Growth and renal function dynamics of renal oncocytomas in patients on active surveillance.

OBJECTIVES: To study the natural history of renal oncocytomas and address indications for intervention by determining how growth is associated with renal function over time, the reasons for surgery and ablation, and disease-specific survival. PATIENTS AND METHODS: The study was conducted in a retrospective cohort of consecutive patients with renal oncocytoma on active surveillance reviewed at the Specialist Centre for Kidney Cancer at the Royal Free London NHS Foundation Trust (2012 to 2019). Comparison between groups was performed using Mann-Whitney U-tests and chi-squared tests. A mixed-effects model with a random intercept for patient was used to study the longitudinal association between tumour size and estimated glomerular filtration rate (eGFR). RESULTS: Longitudinal data from 98 patients with 101 lesions were analysed. Most patients were men (68.3%) and the median (interquartile range [IQR]) age was 69 (13) years. The median (IQR) follow-up was 29 (26) months. Most lesions were small renal masses, and 24% measured over 4 cm. Over half (64.4%) grew at a median (IQR) rate of 2 (4) mm per year. No association was observed between tumour size and eGFR over time (P = 0.871). Nine lesions (8.9%) were subsequently treated. Two deaths were reported, neither were related to the diagnosis of renal oncocytoma. CONCLUSION: Natural history data from the largest active surveillance cohort of renal oncocytomas to date show that renal function does not seem to be negatively impacted by growing oncocytomas, and confirms clinical outcomes are excellent after a median follow-up of over 2 years. Active surveillance should be considered the 'gold standard' management of renal oncocytomas up to 7cm.

Small-cell variant renal oncocytoma: Case report on its clinicopathological and genetic characteristics and literature review.

INTRODUCTION: Small-cell variant of RO is a rare subtype of renal tumor that can be easily misdiagnosed. To date, only 20 cases had been reported, with its genetic alterations largely unknown due to insufficient information. MATERIALS AND METHODS: We report a case of the tumor with genetic characterization using exome sequencing chip. We also reviewed literature on this lesion to summarize clinicopathological presentation and differential diagnosis of the tumor. DISCUSSION: Grossly, the tumor is yellow to grayish brown, with clear boundary, central scar, or cystic degeneration. Microscopically, small-cell variant RO show scant eosinophilic cytoplasm with small-round nuclei, arranged in small acini and tubules. Nucleoli and necrosis are rarely observed. Immunohistochemically, the tumor is positive for EMA, cytokeratin 18, CD117 and E-cadherin. Genetically, 4745 differentially expressed genes in this tumor, which encode tricarboxylic acid cycle enzymes and are involved in mitochondrial respiratory chain. This result strongly supports the diagnosis of small cell variant of RO. Findings from the molecular genetic analysis of our case suggests that metabolic pathway-related genes (PIK3R5, PI3KCB, PLA2G4E, PLA2G2A, PLA2G6, PLCB4, PLCG2) may be exploited as potential targets for diagnosis and treatment when necessary. These genes may provide new clues for future research. CONCLUSION: Small-cell variant of RO is considered benign renal neoplasms with good prognosis. A histochemical and immunohistochemical stains assist in diagnosis of this tumor. Definitive diagnosis can help avoid unnecessary total renal nephrectomy. The exact mechanism of Small-cell variant of RO remains to be further investigated.

Carcinoma adrenocortical oncocítico virilizante / Adrenal oncocytic virilizing carcinoma

Las neoplasias oncocíticas se encuentran raramente en la glándula suprarrenal. Suelen ser benignos y no funcionales. Existen informes extremadamente limitados de neoplasias oncocíticas suprarrenales. Alrededor del 20% de las neoplasias oncocíticas adrenocorticales muestran componentes malignos y el 10-20% produce hormonas que pueden causar desbalances hormonales. Se presenta un carcinoma adrenocortical oncocítico virilizante en mujer de 35 años de edad quien acudió a consulta por presentar hipomenorrea secundaria de seis meses de duración acompañada de hirsutismo y agravamiento del acné que afectaba principalmente la cara. El examen de laboratorio revela niveles elevados de testosterona libre. La tomografía computada mostró tumor multinodular en la glándula suprarrenal derecha con necrosis central y sin evidencia de linfadenopatía o invasión de estructuras que la rodeaban. Se programó la adrenalectomía derecha lográndose resección completa del tumor. Después de la cirugía, se normalizaron los ciclos menstruales, el hirsutismo, el acné y el resto de las pruebas. El examen histopatológico del tumor fue compatible con carcinoma adrenocortical oncocítico(AU)

Oncocytic neoplasms are found more rarely in the adrenal gland. They are usually benign and nonfunctional. There are limited reports of adrenal oncocytic neoplasms. About 20% of adrenocortical oncocytic neoplasms show malignant components and 10-20% produce hormones that can cause hormonal imbalances. We present a virilizing oncocytic adrenocortical carcinoma in a 35-year-old woman who consulted for hypomenorrhea accompanied by hirsutism and face acne worsening. Laboratory test revealed high levels of free testosterone. Computed tomography showed multinodular tumor of the right adrenal gland with central necrosis and without evidence of lymphadenopathy or invasion of surrounding structures. A right adrenalectomy was performed. After surgery, menstrual cycle, hirsutism and acne, as well as hormonal tests were normal. Histopathological examination of tumor showed an oncocytic adrenocortical carcinoma(AU)

Renal Function Recovery after Nephrectomy or Nephron-Sparing Surgery in Children with Unilateral Renal Tumor.

Introduction Children with unilateral renal tumor (URT) and preoperative renal dysfunction (PRD) may benefit from nephron-sparing surgery (NSS). To test this hypothesis, we studied the outcome of baseline renal function after nephrectomy or NSS among children with URT. Materials and Methods Retrospective records review of children with URT who underwent nephrectomy (25 children) or NSS (11 children) at our institution. We analyzed the estimated glomerular filtration rate (eGFR) changes over time among patients, stratified by both preoperative renal function (with or without PRD) and surgical extent (NSS vs. nephrectomy). The primary end point was evaluation of compensatory recovery of preoperative eGFR after surgery. Only children older than 2 years at surgery were included in the study. Renal dysfunction was defined as an eGFR < 90 mL/min/1.73 m2. Results After nephrectomy or NSS, patients with PRD presented, on average during adolescence, a significant increase in eGFR, whereas patients without PRD presented, on average during adolescence, a stable eGFR. However, after nephrectomy, 5 of 17 (29%) and 7 of 8 (87%) adolescent patients with baseline eGFR ≤ or > 100 mL/min/1.73 m2, respectively, achieved or maintained two-kidney eGFR values (T-KEV) (p = 0.01). After NSS, four adolescent patients with PRD and seven without PRD achieved or maintained T-KEV. Conclusion The majority of children with URT and low baseline eGFR present with an impaired renal function recovery after nephrectomy and may benefit from NSS. Collaborative studies are needed to support present findings.

Virilizing adrenal oncocytoma in a 9-year-old girl: rare neoplasm with an intriguing postoperative course.

Adrenal oncocytoma is an extremely rare neoplasm, which is mostly non-functional. Only five cases of childhood adrenal oncocytoma have been described so far, all of which were hormonally active. Currently, guidelines for management and follow-up are not available. We report a 9-year-old girl with benign adrenal oncocytoma, presenting with severe short-term virilization. After diagnostic work-up the patient underwent laparoscopic unilateral adrenalectomy. For the first 2 weeks following surgery she suffered marked mood swings, irritability and fatigue. There were no other clinical and/or laboratory abnormalities except the rapid drop-down of androgen levels to normal values. Follow-up showed no signs of recurrence and in the absence of signs of adrenal insufficiency, we speculate that, the rapid drop of androgen levels after removal of the tumor might be the reason for the deteriorated psychoemotional condition of our patient.

Pituitary metastases from the oncocytic variant of follicular thyroid carcinoma: a case report and diagnostic dilemmas.

Metastases to the pituitary gland and sella turcica are uncommon. The distinction between primary and secondary metastatic pituitary tumours is challenging as carcinomas from distant sites might closely resemble, both clinically and histopathologically, non-functional adenomas or primary pituitary carcinomas. Among metastases to pituitary gland ones from thyroid carcinoma are extremely rare. We present a unique case of a 53-year-old male patient with a past history of thyroid carcinoma who underwent repeated surgeries over a period of 7 years for a sellar-parasellar mass with paranasal sinus involvement. Morphologically, the tumour was composed of solid sheaths of monomorphic cells exhibiting oncocytic features. In electron microscope images, the cytoplasm of tumour cells was filled with numerous mitochondria. The tumour was negative for pituitary hormones but exhibited immunoreactivity for cytokeratin AE1/AE3, thyroglobulin and thyroid transcription factor 1 (TTF-1). Based on the clinical data and immunophenotypic profile, the tumour was finally diagnosed as an oncocytic variant of follicular thyroid carcinoma. To our knowledge, this is probably the first report of such peculiar histopathological variant of follicular thyroid carcinoma metastasizing to the pituitary gland. The diagnostic dilemmas considering oncocytic features of the presented case are discussed.

Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis.

Macroautophagy (autophagy hereafter) degrades and recycles proteins and organelles to support metabolism and survival in starvation. Oncogenic Ras up-regulates autophagy, and Ras-transformed cell lines require autophagy for mitochondrial function, stress survival, and engrafted tumor growth. Here, the essential autophagy gene autophagy-related-7 (atg7) was deleted concurrently with K-ras(G12D) activation in mouse models for non-small-cell lung cancer (NSCLC). atg7-deficient tumors accumulated dysfunctional mitochondria and prematurely induced p53 and proliferative arrest, which reduced tumor burden that was partly relieved by p53 deletion. atg7 loss altered tumor fate from adenomas and carcinomas to oncocytomas-rare, predominantly benign tumors characterized by the accumulation of defective mitochondria. Surprisingly, lipid accumulation occurred in atg7-deficient tumors only when p53 was deleted. atg7- and p53-deficient tumor-derived cell lines (TDCLs) had compromised starvation survival and formed lipidic cysts instead of tumors, suggesting defective utilization of lipid stores. atg7 deficiency reduced fatty acid oxidation (FAO) and increased sensitivity to FAO inhibition, indicating that with p53 loss, Ras-driven tumors require autophagy for mitochondrial function and lipid catabolism. Thus, autophagy is required for carcinoma fate, and autophagy defects may be a molecular basis for the occurrence of oncocytomas. Moreover, cancers require autophagy for distinct roles in metabolism that are oncogene- and tumor suppressor gene-specific.

Parathyroid carcinoma and oxyphil parathyroid adenoma: an uncommon case of misinterpretation in clinical practice.

A 46 year-old male presented with persistently high level of serum parathyroid hormone (PTH), despite successful resection of an oxyphilic cell parathyroid adenoma of the left lower gland. Renal function and serum calcium were normal, leading to vitamin D deficiency being considered. Tc99m-sestamibi parathyroid scintigraphy showed no capitation, but a cervical ultrasound demonstrated an increase in the lower parathyroids. Surgery confirmed that the right gland was normal but the left corresponded to parathyroid carcinoma. The patient developed severe hypocalcemia, with PTH values being consistent with hypoparathyroidism for a few months. However, a progressive increase in calcium and PTH serum levels indicated recurrence of disease. Tc99m-sestamibi scintigraphy demonstrated hyperfixation in topography of the left inferior parathyroid and the patient was subjected to a third and more extensive surgery, with removal of lymph nodes and adjacent thyroid tissue. Serum calcium and PTH remained elevated, requiring loop diuretics and intravenous bisphosphonates to control hypercalcemia. Cervical radiotherapy was implemented as adjuvant therapy. After two months the patient complained of dyspnea, and a CT scan of the chest demonstrated areas of parenchymal condensation, suggestive of actinic pneumonitis. At the 2-year follow-up no major issues were evident.

Functioning glucagonoma associated with primary hyperparathyroidism: multiple endocrine neoplasia type 1 or incidental association?

BACKGROUND: Diagnosis of multiple endocrine neoplasia type 1 (MEN1) is commonly based on clinical criteria, and confirmed by genetic testing. In patients without known MEN1-related germline mutations, the possibility of a casual association between two or more endocrine tumors cannot be excluded and subsequent management may be difficult to plan. We describe a very uncommon case of functioning glucagonoma associated with primary hyperparathyroidism (pHPT) in which genetic testing failed to detect germline mutations of MEN-1 and other known genes responsible for MEN1. CASE PRESENTATION: The patient, a 65-year old woman, had been suffering for more than 1 year from weakness, progressive weight loss, angular cheilitis, glossitis and, more recently, skin rashes on the perineum, perioral skin and groin folds. After multidisciplinary investigations, functioning glucagonoma and asymptomatic pHPT were diagnosed and, since family history was negative, sporadic MEN1 was suspected. However, genetic testing revealed neither MEN-1 nor other gene mutations responsible for rarer cases of MEN1 (CDKN1B/p27 and other cyclin-dependent kinase inhibitor genes CDKN1A/p15, CDKN2C/p18, CDKN2B/p21). The patient underwent distal splenopancreatectomy and at the 4-month follow-up she showed complete remission of symptoms. Six months later, a thyroid nodule, suspected to be a malignant neoplasia, and two hyperfunctioning parathyroid glands were detected respectively by ultrasound with fine needle aspiration cytology and 99mTc-sestamibi scan with SPECT acquisition. Total thyroidectomy was performed, whereas selective parathyroidectomy was preferred to a more extensive procedure because the diagnosis of MEN1 was not supported by genetic analysis and intraoperative intact parathyroid hormone had revealed "adenoma-like" kinetics after the second parathyroid resection. Thirty-nine and 25 months after respectively the first and the second operation, the patient is well and shows no signs or symptoms of recurrence. CONCLUSIONS: Despite well-defined diagnostic criteria and guidelines, diagnosis of MEN1 can still be challenging. When diagnosis is doubtful, appropriate management may be difficult to establish.

Radiofrequency ablation of incidental benign small renal mass: outcomes and follow-up protocol.

OBJECTIVE: To review our 10-year experience with radiofrequency ablation, focusing on the outcomes for the incidental benign renal tumor. Tumor ablation is an alternative minimally invasive approach for the treatment of small renal masses (SRMs), with published series appropriately emphasizing the outcomes for the renal cell carcinoma subset of treated tumors. However, just as with partial nephrectomy, approximately 20% of SRMs are benign. The intermediate- to long-term outcome of the incidentally ablated benign tumor and its appropriate follow-up protocol is unknown. METHODS: All SRMs treated with temperature-based radiofrequency ablation from 2001 to 2011 were reviewed. Of a total of 280 enhancing SRMs biopsied at radiofrequency ablation, 47 were confirmed as benign tumors. Ablation success was defined as the lack of enhancement on the initial postablation axial imaging. Recurrence was defined as tumor growth and enhancement on follow-up axial imaging. RESULTS: Of the 47 benign tumors, 32 were treated percutaneously and 15 laparoscopically. The histologic biopsy finding was angiomyolipoma in 10 and oncocytoma in 37. The median tumor size was 2 cm (range 1-3.6), and the mean follow-up was 45 months. No recurrences developed, and all lesions required only 1 treatment session. The median pre- and postoperative glomerular filtration rate was 77 mL/min/1.73 m(2) (range 39-137) and 68 mL/min/1.73 m(2) (range 36-137). The present study was limited by its retrospective nature and small sample population. CONCLUSION: Radiofrequency ablation of SRMs <3.5 cm found to be benign on concurrent biopsy can be efficaciously treated with a single treatment session. Long-term follow-up imaging might not be required if successful ablation is determined at the initial post-treatment cross-sectional imaging study.

Oncocytoma of the parotid gland causing false-positive result on I-131 whole-body scintigraphy.

A 50-year-old patient underwent near-total thyroidectomy in 1997 because of a T1N0M0 follicular carcinoma in the right lobe of the thyroid gland, followed by I-131 ablation (3700 MBq). Follow-up of I-131 whole-body scintigraphy after 9 years showed pathologic uptake at the left side of the neck. Histopathologic analyses of the resected specimen suggested a cystic metastasis within the parotid gland, probably originating from thyroid carcinoma. However, the patient had been disease-free for over 9 years and thyroglobulin was undetectable in plasma. Revision of the specimen with complementary immunohistochemical staining revealed histopathologic aspects more typical of oncocytoma.

Malignant transformation of a benign oncocytoma of the submandibular gland: a case report.

Oncocytic carcinoma arising in the submandibular gland is an extremely rare tumor and only 11 cases have been reported previously. We report on a 51-year-old man with a previously benign oncocytoma in the submandibular gland that transformed from a benign morphology to malignant cellular atypia and mitosis. To our knowledge, the current report is the first published case of a malignant transformation from benign oncocytoma to oncocytic carcinoma of the submandibular gland. The proliferative activity of the tumor cells was evaluated immunohistochemically using antibodies against Ki-67.

Proliferation of myofibroblasts in the stroma of renal oncocytoma.

OBJECTIVES: Myofibroblasts are a vital component of stroma of many malignant neoplasms, but it is not yet established whether stromal myofibroblasts also exist in benign tumours such as oncocytoma of the kidney. MATERIALS AND METHODS: Histomorphological and immunohistochemical analysis of 16 renal oncocytomas diagnosed at Chang Gung Memorial Hospital, Taiwan, has been performed. RESULTS: Renal oncocytomas were composed of oncocytes, large cells with granular eosinophilic cytoplasm, arranged mostly in sheets, in tubulocystic or combined pattern. Few oncocytes appeared to be undergoing proliferation or apoptosis. MIB-1 and active caspase 3 indices were low, but higher in tumour than in surrounding non-tumour parenchyma (MIB-1: 0.93 +/- 0.09 versus 0.46 +/- 0.07, P < 0.001 and active caspase 3: 0.76 +/- 0.08 versus 0.41 +/- 0.09, P < 0.001). Wnt/beta-catenin signalling was not implicated in this neoplasm, as there was no loss of E-cadherin membranous localization or expression of intranuclear beta-catenin in the cells. Clumps of oncocytes were stained with periodic acid Schiff and had collagen I-, collagen III- and fibronectin-positive, but desmin- and human caldesmon-negative stromas. Importantly, alpha-smooth muscle actin (SMA)-immunostaining established the myofibroblastic nature of many of the stromal cells. Some of the myofibroblasts were also positive for MIB-1, indicating a proliferative role for them in the stroma. CONCLUSIONS: Renal oncocytomas were composed of two independent compartments: benign oncocytes and pronounced fibrotic stroma, which consisted of proliferating myofibroblasts (SMA- and MIB-1-positive) which were associated with excessive deposition of extracellular matrix (periodic acid Schiff-component, collagen I-, collagen III- and fibronectin-positive, and desmin- and human caldesmon-negative).

Molecular pathogenesis of follicular cell derived thyroid cancers.

Thyroid cancers are the most common endocrine malignancy. Radiation exposure, family history of thyroid cancer and some inherited conditions are the most important predisposing factors for the development of thyroid cancer. Three mitogenic signalling pathways have been described in the thyroid cell, which are influenced by various stimulatory and inhibitory hormones, growth factors and neurotransmitters. Various proto-oncogenes and oncogenes like ras, braf, trk, met and RET also play a role in the signal transduction systems. Two theories have been described in thyroid cancer pathogenesis, the foetal cell carcinogenesis theory and the more common, multistep carcinogenesis theory. The multistep carcinogenesis theory is now the accepted model in many human cancers, including thyroid cancer. The early events of tumour formation are the consequence of activation of either various growth factors or the proto-oncogenes like ras, met or ret. This results in the formation of differentiated thyroid cancers like the papillary, follicular or Hurthle cell cancers. The later stages of tumour formation involve further activation of proto-oncogenes and loss or inactivation of tumour suppressor genes like p53. Based on this theory, follicular carcinomas are generated from follicular adenomas and papillary carcinomas from precursor cells generated from thyrocytes. Anaplastic carcinoma may develop from papillary or follicular carcinoma by dedifferentiation. In this review article, we highlight the molecular pathogenesis of thyroid tumours.

Rapidly recurring folliculostellate cell tumor of the adenohypophysis with the morphology of a spindle cell oncocytoma: case report with electron microscopic studies.

We report a rapidly recurring folliculostellate cell tumor of the adenohypophysis in a 63-year-old woman. Morphologically the tumor had the typical appearance of a spindle cell oncocytoma of the adenohypophysis. It recurred within 5 months of selective transsphenoidal resection, requiring a second transsphenoidal operation followed by radiation therapy. The spindle cell oncocytoma (SCO) of the adenohypophysis is a relatively recently described entity and a new addition to the fourth edition of the WHO Classification of Tumors of the Central Nervous System. In our case, the ultrastructural features were significantly different from those so far described in SCO, in that tumor cells formed a network of structures indistinguishable from pituitary follicles. In addition, a minority of tumor cells exhibited endocrine differentiation.

Functioning adrenocortical oncocytoma: a case report and review of literature.

Adrenocortical oncocytoma is very rare. Less than five functioning types of them are reported and most of the reported cases are incidentally found. We herein report a case of functioning adrenocortical oncocytoma of the left adrenal cortex in a young woman.

Functioning adrenocortical oncocytoma: the first documented case producing interleukin-6 and review of the literature.

Adrenocortical oncocytoma is an extremely rare and predominantly non-functioning tumor. We herein report the first case of an adrenocortical oncocytoma that produces interleukin (IL)-6. A 38-yr-old woman was referred for treatment of a 4-cm adrenal mass. Laboratory test results showed elevated inflammatory parameters. Intriguingly, IL-6 serum level was also high at 30 pg/ml (normal 0-4 pg/ml). The patient underwent laparoscopic right adrenalectomy. Microscopic examination showed that the tumor was an adrenocortical oncocytoma with a unique peripheral lymphoid cuff with germinal centers. Electron microscopy demonstrated that the cytoplasm of the neoplastic cells was packed with numerous abnormal mitochondria. Three observations lead us to consider that this tumor was the primary source of serum IL-6. First, the IL-6 level in blood collected from the right adrenal vein was highest (527 pg/ml) among intra-operative blood samples. Second, neoplastic cells stained positively for IL-6. Third, the serum IL-6 returned to normal levels immediately after surgery.

Functioning adrenocortical oncocytoma: a case report and review of the literature.

Adrenocortical oncocytoma is exceptionally rare. Most of these tumors are benign and nonfunctioning. We report a case of functioning adrenocortical oncocytoma located in the right adrenal gland in a 53-year-old woman who presented with Cushing's syndrome. The tumor was small, with exclusively oncocytic histologic features. A discussion of this case and a review of the literature on this entity is presented.