DTD” in 58 patients. The presence of two or more CT features of DTD, which was classified as “suspicious for DTD” by all radiologists, had the largest area under the receiver-operating characteristic curve (Az = 0.820; 95% confidence interval: 0.764, 0.868), with sensitivity of 85.9% and specificity of 78.2%. However, no statistical significance between readers’ experience and their diagnostic accuracy was found. In conclusion, evaluations of CT images are helpful for differentiating DTD from NTP.

Pathological Findings in the Adrenal Glands of 80 Dogs

Background: The adrenal glands development important endocrine functions and can be affected by primary or secondary diseases. These adrenal gland pathologies may induce clinical syndromes resulting from abnormalities in the production and secretion of hormones. Data about pathological changes in dogs are scarce. Therefore, the aim of the present study was to identify and evaluate the histopathological and epidemiological features of adrenal changes in dogs submitted to necropsy examination from 2005 to 2016 in a Veterinary Teaching Hospital, Londrina, Paraná, Brazil.Material, Methods &amp; Results: During this period, 80 animals presented alterations of adrenal gland, representing 5.5% of all necropsied dogs. The pure breed dogs representing 58.6% and mixed breed 41.4%; 53.4% were female and 46.6% were male. The non-neoplastic adrenal lesions were more frequently (57.5%) compared to the neoplastic changes (42.5%). Most of the adrenal glands lesions occurred in older dogs (60%), following by the middle aged (31.25%) and young dogs (8.75%). The main non-neoplastic lesions observed in the adrenal glands were of hyperplastic (69.5%) and circulatory (26%) origin, among the earlier, 68.8% were diffuse hyperplasia and 31.2% nodular hyperplasia. The nodular hyperplasia was classified as micronodular multifocal in 40% of the glands with nodular hyperplasia, macronodular multifocal in 30%, micronodular diffuse in 20%, and micronodular focal in 10%. The neoplasms observed were adrenocortical adenoma (ACA) in 44.1%, pheochromocytomas in 23.5% and adrenocortical carcinomas (ACC) in 11.7% of the dogs with adrenal tumors. Metastasis from other primary tumors were observed in 20.6%.Discussion: The data in veterinary literature about the frequency of changes in adrenal gland of dogs are scarce and focus features of diagnosis by ultrasound examination. Most of the adrenal changes observed in the present study were incidental findings observed during the necropsy examination and no specific clinical signs were observed. Non-neoplastic adrenal lesions, mainly of hyperplastic origin, were more frequently observed compared to the neoplastic changes. Differing from previous studies, the diffuse hyperplasia was the most common non neoplastic finding in the adrenal glands. Considering the subclassification of nodular hyperplasia, the multifocal micronodular and macronodular multifocal pattern were the most frequent. In veterinary literature, there are no data about frequency of nodular hyperplastic subtypes. However, in humans the subclassification of nodular hyperplasia is associated to development of endocrine disorders. Previous studies reported lower incidence of neoplastic changes in adrenal gland of dogs compared to the present results. The adrenocortical adenoma was the most common primary tumor, followed by the adrenocortical carcinoma, pheochromocytoma and adrenocortical carcinoma. Congestion and hemorrhage were common findings observed in the adrenal gland primary tumors. On the other hand, necrosis and inflammatory infiltrate were observed only in the adrenocortical carcinomas. These histopathological features may be used as tool in the differential diagnosis between well differentiated adrenocortical carcinoma and adenoma. The histopathological examination was fundamental to differential and definitive diagnosis of all canine adrenal gland disorders observed.

Neuroendocrine cell proliferations in lungs explanted for fibrotic interstitial lung disease and emphysema

Using recently proposed pathological criteria, we determined the incidence of neuroendocrine cell proliferation ina series of explants with lung disease. Cases were definedas NECH (≥3 bronchioles with ≥5 endocrine cells), borderline diffuse neuroendocrine cell hyperplasia (DPNECH) (1-3 tumourlets with or without NECH), and DPNECH (≥3 tumourlets with NECH). Endocrine cells were identified by immunohistochemical staining for synaptophysin. There were 65 explants with interstitial lung disease (57 with non-sarcoid fibrotic lung disease, 8 with sarcoidosis), and 21 with centrilobular emphysema. Over one-third of all explant cases demonstrated histological criteria for NECH. There were three cases of DPNECH in the non-sarcoid fibrotic lung disease group (5%) and 20 cases of NECH (35%). The emphysema group had one case of DPNECH (5%), two cases of borderline DPNECH (10%), and seven cases with NECH (33%). The sarcoidosis group had two cases of DPNECH (25%) and three cases of NECH (38%). NECH is common in interstitial lung disease and emphysema. These results suggest that fibrotic lung disease is a predisposing factor for neuroendocrine cell proliferation, in addition to the known risk of epithelial neoplasms.

DIPNECH: A UNIQUE PRESENTATION OF A RARE DISEASE

SESSION TITLE: Diffuse Lung Disease 2 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 pm - 02:15 pm INTRODUCTION: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a very rare disease that consists of a proliferation of scattered single cells, small nodules, or linear proliferations of pulmonary neuroendocrine cells (1). The entity has been described as a precursor to pulmonary carcinoid tumors (2), is thought to be more common in middle-aged women, and can be associated with slowly-progressive cough or shortness of breath with exertion (1,3). CASE PRESENTATION: We present a case of a 42-year-old female with a complicated pulmonary history including a childhood diagnosis of asthma, two spontaneous pneumothoraces, chronic daily cough, dyspnea on exertion, and a seven-year history of incidentally-noted pulmonary nodules. An initial workup for her nodules was negative for fungal or autoimmune etiologies. An interval CT scan was obtained and showed an increase in nodule size which was further evaluated with a PET-CT. While none of the lung nodules were PET-avid, a hypermetabolic thyroid nodule was incidentally noted, which was biopsied and found to be papillary thyroid cancer. Pulmonary function testing was obtained for her dyspnea and showed mild restriction with no evidence of obstruction and normal diffusion capacity. After a non-diagnostic CT-guided biopsy of a right middle lobe lung nodule led to an iatrogenic pneumothorax requiring chest tube placement, she eventually underwent video assisted thoracoscopic surgery and right middle and lower lobe wedge resections. Biopsy showed the presence of a typical carcinoid tumor as well as neuroendocrine hyperplasia consistent with DIPNECH. DISCUSSION: This case represents an atypical presentation of a rare disease. Though pulmonary nodules, shortness of breath, and cough are common findings in DIPNECH, the occurrence of spontaneous pneumothoraces is not. Few case reports have described spontaneous pneumothoraces in patients with large endobronchial carcinoid tumors; however, this patient had no evidence of endobronchial obstruction and thus represents a unique presentation of the disease (4,5). This case also demonstrates the importance of maintaining a broad differential in the approach to patients presenting with dyspnea, cough, and pulmonary nodules. While the DIPNECH is very rare, appropriate diagnosis and close follow-up is important given the association of DIPNECH with subsequent development of carcinoid tumors (6). CONCLUSIONS: The differential for diffuse pulmonary nodules in the setting of chronic cough or dyspnea is incredibly broad. After more common etiologies like metastatic disease, granulomatous disease, autoimmune, and infectious disorders are ruled out, one should consider the diagnosis of DIPNECH, particularly in a middle-aged female with chronic, otherwise-unexplained respiratory symptoms and especially with an associated diagnosis of a carcinoid tumor (2). Reference #1: Travis WD, Brambilla EW, Burke AP, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus, and Heart, IARC Press, Lyon 2015. Reference #2: Gorshtein, A., Gross, D. J., Barak, D., Strenov, Y., Refaeli, Y., Shimon, I. and Grozinsky-Glasberg, S. (2012), Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors. Cancer, 118: 612–619. https://doi.org/10.1002/cncr.26200. Reference #3: Nassar A. A., Jaroszewski D. E., Helmers R. A., Colby T. V., Patel B. M., Mookadam F. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia—a systematic overview. American Journal of Respiratory and Critical Care Medicine. 2011;184(1):8–16. https://doi.org/10.1164/rccm.201010-1685pp. DISCLOSURES: No relevant relationships by Carleen Risaliti, source=Web Response No relevant relationships by Kyle Stinehart, source=Web Response

A13439 Cellular and Genetic Causes of Idiopathic Hyperaldosteronism

Objectives: Primary aldosteronism (PA) affects ∼10% of hypertensive patients and has unilateral and bilateral forms (30%:70%). Most unilateral PA is caused by computed tomography (CT)- detectable aldosterone-producing adenomas (APA), which express CYP11B2 (aldosterone synthase), and frequently harbor somatic mutations in aldosterone-regulating genes (KCNJ5 >> CACNA1D). The etiology of the more common bilateral PA (often termed idiopathic hyperaldosteronism [IHA]) has long been believed to result from diffuse hyperplasia of adrenal cortex cells without incorporation of CYP11B2 expression. Methods: Herein, fifteen IHA adrenals from a multi-institution cohort were examined using CYP11B2 immunohistochemistry and next generation sequencing (NGS). Results: CYP11B2 immunoreactivity in the adrenal cortex was diffusely positive in only 4/15 IHA adrenals, arguing against this as the common cause of IHA. Instead, all adrenals harbored at least one CT-undetectable CYP11B2-expressing cell clusters (termed aldosterone-producing microscopic lesions [APML]), which existed sporadically in adrenal cortex. The median number per case and individual area of APML in IHA was significantly larger than those in normotensive controls. NGS of DNA from 99 adrenal APML demonstrated somatic mutations in CACNA1D (57 / 58%) and KCNJ5 (1 / 1%). Conclusion: These data indicate that the most common cause of PA, IHA, results from the accumulation of image-undetectable aldosterone producing cells harboring somatic aldosterone-driver gene mutations. The high prevalence of mutations in CACNA1D, an L-type calcium channel, indicate a potential actionable therapeutic target to inhibit aldosterone overproduction in IHA patients.

Cellular and Genetic Causes of Idiopathic Hyperaldosteronism.

Primary aldosteronism affects ≈5% to 10% of hypertensive patients and has unilateral and bilateral forms. Most unilateral primary aldosteronism is caused by computed tomography-detectable aldosterone-producing adenomas, which express CYP11B2 (aldosterone synthase) and frequently harbor somatic mutations in aldosterone-regulating genes. The cause of the most common bilateral form of primary aldosteronism, idiopathic hyperaldosteronism (IHA), is believed to be diffuse hyperplasia of aldosterone-producing cells within the adrenal cortex. Herein, a multi-institution cohort of 15 IHA adrenals was examined with CYP11B2 immunohistochemistry and next-generation sequencing. CYP11B2 immunoreactivity in adrenal glomerulosa harboring non-nodular hyperplasia was only observed in 4/15 IHA adrenals suggesting that hyperplasia of CYP11B2-expressing cells may not be the major cause of IHA. However, the adrenal cortex of all IHA adrenals harbored at least 1 CYP11B2-positive aldosterone-producing cell cluster (APCC) or micro-aldosterone-producing adenomas. The number of APCCs per case (and individual APCC area) in IHA adrenals was significantly larger than in normotensive controls. Next-generation sequencing of DNA from 99 IHA APCCs demonstrated somatic mutations in genes encoding the L-type calcium voltage-gated channel subunit α 1-D ( CACNA1D, n=57; 58%) and potassium voltage-gated channel subfamily J-5 ( KCNJ5, n=1; 1%). These data suggest that IHA may result from not only hyperplasia but also the accumulation or enlargement of computed tomography-undetectable APCC harboring somatic aldosterone-driver gene mutations. The high prevalence of mutations in the CACNA1D L-type calcium channel provides a potential actionable therapeutic target that could complement mineralocorticoid blockade and inhibit aldosterone overproduction in some IHA patients.

Clinical and Molecular Characteristics May Alter Treatment Strategies of Thyroid Malignancies in DICER1 Syndrome.

DICER1 syndrome is a rare autosomal-dominantly inherited disorder that predisposes to a variety of cancerous and noncancerous tumors of mostly pediatric and adolescent onset, including differentiated thyroid carcinoma (DTC). DTC has been hypothesized to arise secondarily to the increased prevalence of thyroid hyperplastic nodules in syndromic patients. To determine somatic alterations in DICER1-associated DTC and to study patient outcomes. Retrospective series. Tertiary referral centers. Ten patients with germline pathogenic DICER1 variants and early-onset DTC. Somatic DICER1 mutation analysis, extensive somatic DNA variant and gene fusion analyses were performed on all tumors. Median age at DTC diagnosis was 13.5 years and there was no recurrent or metastatic disease (median follow-up, 8 years). All thyroid specimens showed diffuse nodular hyperplasia with at least one focus suspicious of DTC but without infiltrative growth, extrathyroidal extension, vascular invasion, or lymph node metastasis. Most of the individual nodules (benign and malignant) sampled from the 10 tumors harbored distinct DICER1 RNase IIIb hotspot mutations, indicating a polyclonal composition of each tumor. Furthermore, nine of 10 DICER1-related DTCs lacked well-known oncogenic driver DNA variants and gene rearrangements. On the basis of our clinical, histological, and molecular data, we consider that most DICER1-related DTCs form a low-risk subgroup. These tumors may arise within one of multiple benign monoclonal nodules; thus, hemi-thyroidectomy or, more likely, total thyroidectomy may often be required. However, radioiodine treatment may be unnecessary given the patients' ages and the tumors' low propensity for metastases.