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Objective: The association between autoimmunity-related tissue injury and thyroid cancer development remains an area of interest. Evidence suggests that patients with Graves disease (GD) may have an elevated risk for differentiated thyroid cancer. Multicenter studies are needed to gain insight into the correlates of papillary thyroid carcinoma (PTC) identified in this particular group of patients. This study aimed to investigate the prevalence of PTC and synchronous thyroid nodules in thyroidectomy specimens from GD patients in an endemic goiter region. Material and Methods: A retrospective review of institutional pathology records at two tertiary care centers identified 237 surgically treated patients with GD. Patients were categorized as having nodular Graves disease (N-GD) if synchronous nodular thyroid was identified by ultrasonography, while those without synchronous thyroid nodules were categorized as non-nodular or simple Graves disease (S-GD). The prevalence of PTC, histopathological correlates, and demographic characteristics were recorded and compared between groups N-GD and S-GD. Results: One hundred thirty-one and 106 patients were assigned to N-GD and S-GD, respectively. The mean age was significantly higher in N-GD (mean 45.52 years) compared to S-GD (mean 35.18 years) (p0.05). The group of S-GD was enriched in BRAF-like PTCs, whereas N-GD had equal distribution for RAS- and BRAF-like tumors. Conclusion: This study underscores that the majority of PTCs encountered in GD were enriched in low-risk subcentimeter PTCs with a prevalence that varies depending on the presence of underlying nodular thyroid tissue.

Pheochromocytoma and abdominal paraganglioma (PPGL) are rare catecholamine-producing, keratin-negative, non-epithelial neuroendocrine neoplasms characterized by a unique association with syndromic diseases caused by constitutional mutations in a wide range of susceptibility genes. While PPGLs are recognized for their malignant potential, the risk of metastatic disease varies depending on several clinical, histological, and genetic factors. Accurate diagnosis and prognosis of these tumors require a multidisciplinary approach, integrating insights from various medical specialties. Pathologists play a crucial role in this complex task, as numerous morphological, immunohistochemical, and genetic findings can be linked to worse outcomes. Therefore, it is vital to stay informed about the latest advancements in PPGL pathology. This brief review provides an overview of the challenges associated with PPGLs and highlights the most recent developments in tumor prognostication.

Most follicular cell-derived differentiated thyroid carcinomas are regarded as low-risk neoplasms prompting conservative therapeutic management. Here, we provide consensus recommendations reached by a multidisciplinary group of endocrinologists, medical oncologists, pathologists, radiation oncology specialists, a surgeon and a medication reimbursement specialist, addressing more challenging forms of this malignancy, focused on radioactive iodine (RAI)-resistant or -refractory differentiated thyroid carcinoma (RAIRTC). In this document we highlight clinical, radiographic, and molecular features providing the basis for these management plans. We distinguish differentiated thyroid cancers associated with more aggressive behavior from thyroid cancers manifesting as poorly differentiated and/or anaplastic carcinomas. Treatment algorithms based on risk-benefit assessments of different multimodal therapy approaches are also discussed. Given the scarcity of data supporting management of this rare yet aggressive disease entity, these consensus recommendations provide much needed guidance for multidisciplinary teams to optimally manage RAIRTC.

Abstract Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the VHL gene causing predisposition to multi-organ benign and malignant neoplasms. A germline VHL variant is identified in 95–100% of individuals with a clinical diagnosis of VHL. Here, we present the case of an individual with a clinical diagnosis of VHL disease where peripheral blood DNA analysis did not detect a VHL variant. Sequencing of four tumor tissues (ccRCC, pheochromocytoma, lung via sputum, liver) revealed a VHL c.593 T > C (p.Leu198Pro) variant at varying allele fractions (range: 10–55%) in all tissues. Re-examination of the peripheral blood sequencing data identified this variant at 6% allele fraction. Tumor analysis revealed characteristic cytomorphological, immunohistochemical reactivity for alpha-inhibin, and CAIX, and reduced pVHL reactivity supported VHL-related pseudohypoxia. This report of a rare case of VHL mosaicism highlights the value of tissue testing in VHL variant negative cases.

ObjectiveThe main objective of this study was to review the clinicopathologic characteristics and outcome of patients with oncocytic papillary thyroid carcinoma (PTC) and oncocytic poorly differentiated thyroid carcinoma (PDTC). The secondary objective was to evaluate the prevalence and outcomes of RAI use in this population.MethodsPatients with oncocytic PTC and PDTC who were treated at a quaternary cancer centre between 2002 and 2017 were retrospectively identified from an institutional database. All patients had an expert pathology review to ensure consistent reporting and definition. The cumulative incidence function was used to analyse locoregional failure (LRF) and distant metastasis (DM) rates. Univariable analysis (UVA) was used to assess clinical predictors of outcome.ResultsIn total, 263 patients were included (PTC [n=218], PDTC [n=45]) with a median follow up of 4.4 years (range: 0 = 26.7 years). Patients with oncocytic PTC had a 5/10-year incidence of LRF and DM, respectively, of 2.7%/5.6% and 3.4%/4.5%. On UVA, there was an increased risk of DM in PTC tumors with widely invasive growth (HR 17.1; p

Background: Rathke’s cleft cysts (RCC) arise from the pars intermedia because of incomplete regression of the embryologic Rathke pouch. A subset of RCC becomes symptomatic causing headaches, visual and endocrinological disturbances such that surgical intervention is indicated. Several points in surgical management remain controversial including operative strategy (simple fenestration (SF) vs complete cyst wall resection (CWR)) as well as reconstructive techniques. Methods: A retrospective analysis was conducted of pathologically confirmed RCC operated on by endoscopic endonasal approach from 2006 to 2019. Pre-operative symptoms, imaging characteristics, operative strategy, symptom response, complications and recurrences were recorded. Results: Thirty-nine patients were identified. Thirty-three underwent SF and six underwent CWR. Worsening pituitary function was significantly increased with CWR (50%) compared to SF (3%) (p = 0.008). All patients underwent “closed” reconstruction with a post-operative CSF leak rate of 5% (3% SF vs 16% CWR, p = 0.287). Six (15%) recurrences necessitating surgery were reported. Recurrence rates stratified by surgical technique (18% SF vs 0% CWR, p = 0.564) were not found to be significantly different. Conclusions: The current series illustrates variability in the surgical management of RCCs. SF with closed reconstruction is a reasonable operative strategy for most symptomatic RCCs cases while CWR can be reserved for selected cases.

Oncocytes are cells that have abundant eosinophilic cytoplasm due to the accumulation of mitochondria; they are also known as oxyphils. In the thyroid they have been called Hürthle cells but this is a misnomer, since Hürthle described C cells; for this reason, we propose the use of “oncocyte” as a scientific term rather than an incorrect eponym. Oncocytic change occurs in nontumorous thyroid disorders, in benign and malignant tumors of thyroid follicular cells, in tumors composed of thyroid C cells, and intrathyroidal parathyroid proliferations as well as in metastatic lesions. The morphology of primary oncocytic thyroid tumors is similar to that of their non-oncocytic counterparts but also is complicated by the cytologic features of these cells that include both abundant eosinophilic cytoplasm and large cherry red nucleoli. The molecular alterations in oncocytic thyroid tumors echo those of their non-oncocytic counterparts but in addition feature mitochondrial DNA mutations as well as chromosomal gains and losses. In this review we emphasize the importance of recognition of the spectrum of oncocytic thyroid pathology. The cell of origin, morphologic features including architecture, nuclear atypia and invasive growth, as well as high grade features such as mitoses and necrosis, enable accurate classification of these lesions. The molecular alterations underlying the pathological entity are associated with genetic alterations associated with oncocytic change. The arbitrary cut-off of 75% oncocytic change to classify a lesion as an oncocytic variant brings another complexity to the classification scheme of tumors that frequently have mixed oncocytic and non-oncocytic components. This controversial and often confusing area of thyroid pathology requires thoughtful and cautious investigation to clarify accurate diagnosis, prognosis and prediction for patients with oncocytic thyroid lesions.

BackgroundGlucocorticoid excess in Cushing disease (CD) leads to negative feedback suppression, resulting in Crooke's hyaline change (CC) of nontumorous pituitary corticotrophs. We aimed to determine the predictive value of CC of nontumorous corticotrophs in CD.MethodsThe retrospective chart review study included patients with clinical, biochemical, radiologic and outcome data and evaluable histopathology specimens from pituitary surgery for CD. The main outcome was remission of CD, defined by clinical features, biochemical testing, and corticosteroid dependency.ResultsOf 144 CD patients, 60 (50 women, mean age 43.6±14) had clinical follow-up, biochemical data and histopathology specimens that included evaluable nontumorous adenohypophysis. Specimens from 50 patients (83.3%) demonstrated CC in nontumorous corticotrophs, and 10 (16.7%) had no CC (including 3 with corticotroph hyperplasia). One patient with CC was lost to follow-up and one without CC had equivocal outcome results. During a mean (SD) follow-up period of 74.9 months (61.0), recurrent or persistent disease was documented in 18 patients (31.0%), while 40 (69.0%) were in remission. In patients with CC, the remission rate was 73.5% (95% CI, 59.7%-83.7%) (36/49), whereas it was 44.4% (95% CI, 18.9%-73.3%) (4/9) in patients with no CC. The combination of serum cortisol >138 nmol/L within a week of surgery coupled with absence of nontumorous CC greatly improved the prediction of recurrent or persistent disease.ConclusionsCC of nontumorous corticotrophs was observed in 83% of patients with CD, and most patients with CC experienced remission. Absence of CC in nontumorous corticotrophs may serve as a predictor of reduced remission in patients with CD.

ABSTRACT Primary hyperparathyroidism is a condition that occurs infrequently in children. Parathyroid carcinoma, as the underlying cause of hyperparathyroidism in this age group, is extraordinarily rare, with only a few cases reported in the literature. We present a 13‐year‐old boy with musculoskeletal pain who was found to have brown tumors from primary hyperparathyroidism caused by parafibromin‐immunodeficient parathyroid carcinoma. Our patient had no clinical, biochemical, or radiographic evidence of pituitary adenomas, pancreatic tumors, thyroid tumors, pheochromocytoma, jaw tumors, renal abnormalities, or testicular lesions. Germline testing for AP2S1, CASR, CDC73/HRPT2, CDKN1B, GNA11, MEN1, PTH1R, RET, and the GCM2 gene showed no pathological variants, and a microarray of CDC73/HRPT2 did not reveal deletion or duplication. He was managed with i.v. fluids, calcitonin, pamidronate, and denosumab prior to surgery to stabilize hypercalcemia. After removal of a single parathyroid tumor, he developed severe hungry bone syndrome and required 3 weeks of continuous i.v. calcium infusion, in addition to oral calcium and activated vitamin D. Histopathological examination identified an angioinvasive parathyroid carcinoma with global loss of parafibromin (protein encoded by CDC73/HRPT2).HRpQCT and DXA studies were obtained prior to surgery and 18‐months postsurgery. HRpQCT showed a resolution of osteolytic lesions combined with structural improvement of cortical porosity and an increase in both cortical thickness and density compared with levels prior to treatment. These findings highlight the added value of HRpQCT in primary hyperparathyroidism. In addition to our case, we have provided a review of the published cases of parathyroid cancer in children. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Background: Parathyroid carcinoma is rare, representing

Thyroid tumors usually present as masses in the thyroid gland. While the majority of these tumors represent neoplasms of thyroid tissues, mainly of follicular epithelial cell differentiation, the differential diagnosis includes other lesions, such as C cell neoplasms (medullary thyroid carcinoma), intrathyroidal parathyroid, or thymic tumors, soft tissue tumors, and hematologic neoplasms as well as metastatic malignancies. Rare tumors are of salivary gland types. This case illustrates an unusual tumor of salivary gland type, an intrathyroidal mammary analog secretory carcinoma (MASC). The pathogenesis, diagnostic pitfalls, and therapeutic implications of this unusual tumor are discussed.

ABSTRACT: Objective: To report the role of liver transplantation in the management of refractory carcinoid syndrome. Methods: We describe the clinical course, biochemical, radiographic, and histopathologic features of a patient with severe refractory carcinoid syndrome due to a metastatic well-differentiated enterochromaffin cell neuroendocrine tumor of the jejunum. We also review and summarize the literature on liver transplantation in this setting. Results: An 18-year-old patient presented with a 3-year history of progressive palpitations, flushing, abdominal pain, and diarrhea. Initial imaging studies demonstrated multiple cystic liver lesions; biochemistry confirmed elevated 24-hour urinary 5-hydroxy-indolacetic acid (5-HIAA) levels. She was managed with somatostatin analogues followed by a partial small-bowel resection. Five sessions of liver embolization and escalating somatostatin analogues failed to control her symptoms or normalize urinary 5-HIAA levels. Cross-sectional imaging detected disease only in the liver. Due to progressively worsening symptoms, liver transplantation was offered as a therapeutic option at age 21 years. One year following the procedure, her condition improved clinically and biochemically with minimal disease outside the liver. Conclusion: Liver transplantation represents a potential therapeutic option in selected patients with refractory carcinoid syndrome.

Adrenal cortical tumors constitute a heterogeneous group of neoplasms with distinct clinical, morphological, and molecular features. Recent discoveries of specific genotype–phenotype correlations in adrenal cortical adenomas have transformed our understanding of their respective endocrine syndromes. Indeed, a proportion of patients with primary aldosteronism are now known to harbor adrenal cortical adenomas with heterogeneous molecular alterations (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) involving the calcium/calmodulin kinase signaling pathway. Several lines of evidence suggest that KCNJ5-mutant aldosterone-producing adenomas have distinct clinicopathological phenotype compared to those harboring ATP1A1, ATP2B3, and CACNA1D mutations. Benign adrenal cortical tumors presenting with Cushing syndrome often have diverse mutations (PRKACA, PRKAR1A, GNAS, PDE11A, and PDE8B) involving the cyclic AMP signaling pathway. In addition to cortisol-producing adenomas, bilateral micronodular adrenocortical disease and primary bilateral macronodular adrenal hyperplasia (PBMAH) have also expanded the spectrum of benign neoplasms causing adrenal Cushing disease. The recent discovery of inactivating ARMC5 germline mutations in PBMAH has challenged the old belief that this disorder is mainly a sporadic disease. Emerging evidence suggests that PBMAH harbors multiple distinct clonal proliferations, reflecting the heterogeneous genomic landscape of this disease. Although most solitary adrenal cortical tumors are sporadic, there is an increasing recognition that inherited susceptibility syndromes may also play a role in their pathogenesis. This review highlights the molecular and morphological heterogeneity of benign adrenal cortical neoplasms, reflected in the diverse presentations of primary aldosteronism and adrenal Cushing syndrome.

A 71-year-old man with known history of atrial fibrillation (treated with routine rivaroxaban therapy) was found to have incidental biochemical elevated calcium and parathyroid hormone (PTH) levels. His physical examination demonstrated the presence of a palpable right neck mass. Subsequent imaging studies revealed a large parathyroid mass as well as multiple bone lesions, raising the suspicion of parathyroid carcinoma. The anticoagulant therapy was stopped 5 days prior to his elective surgery. The night before his elective surgery, he presented to the emergency room with profound hypocalcemia. The surgery was postponed and rescheduled after calcium correction. Intraoperative findings and detailed histopathological examination revealed an infarcted 4.0 cm parathyroid adenoma with cystic change. His bony changes were related to brown tumors associated with long-standing hyperparathyroidism. Autoinfarction of a large parathyroid adenoma causing severe hypocalcemia is a rare phenomenon and may be considered in patients with large parathyroid adenomas after withdrawal of anticoagulants.

ABSTRACT: Objective: To report a rare case of malignant ovarian steroid cell tumor with androgen excess.Methods: We describe the clinical presentation and management of a malignant ovarian steroid tumor with severe hyperandrogenism in a postmenopausal woman.Results: An 83-year-old patient had a 6-year history of features of androgen excess. Biochemistry confirmed elevated testosterone and dehydroepiandrosterone sulfate; investigations identified a 4.5-cm adnexal mass that was resected, and the histopathology diagnosis was a malignant steroid cell tumor. Eight months later, disease recurrence prompted a second surgical intervention, and a 3.5-cm mass adherent to the right pelvic sidewall was removed. The patient was not able to tolerate mitotane due to severe side effects. Eighteen months later, the disease relapsed with recurrence of clinical and biochemical features of androgen excess.Conclusion: This case illustrates the challenges of diagnosis and management of malignant ovarian steroid cell tumors.Abbreviations: CT computed tomography; DHEAS dehydroepiandrosterone sulfate; GnRH gonadotropin-releasing hormone; MRI magnetic resonance imaging; SCT steroid cell tumor

Objective: Capsular contracture is the most common complication reported after breast augmentation. Recent studies have established the role of leukotriene receptors in capsular contracture formation. Zafirlukast is a leukotriene receptor antagonist, and its effects on experimental models of periprosthetic capsular fibrosis have been shown to decrease capsule thickness and reduce factors that are directly and indirectly involved in capsular contracture. The goal of this study was to improve the periprosthetic capsular formation model in rats and demonstrate the effects of oral Zafirlukast administration on capsular fibrosis. Methods: Forty-eight adult female Sprague-Dawley rats were divided into four groups. Smooth-surfaced, gel-filled prostheses were implanted in 36 rats. Group A: The day of the operation, 12 animals received Zafirlukast treatment for 14 weeks (oral gavage, once a day, 6 days a week, 4 mg/kg/day); Group B: 10 weeks after the operation, 12 animals received Zafirlukast treatment for 4 weeks; Group C: 12 animals were implanted but did not receive treatment; Group D: 12 animals did not have an operation, but for 14 weeks received oral gavage containing water instead of Zafirlukast. At the end of the 14 weeks, the implants with the surrounding capsules were extracted. Blind macroscopic inspectional evaluation of the capsules was performed, and microscopic capsular thickness measurements were made. Results: The mean capsular thickness was 0.033 mm (SD: 0.011) in Group A, and 0.089 mm (SD: 0.023) and 0.125 mm (SD: 0.025) in Groups B and C, respectively. Differences between Groups A and C and between Groups A and B were significant (p0.05). Similarly, Macroscopic Inspectional Fibrosis Scoring showed a significant difference between Groups A and C and a non-significant difference between Groups B and C. Conclusion: Daily prophylactic oral administration of Zafirlukast immediately after implantation significantly diminishes the development of fibrotic capsules around the silicone prostheses. [Arch Clin Exp Surg 2014; 3(3.000): 139-146]

Background: Proliferation markers, especially Ki67, are increasingly important in diagnosis and prognosis. The best method for calculating Ki67 is still the subject of debate. Materials and Methods: We evaluated an image analysis tool for quantitative interpretation of Ki67 in neuroendocrine tumors and compared it to manual counts. We expanded a primary digital pathology platform to include the Leica Biosystems image analysis nuclear algorithm. Slides were digitized using a Leica Aperio AT2 Scanner and accessed through the Cerner CoPath LIS interfaced with Aperio eSlideManager through Aperio ImageScope. Selected regions of interest (ROIs) were manually defined and annotated to include tumor cells only; they were then analyzed with the algorithm and by four pathologists counting on printed images. After validation, the algorithm was used to examine the impact of the size and number of areas selected as ROIs. Results: The algorithm provided reproducible results that were obtained within seconds, compared to up to 55 min of manual counting that varied between users. Benefits of image analysis identified by users included accuracy, time savings, and ease of viewing. Access to the algorithm allowed rapid comparisons of Ki67 counts in ROIs that varied in numbers of cells and selection of fields, the outputs demonstrated that the results vary around defined cutoffs that provide tumor grade depending on the number of cells and ROIs counted. Conclusions: Digital image analysis provides accurate and reproducible quantitative data faster than manual counts. However, access to this tool allows multiple analyses of a single sample to use variable numbers of cells and selection of variable ROIs that can alter the result in clinically significant ways. This study highlights the potential risk of hard cutoffs of continuous variables and indicates that standardization of number of cells and number of regions selected for analysis should be incorporated into guidelines for Ki67 calculations.

Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic tumor associated with aggressive clinical behavior, metastasis and low survival. We report a case of CCOC affecting the maxilla of 62 year-old woman. It was first described as a clinicopathological entity in 1985 and to date only 67 cases were described in the English literature. We are understanding of the behavior of this carcinomas was depend on limited case reports. For these reason we found important to report this case of CCOC in the maxilla.

BackgroundThe increasing incidence and heterogeneous behavior of intestinal neuroendocrine tumors (iNETs) pose a clinicopathological challenge. Our goal was to decribe the prognostic value of the new WHO 2010 grading and the AJCC/UICC TNM staging systems for iNETs. Moreover, outcomes of patients treated with somatostatin analogs were assessed.MethodsWe collected epidemiological and clinicopathological data from 93 patients with histologically proven iNETs including progression and survival outcomes. The WHO 2010 grading and the AJCC/UICC TNM staging systems were applied for all cases. RECIST criteria were used to define progression. Kaplan-Meier analyses for progression free survival (PFS) and overall survival (OS) were performed.ResultsMean follow-up was 58.6 months (4-213 months). WHO 2010 grading yielded PFS and disease-specific OS of 125.0 and 165.8 months for grade 1 (G1), 100.0 and 144.2 months for G2 and 15.0 and 15.8 months for G3 tumors (p = 0.004 and p = 0.001). Using AJCC staging, patients with stage I and II tumors had no progression and no deaths. Stage III and IV patients demonstrated PFS of 138.4 and 84.7 months (p = 0.003) and disease-specific OS of 210.0 and 112.8 months (p = 0.017). AJCC staging also provided informative PFS (91.2 vs. 50.0 months, p = 0.004) and OS (112.3 vs. 80.0 months, p = 0.005) measures with somatostatin analog use in stage IV patients.ConclusionOur findings underscore the complementarity of WHO 2010 and AJCC classifications in providing better estimates of iNETS disease outcomes and extend the evidence for somatostatin analog benefit in patients with metastatic disease.