Benign Adenoma Research Articles

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.

Safety of Endoscopic Snare Ampullectomy for Adenomatous Ampullary Lesions: Focus on Pancreatic Stent Placement to Prevent Pancreatitis.

Ampullary tumors, although relatively uncommon, are increasingly diagnosed due to ongoing progress in imaging technology and the diagnostic accuracy of endoscopic ultrasound and magnetic resonance cholangiopancreatography. Endoscopic ampullectomy (EA) has become the preferred treatment option over surgery due to its lower morbidity for benign ampullary adenomas. This study aims to evaluate the efficacy, safety, and outcome of EA in 30 patients with benign-appearing ampullary lesions with particular emphasis on the accuracy of preampullectomy histology and technical details of the pancreatic duct drainage to prevent postprocedural pancreatitis. Data from a cohort of 30 patients who underwent EA were retrospectively analyzed. Histologic characteristics of the ampullomas, accuracy of histology of pre-EA biopsy specimen, safety of the procedure, recurrence rate, as well as the clinical outcome of all patients, are analyzed and discussed. Endoscopic resection was successful as a definitive treatment in 25 patients (83.3%). Five patients required additional surgery. In 8 patients, a definitive histologic specimen revealed an adenocarcinoma (3 in situ and 5 invasive). The diagnostic accuracy obtained by preresection biopsy specimen was low (0.70). Pancreatic duct stent placement after snare resection was unsuccessful in 9 patients, and 3 of them developed pancreatitis after EA. EA appears to be a relatively safe alternative to surgery as the first therapeutic option for selected patients with benign-appearing ampullary adenomas. A correct preoperative evaluation by endoscopic ultrasound and magnetic resonance cholangiopancreatography can help to define the anatomy of the pancreatic duct to improve the success rate of pancreatic stent placement which seems to offer a protective role in the prevention of postprocedural pancreatitis.

Unexpected Lung Metastasis After Left Hemithyroidectomy for Follicular Adenoma in a Young Adult Male: A Case Report

Follicular neoplasms of the thyroid gland are benign follicular adenoma and follicular carcinoma. To distinguish follicular carcinoma from a follicular adenoma based on cytologic, sonographic or clinical features alone is very difficult. As follicular adenoma of the thyroid is a benign tumor usually do not metastasize. Here, a case is presented with follicular variant of papillary thyroid carcinoma (FVPTC) with lung metastasis which was treated as follicular adenoma four years back. Patient had left hemithyroidectomy for follicular adenoma and ignored to have regular follow up. He suddenly developed fever, chest pain and dry cough. CT scan evaluated a fairly big lung mass which eventually came out as metastatic follicular carcinoma. From this reported case, it is evident that regular checkup of patient with follicular adenoma should be ensured for early diagnosis of further transformation of adenoma to malignancy.
 Bangladesh J. Nuclear Med. 22(2): 157-160, Jul 2019

Tubulovillous Adenoma of Duodenum: A Case Report

Tumors arising from the upper GIT are usually of epithelial origin and are mostly benign. Even when they do occur, they are usually considered as premalignant lesions with a risk of transformation to malignant ones.Tubulo-villous adenomas represent lesions that are histologically intermediate between tubular and villous polyps. These account for the majority of colonic polyps.We present a case of benign adenomas arising from the duodenum, an extremely rare diagnosis with an average annual incidence rate of 9.9 per million people.Among these uncommon tumors,Duodenal tumors are even rarer with average incidence rate of 0.4% only. Histopathological examination mostly shows villous type.Tubulovillous histology is extremely rare with an incidence of less than 1% of all duodenal tumors. However, these tumors are being diagnosed with increasing frequency due to more widespread use of endoscopy.
 J Shaheed Suhrawardy Med Coll, December 2020, Vol.12(1); 58-60

A Bronze Age mandibular anomaly from Gansu, China

AbstractBone defect in the mandible due to developmental defects, trauma, or diseases is common. However, large scale of mandibular bone atrophy induced by long‐term pressure is rare. This study reported a mandibular anomaly, possibly a secondary lesion, from a Bronze Age adult male excavated from the Dunping cemetery during the Eastern Zhou Dynasty (770–256 BCE), Zhang County, Gansu Province, China. The defect presents as an absence of bone mass at the angle of inferior lingual aspect of the mandibular corpus, incorporating the gonial angle of the mandible on the left side. Overall profile of the defect was assessed using morphological observations of the mandible, accompanied by computed tomography (CT) imaging and panoramic dental X‐ray images of the jaws used to assist with the diagnosis. There were no signs of trauma, osteogenic neoplasms, or osteolytic lesions. Pressure resorption, a Stafne defect, was postulated as the primary cause of bone atrophy due to a long‐term lesion of the neighboring submandibular gland, namely, chronic sialadenitis or a benign neoplasm pleomorphic adenoma. This is for the first reported case of a mandible anomaly as such identified from ancient China. This reporting enriches the knowledge of long‐term effects of pressure resorption in the human mandible.

Histological Effect of Androgenic Anabolic Steroids on Liver

Abstract: Anabolic androgenic steroids (AAS) they are the synthetic type of the natural male sex hormone(testosterone), they are widespread used amongst athletes to enhance performance. Abuse of AAS is commonamongst players and it is usually accompanied by a many medically based complications. It was reportedthat hepatic problems include cholestasis, elevation of liver enzymes e.g. aminotransferases, as well as,benign hepatic adenomas, jaundice and to less extent of hepatocellular carcinoma was associated with theiruse.A total of (12) adult New Zealand rabbits (Oryctolagus cuniculus) male, aged one year was selected. 2control animals and 10 were treated with injections intramuscularly of the AAS, nandrolone decanoate(15 mg/kg) three times a week for 12 weeks. At the end of experiment the animals were sacrificed and theliver was dissected out and fixed using 10% buffered formalin-saline to prepare blocks for staining withhaematoxylin and eosin for histological examination using the light microscope.The liver of treated animals reveals that there are a mild to severe vascular congestion. There is swelling ofhepatocytes, and inflammatory cell infiltration. Perivascular fibrosis, cellular necrosis was observed in otherslides with sinusoidal congestions and extrabiliary bile pigments deposits.The benefit of AAS comes with unwanted side effects. The total volume of the hepatocytes and sinusoidswere increased in the studied animals. The total number of hepatocytes nuclei in experimental group alsoincreased. The damage of the liver cells or at least increased permeability of the hepatocellular membranewhich is noticed in the present work could explain the increment of plasma levels of liver enzymeswhich was studied by other researchers, as they notice an elevation liver enzymes activity such as alanineaminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), gamma glutamyltranspeptidase (GGT), and lactate dehydrogenase(LDH)..Patients and physicians must kept in mind that the sequelae of AAS abuse are life threatening. So peopleshould be aware about the complications of AAS use and a periodic examination of liver function and checkout should be done to those treated groups.

DNA Methylation Haplotype Block Markers Efficiently Discriminate Follicular Thyroid Carcinoma from Follicular Adenoma.

ContextFollicular thyroid carcinoma (FTC) is the second most common type of thyroid carcinoma and must be pathologically distinguished from benign follicular adenoma (FA). Additionally, the clinical assessment of thyroid tumors with uncertain malignant potential (TT-UMP) demands effective indicators.ObjectiveWe aimed to identify discriminating DNA methylation markers between FA and FTC.MethodsDNA methylation patterns were investigated in 33 FTC and 33 FA samples using reduced representation bisulfite sequencing and methylation haplotype block–based analysis. A prediction model was constructed and validated in an independent cohort of 13 FTC and 13 FA samples. Moreover, 36 TT-UMP samples were assessed using this model.ResultsA total of 70 DNA methylation markers, approximately half of which were located within promoters, were identified to be significantly different between the FTC and FA samples. All the Gene Ontology terms enriched among the marker-associated genes were related to “DNA binding,” implying that the inactivation of DNA binding played a role in FTC development. A random forest model with an area under the curve of 0.994 was constructed using those markers for discriminating FTC from FA in the validation cohort. When the TT-UMP samples were scored using this model, those with fewer driver mutations also exhibited lower scores.ConclusionAn FTC-predicting model was constructed using DNA methylation markers, which distinguished between FA and FTC tissues with a high degree of accuracy. This model can also be used to help determine the potential of malignancy in TT-UMP.

Increased BMI, Sedentary Lifestyle & Metabolic Syndrome as Independent Risk Factors for Development of Colorectal Adenomas: A Prospective Study

<i>Background</i>: Several risk factors for development of colorectal adenomas has been studied over the years. But the effect of increased BMI, sedentary lifestyle and metabolic syndrome on the development of colorectal adenoma has been minimally studied. This study describes the influence of increased BMI, sedentary lifestyle & metabolic syndrome on the prevalence of colorectal adenoma. Secondary objective was to determine whether these factors influence the progression of benign adenomas into advanced adenomas or not. <i>Methods</i>: A total of 697 consecutive cases were included. Asymptomatic subjects aged more than 40 years who were undergoing their first colonoscopy were included in the study. Patients with a history of colonic neoplasia, IBD, colonoscopic polypectomy or colectomy were excluded from the study. Details of colonoscopy, polypectomy and histology were recorded. Data were analyzed by SPSS version 22.0. Chi-square (X²) test was done to assess the association of different risk factors with the development of colonic adenomas. Odds ratio (OR) along with its 95% CI was calculated for every individual risk factor under evaluation. A p-value<0.05 was considered as significant. <i>Result</i>: Colonic polyps were detected in 153 (21.95%) subjects. Out of these 153 subjects 81 (11.62%) had histologically proved adenomas. Benign adenomas were detected in 63 (9.03%) cases, whereas advanced adenomas were detected in 18 (2.58%) cases. A BMI of≥30 showed an OR of 2.94 (1.64-4.24) for the development of colorectal adenomas. Presence of metabolic syndrome showed an OR of 1.74 (1.14-2.34) for the development of adenomas. Sedentary lifestyle showed an OR of 1.91 (1.31-2.51) for the development of colorectal adenomas. An age of≥50 years also showed significant effect (OR=1.39) on the development of colonic adenomas. Lastly the presence of increased BMI, sedentary lifestyle and metabolic syndrome was identified as individual risk factors for the progression of adenoma towards advanced adenomas with an OR of 1.67, 2.14 & 2.92 respectively. <i>Conclusion</i>: This study demonstrates that increased BMI, sedentary lifestyle and metabolic syndrome are associated with increased risk of development of colorectal adenomas. Moreover, increasing age (>50 years) also contribute to the increased risk of development of colorectal adenomas. And lastly it has been showed that increased BMI, sedentary lifestyle and metabolic syndrome individually contribute to the increased risk of progression of benign colonic adenomas to a more advanced adenoma.

Predictive model using hemoglobin, albumin, fibrinogen, and neutrophil-to-lymphocyte ratio to distinguish patients with colorectal cancer from those with benign adenoma.

Colorectal cancer (CRC) is associated with inflammation, activation of coagulation, and mild anemia. Hematological parameters reflecting ongoing cancer may have the potency to be effective for early diagnostics of CRC. The aim of this study was to examine the validity and relationship between some biochemical and hematological parameters for the early diagnosis of CRC. We designed a prospective observational cohort study to analyze whether these laboratory markers have the potency to distinguish benign tumors from malignant before planned surgery. The clinical data were collected from 208 patients with suspected benign or malignant colorectal tumors who were eligible for elective surgery between September 2018 and January 2020. Blood samples were collected one day before surgery, examined parameters included: complete blood count, hemoglobin (HGB) concentration, albumin (ALB), C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen (FG). Absolute neutrophil and lymphocyte counts were used for the calculation of the neutrophil-to-lymphocyte ratio (NLR). The diagnosis was confirmed by histopathological examination. The 197 patients were divided into the group of benign (B group = 52 patients) or malignant tumors (CRC group = 145 patients). ROC curves and cut-off values of NLR, HGB, FG, and ALB concentration, serum CRP and IL-6 levels. In the cohort of 197 adult patients submitted for the elective colorectal surgery, the complete blood samples drawn one day before surgery showed significant differences between patients with benign tumors and colorectal carcinoma: HGB (mean 139.9 g/l vs. 129.9; p<0.001), FG (mean 3.36 g/l vs. 3.94 g/l; p<0.001), ALB (mean 43.4 g/l vs. 41.1 g/l; p=0.001), NLR (mean 2.73 vs. 3.88; p=0.016), respectively. CRP (mean 2.9 mg/l vs. 4.4 mg/l; p=0.011), thrombocyte count (mean 235×109/l vs. 265×109/l; p<0.029). Differences in IL-6 concentrations were not significant (2.9 pg/ml vs. 4.15 pg/ml; p=0.052). Using multivariable logistic regression analysis, four valid parameters (HGB, FG, ALB, and NLR) were suitable for the construction of a diagnostic predictive model for the identification of CRC. In conclusion, a panel of routinely examined blood parameters like HGB, FG, ALB, and NLR has the potency to distinguish patients with benign tumors from malignant by applying a diagnostic predictive model for early laboratory detection of CRC.

Expression of Beta-Catenin in Colorectal Carcinoma and its Association with Various Clinicopathological Parameters

Introduction: Colorectal Carcinoma (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer related mortality globally. It is a source of concern for researchers worldwide and hence, a lot of emphasis is being given towards early detection and targeted drug therapy to improve the survival rate. Aim: To study the expression of beta-catenin in colonic polyps, adenomas and CRC and to associate beta-catenin expression with various clinicopathological features. Materials and Methods: This was a prospective cross-sectional study conducted in the Department of Pathology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India from September 2018 to August 2020. Colonoscopic biopsies, mucinous carcinoma and poorly preserved tissue were excluded. Histopathological study and Immunohistochemistry evaluation of beta-catenin was done. Statistical analysis was done by using appropriate tests. A p-value of less than 0.05 was taken as statistically significant. Results: Out of 80 cases, 40 cases were benign lesions Non neoplastic polyp and adenoma) and 40 cases were adenocarcinoma. It was observed that benign lesions had maximum cases with preserved membranous expression (36/40) and very few cases (4/40) showed cytoplasmic expression of beta-catenin. But in carcinoma, high cytoplasmic expression was seen in 20/40 (50%) whereas 8/40 (20%) cases had nuclear positivity. Membranous beta-catenin expression was significantly higher in benign lesions than in the malignant lesions (IS:8.75±3.09 versus 4.30±2.70) respectively; (p&lt;0.0001). But cytoplasmic beta-catenin expression was low in benign lesion as compared to malignant lesion (IS: 2.07±3.46 versus 5.35±3.14), respectively; (p&lt;0.0001). However, nuclear beta-catenin expression was extremely low in benign lesions than in malignant lesions (0.08±0.47 versus 1.90±3.49), respectively; (p=0.0016), this difference was statistically significant. Conclusion: The present study demonstrates the change in beta-catenin expression with gradual transition from predominantly membranous pattern to cytoplasmic or nuclear as we progress from normal colorectal tissues to polyps, benign premalignant lesions and malignant neoplasms. This property of beta-catenin helps in determining malignant potential of various premalignant neoplasms of large intestine which in turn helps in initiating early prophylactic treatment.

Clinical and pathologic features for predicting malignancy in thyroid follicular neoplasms.

The cytologic findings of follicular neoplasm do not distinguish between benign follicular adenoma and follicular thyroid carcinoma (FTC). The objective of this retrospective study was to identify clinical and cytologic/pathologic features to predict malignancy in patients preoperatively diagnosed with follicular neoplasms. In total, 416 patients with follicular neoplasms who underwent thyroidectomy were reviewed at Seoul St. Mary's Hospital (Seoul, Korea) from January 2010 to June 2018. Clinicopathological features were analyzed retrospectively by complete medical chart review and pathologic slide review. Thyroid malignancy/noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was diagnosed in 209 patients (50.2%). In total, 59 patients (14.2%) were diagnosed with FTC, 55 patients (13.3%) were diagnosed with follicular variant papillary thyroid carcinoma (fvPTC). The number of patients with PTC-related nuclear changes was higher in the malignancy/NIFTP group than in the benign group (16.3% vs. 1.9%, P<0.001). Multivariate analysis indicated that the significant risk factors for the diagnosis of malignancy/NIFTP include cytologic or pathologic diagnosis with PTC-related nuclear changes, NRAS mutation, and male sex. The prevalence of malignancy in patients with a preoperative diagnosis of follicular neoplasm was much higher in our study than in previous reports. Cytologic or pathologic PTC-related nuclear changes is a useful predictor of the presence of malignancy. Further studies must be conducted to support our results.

Laparoscopic enucleation and spleen saving distal pancreatectomy for synchronous insulinoma and nesidioblastosis in an adult patient

Introduction: Insulinoma is the most common functional neoplasm of the endocrine pancreas. Patients typically present with features known as Whipple triad. 90% of insulinomas are found to be benign solitary adenomas amenable to surgical resection. Method: We present a case of a lady who had endogenous hyperinsulinism with two DOTATATE avid nodules in the pancreatic body and tail who subsequently underwent laparoscopic enucleation and spleen saving distal pancreatectomy. Results: The patient presented initially with features suggestive of Whipple triad. Further workup by the endocrinologist showed results consistent with endogenous hyperinsulinism. Computed Tomography (CT) scan and DOTATATE scan showed that she had one intensely DOTATE-avid exophytic nodule arising from the pancreatic body that is suspicious for a neuroendocrine tumour while the second DOTATATE-avid nodule is close to the pancreatic tail. There is no suspicious nodal or distant DOTATATE-avid metastasis detected. Her case was discussed in the multidisciplinary meeting and the decision was to proceed with laparoscopic enucleation of both lesions. She subsequently underwent laparoscopic enucleation of pancreatic body lesion with spleen saving distal pancreatectomy. She was discharged well on post operative day 3 and remained symptom free during subsequent follow-ups. Final histology came back as grade 1, well differentiated insulinoma of the pancreatic body and incidental pancreatic nesidioblastosis in the pancreatic tail. Conclusion: Laparoscopic enucleation of pancreatic neuroendocrine tumour is feasible and safe method to resect pancreatic neuroendocrine tumour with less morbidity.

Histopathological study of ovarian lesions at a tertiary care hospital

Background: Ovary is the commonest site of neoplastic and non-neoplastic lesion, can present in childhood to postmenopausal age group and accounts for the most prevalent cause of hospital admissions. Aims & Objectives: (1) To know about various histopathological types of ovarian lesions presented and diagnosed. (2) To study the incidence of ovarian lesions with respect to patient’s age. (3) To study the frequency of ovarian lesions in terms of non-neoplastic or neoplastic, benign or malignant, unilateral or bilateral, etc.Materials and Method: This is a descriptive study which was carried out at B.J. Medical College, Ahmedabad for a period of three years from 1st January 2018 to 31st December 2020. A Total of 225 cases of ovarian lesions were received and processed in the Pathology Department. Hematoxylin and Eosin stained slides were examined. We have included parameters like Age wise incidence, Nature of Lesion, Frequency & Laterality in this study.Results: Out of 225 cases, 197 cases (87.56%) were unilateral and 28cases (12.44%) were bilateral, 98 cases (43.56%) were non neoplastic & 127 cases (56.44%) were neoplastic. Majority of cases 112(49.78%) belong to age group of 20-39 years. The most common non-neoplastic lesion seen was Follicular Cyst followed by simple and corpus luteal cyst. Among neoplastic lesions, 120 cases (94.49%) were benign & 1 case (0.78%) was borderline & 6 cases (4.73%) were malignant. In benign ovarian neoplasm, most commonly seen lesion were serous cyst adenoma followed by benign cystic teratoma and mucinous cyst adenoma. In malignant cases, maximum were of serous cyst adenocarcinoma and endometrioid carcinoma. Conclusion: Ovarian Lesions both non-neoplastic and neoplastic include a variety of morphological features and show a particular age wise incidence. Role of histopathological evaluation remains always important in both diagnosis & management of such cases, particularly in cases of Malignant Lesions in order to save the patient’s life.

Coexistence of pituitary incidentaloma and primary hyperparathyroidism mimicking multiple endocrine neoplasia Type 1: A case report

The widespread use of imaging procedures has led to an increased discovery of incidental masses in the pituitary gland. Although the majority of pituitary incidentalomas are non-functioning benign adenomas but their increased prevalence poses a diagnostic and therapeutic challenge. These masses may cause various hormonal disturbances as well as they might also be a component of multiple endocrine neoplasia syndromes type 1 (MEN-1) or type 4 (MEN-4). In both syndromes, primary hyperparathyroidism frequently accompanies with pituitary adenomas. Herein we present a 56-year-old man with pituitary incidentaloma who is also detected primary hyperparathyroidism. Contrary to our expectations, any gene defects could be found related with neither MEN-1 nor MEN-4 in the genetic examination.

Normotensive presentation in primary aldosteronism: A report of two cases

Normotensive patients with primary aldosteronism (PA) are relatively rare. Herein, we report two patients with normotensive PA and present a literature review to improve an understanding of the disease. Patient 1, a 56-year-old man, presented with recurrent hypokalemia that lasted for more than 2 years. Patient 2 was a 33-year-old man who presented with sexual dysfunction and was diagnosed with a prolactinoma combined with adrenal insufficiency and hypogonadism. Neither of these patients had hypertension that was detectable on repeated manual measurements. In both patients, a typical biological profile of PA was demonstrated that included hypokalemia with kaliuresis, elevated plasma aldosterone concentration (PAC), suppressed plasma renin concentration, and a high aldosterone-to-renin ratio. Both patients did not have sufficiently suppressed PAC on the saline infusion test, confirming the diagnosis of PA. Computed tomography of the adrenal gland and adrenal venous sampling suggested an aldosteronoma, which was confirmed by lateralized hypersecretion of aldosterone. After removal of the benign adenoma, the biochemical abnormalities were corrected. As hypertension is not necessarily a sign of PA, we propose that all patients with hypokalemia should be screened for PA in order to prevent cardiovascular complications while balancing economics and effectiveness.

β-catenin in adrenal zonation and disease

The Wnt signaling pathway is a critical mediator of the development and maintenance of several tissues. The adrenal cortex is highly dependent upon Wnt/β-catenin signaling for proper zonation and endocrine function. Adrenocortical cells emerge in the peripheral capsule and subcapsular cortex of the gland as progenitor cells that centripetally differentiate into steroid hormone-producing cells of three functionally distinct concentric zones that respond robustly to various endocrine stimuli. Wnt/β-catenin signaling mediates adrenocortical progenitor cell fate and tissue renewal to maintain the gland throughout life. Aberrant Wnt/β-catenin signaling contributes to various adrenal disorders of steroid production and growth that range from hypofunction and hypoplasia to hyperfunction, hyperplasia, benign adrenocortical adenomas, and malignant adrenocortical carcinomas. Great strides have been made in defining the molecular underpinnings of adrenocortical homeostasis and disease, including the interplay between the capsule and cortex, critical components involved in maintaining the adrenocortical Wnt/β-catenin signaling gradient, and new targets in adrenal cancer. This review seeks to examine these and other recent advancements in understanding adrenocortical Wnt/β-catenin signaling and how this knowledge can inform therapeutic options for adrenal disease.

The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas

Most pituitary adenomas (PAs) are considered benign tumors, but approximately 0.2% can present metastasis and are classified as pituitary carcinomas (PCs). Refractory PAs lie between benign adenomas and true malignant PC and are defined as aggressive-invasive PAs characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments, including temozolomide. It is notoriously difficult to manage refractory PAs and PC because of the limited therapeutic options. As a promising therapeutic approach, cancer immunotherapy has been experimentally used for the treatment of many tumors, including pituitary tumors. The purpose of this review is to report the progress of immunotherapy in pituitary tumors, including refractory PAs and PCs. The tumor immune microenvironment has been recognized as a key contributor to tumorigenesis, progression, and prognosis. One study indicated that the number of CD68+ macrophages was positively correlated with tumor size and Knosp classification grade for tumor invasiveness. The infiltration of CD4+ and CD8+ T cells was relatively scant in these adenomas, but pituitary growth hormone (GH) adenomas exhibited significantly more CD4+ and CD8+ T cells than non-GH adenomas. These results suggest an association of CD68+ macrophage infiltration with an increase in pituitary tumor size and invasiveness. Another study suggested that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogs in acromegaly patients, highlighting a potential role of the tumor immune microenvironment in determining the prognosis of somatotroph pituitary tumors. Preclinical studies have indicated that widely varying degrees of programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) are found among different subtypes. Functional PAs and aggressive PAs express significantly higher levels of PD-L1 and TILs than other subtypes, indicating that PD-1 blockade might be a promising alternative therapy for patients with aggressive PAs. PD-L1 transcript and protein levels were found to be significantly increased in functioning (GH and prolactin-expressing) pituitary tumors compared to nonfunctioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary tumors harbored higher levels of PD-L1 mRNA than recurrent tumors. These findings suggest the possibility of considering checkpoint blockade immunotherapy for functioning pituitary tumors refractory to conventional management. Animal models of Cushing’s disease also demonstrated PD-L1 and TIL expression in cultured tumors and murine models, as well as the effectiveness of checkpoint blockade therapy in reducing the tumor mass, decreasing hormone secretion, and increasing the survival rate. Clinical studies show that immunotherapy may be an effective treatment in patients with pituitary tumors. One corticotroph carcinoma patient showed a significant reduction in hormone levels and shrinkage of the tumor size of primary and metastatic lesions immediately after investigational treatment with ipilimumab and nivolumab. However, another patient with corticotroph adenoma progressed rapidly after four cycles of anti-PD-1 (pembrolizumab) treatment. To date, there are two registered clinical trials of immunotherapy for pituitary tumors. One of them is the phase II clinical trial of nivolumab combined with ipilimumab for patients with aggressive pituitary tumors (NCT04042753). The other one is also a phase II clinical trial of the combination of nivolumab and ipilimumab for rare tumors, including pituitary tumors (NCT02834013). Both clinical trials are in the stage of recruiting patients and have not been completed. In summary, the results from preclinical research and clinical studies indicated that immunotherapy might be a promising alternative therapy for PCs and refractory PAs resistant to conventional treatments. The combination of immunotherapy and radiotherapy or temozolomide may have synergistic effects compared to a single treatment. More preclinical and clinical studies are needed to further indicate the exact efficacy of immunotherapy in pituitary tumors.

Is there adenoma-carcinoma sequence between benign adenoma and papillary cancer of thyroid: A genomic linkage study

BackgroundThe adenoma-carcinoma sequence in thyroid nodules is an enigmatic phenomenon. Genomics is the only definitive modality to resolve this hypothesis. Adenomas and papillary carcinomas tend to have mutations in RAS and highly specific BRAF gene respectively. In this context, we set out study the prevalence and clinical significance of these somatic mutations in surgical tissue samples. Material and methodsThis retrospective study was conducted on surgically managed thyroid nodule patients. Institutional ethical committee approval was obtained. Diagnosis was based on biochemical confirmation, imaging, fine needle aspiration cytology and later confirmed by histopathology. We selected 100 benign thyroid adenomas (BTA) and 100 papillary thyroid carcinoma (PTC) cases. Archived tumour tissue samples of selected cases were retrieved. After appropriate processing of samples, DNA extraction, cDNA preparation, PCR amplification, application of 4 sets of Primers were performed as part of mutational analysis of RAS (H-,K-,N-) and BRAF genes. ResultsHomozygous mutations in N-RAS were found in 36/100 (36%) of BTA and 7/100 (7%) of PTC cases. No H-RAS or K-RAS mutations were found in both groups. Homozygous mutations were found in BRAF gene in 4/100 (4%) of BTA cases and 52/100 (52%) of PTC cases. The differences were statistically significant. ConclusionsSimilar N-RAS and BRAF mutations were prevalent in both benign and malignant thyroid nodules giving some evidence for linkage between them. Though not robust, we opine that there is possibility of adenoma-carcinoma sequence in thyroid nodules.

Current surgical management of follicular thyroid carcinoma

: Follicular thyroid carcinoma (FTC) comprises a heterogenous group of tumors, which divides into subtypes with different malignant potential: minimally invasive (excellent prognosis), encapsulated angioinvasive and widely invasive FTC (higher risk metastasis and recurrence). Numerous clinical risk factors (presence of metastases, advanced patient age, tumor size and others), which can be used to assess FTC aggressiveness, are discussed with regard to the present literature. The definitive characterization of follicular neoplasms depends on postoperative histology, due to the incapability of preoperative imaging, fine-needle aspiration cytology or molecular analysis to clearly distinguish between FTC and benign follicular thyroid adenoma. In this review, treatment strategies for FTC (according to the WHO 2017 classification of endocrine neoplasms) are presented, as recommended by the leading expert societies American Thyroid Association (ATA), British Thyroid Association (BTA), German Society of Endocrine Surgery (CAEK) and European Society of Endocrine Surgery (ESES). Hemithyroidectomy is sufficient in low-risk FTC (capsular invasion only). Thyroidectomy with postoperative radioiodine therapy is recommended for high-risk FTCs (angioinvasion; widely invasive histology). Prophylactic lymphadenectomy is not necessary. Considering clinical risk factors, an individual surgical approach should be chosen, following a stepwise, escalating surgical management with restricted primary resection (hemithyroidectomy) and, if necessary, completion surgery based on the definitive histopathology.

TB-02 Comprehensive analysis of expandable benign pituitary adenomas without genetic manipulations

Background: Since most pituitary adenomas are benign, there is no model of pituitary adenomas that can be continuously cultured without genetic manipulation. In this study, we analyzed the genetic characteristics of the established cell lines by continuous culture of benign pituitary adenomas without genetic manipulation. Method: The pituitary adenoma was continuously cultured by modifying the conditional reprogramming (CR) method, and the morphology was observed and fluorescent immunostaining (IF) was performed. In addition, genetic characteristics were comprehensively analyzed, differences from the surgical samples were analyzed by enrichment analysis using GSEA, and network analysis was performed using cytoscape based on the protein-protein interaction database. (Results) 1) Of the 14 cases of pituitary adenoma that had undergone primary culture (median MIB-1 labeling index 1.5%), 12 cases were capable of continuous culture for more than 2 months. (6 months or more: 5 cases) 2) After 2 weeks of culturing, the cell morphology changed dramatically. These cultured cells were positive for follicular cell marker s100, ectodermal nervous system markers Nestin, Notch1, and mesodermal marker Vimentin. In these cells, synaptophysin, which was strongly positive in the surgical specimen collected at the same time as the culture, disappeared. 3) Enrichment analysis revealed that gene expression such as epithelial mesenchymal transition(EMT), angiogenesis, IL6 signaling via NFkB, extracellular degradation, integrin cell surface interaction increased in cultured cells, and gene expression such as neurotransmitter including synaptophysin decreased significantly.(Conclusion) 1) The modified CR method allowed continuous culture of pituitary adenoma cells. 2) The cultured cells showed characteristic change of EMT, which was seen in invasive pituitary adenoma.