Papillary renal neoplasm with reverse polarity is biologically and clinically distinct from eosinophilic papillary renal cell carcinoma.

Papillary renal neoplasm with reverse polarity (PRNRP) is a recently described indolent entity with distinct features and its recognition from other oncocytic/eosinophilic papillary renal cell carcinoma (ePRCC) has important prognostic implications. ABCC2, a renal drug transporter, is overexpressed in aggressive PRCCs. In this study, we compared the clinicopathological parameters and the biological ABCC2 expression between PRNRP and ePRCC. PRNRP (n = 8) and ePRCC (n = 21) cases were selected from resection specimens and corresponding clinicopathological data were collected. ABCC2 immunohistochemical (IHC) staining was performed and ABCC2 staining patterns were classified as negative, cytoplasmic, and brush-border. RNA in-situ hybridization (ISH) was used to assess ABCC2 transcript levels. All eight PRNRP cases had weak cytoplasmic ABCC2 IHC reactivity; however, they showed no detectable ABCC2 transcripts on RNA ISH. In comparison, 76% (16/21) of ePRCCs showed ABCC2 IHC brush-border expression and significantly higher ABCC2 RNA ISH transcript levels (p < 0.001). Additionally, the ePRCC group showed a significantly larger tumor size (p = 0.004), higher WHO/ISUP grade (p < 0.001), and stage (p = 0.044). None of the PRNRP cases showed disease progression, while 9.5% (2/21) ePRCCs had disease progression. PRNRP is clinically and biologically distinct from ePRCC. Hence, it is crucial to differentiate between these two entities, particularly in needle core biopsies.

ABCC2 brush-border expression predicts outcome in papillary renal cell carcinoma: a multi-institutional study of 254 cases.

AIMS: Papillary renal cell carcinoma (PRCC) histologic subtyping is no longer recommended in the 2022 WHO classification. Currently, WHO/ISUP nucleolar grade is the only accepted prognostic histologic parameter for PRCC. ABCC2, a renal drug transporter, has been shown to significantly predict outcomes in PRCC. In this study we evaluated the prognostic significance of ABCC2 IHC staining patterns in a large, multi-institutional PRCC cohort and assessed the association of these patterns with ABCC2 mRNA expression. METHODS AND RESULTS: We assessed 254 PRCCs for ABCC2 IHC reactivity patterns that were stratified into negative, cytoplasmic, brush-border <50%, and brush-border ≥50%. RNA in situ hybridization (ISH) was used to determine the transcript level of each group. Survival analysis was performed with SPSS and GraphPad software. RNA-ISH showed that the ABCC2 group with any brush-border staining was associated with a significant increase in the transcript level, when compared to the negative/cytoplasmic group (P = 0.034). Both ABCC2 groups with brush-border <50% (P = 0.024) and brush-border ≥50% (P < 0.001) were also associated with worse disease-free survival (DFS) in univariate analysis. Multivariate analysis showed that only ABCC2 IHC brush-border (<50% and ≥50%) reactivity groups (P = 0.037 and P = 0.003, respectively), and high-stage disease (P < 0.001) had a DFS of prognostic significance. In addition, ABCC2 brush-border showed significantly worse DFS in pT1a (P = 0.014), pT1 (P = 0.013), ≤4 cm tumour (P = 0.041) and high stage (P = 0.014) groups, while a similar analysis with high WHO/ISUP grade in these groups was not significant. CONCLUSION: ABCC2 IHC brush-border expression in PRCC correlates with significantly higher gene expression and also independently predicts survival outcomes.

Integrated Molecular Analysis of Papillary Renal Cell Carcinoma and Precursor Lesions Unfolds Evolutionary Process from Kidney Progenitor-Like Cells.

Papillary renal cell carcinoma (PRCC) is the most common type of RCC in end-stage kidney disease (ESKD). Papillary adenoma (PA) is a small benign lesion morphologically similar to PRCC and is suggested to be its precursor. PA is also prevalent in ESKD. The evolution of PAs to PRCCs and their relationship to ESKD are poorly understood. A total of 140 PAs, normal kidneys, ESKDs, and PRCCs were analyzed. Previously described markers of renal tubular progenitor cells were analyzed using immunohistochemistry and quantified with digital analysis. Progenitor cells were significantly increased in ESKD (P < 0.0001) and PAs (P = 0.02) in comparison with the normal kidney. Pathway analysis using global miRNA and chromosomal copy number variations revealed a common developmental theme between PA and the PRCCs. Whole exome sequencing showed a KMT2C-specific pathogenic mutation among all PAs and PRCCs. KMT2C is a chromosome 7 epigenetic regulator implicated in development and oncogenesis. Collectively, results show possible connection of PRCCs to PA and the progenitor-like cell population, which are increased in response to renal tubular injury. In addition, each PRCC histologic subtype had its own set of mutational changes, indicating divergence from a common precursor. The study reports previously unknown biological aspects of PRCC development and could influence current surveillance criteria and early detection strategies of PRCC tumors.

Leuprolide Acetate, a GnRH Agonist, Improves the Neurogenic Bowel in Ovariectomized Rats with Spinal Cord Injury.

BACKGROUND: Electromyographic studies have shown that external anal sphincter activity is modified in response to distension in animals with spinal cord injury. Gonadotropin-releasing hormone and its agonist leuprolide acetate have neurotrophic properties in animals with spinal cord injury. AIM: This study was to determine the effects of leuprolide acetate treatment on electromyographic activity of the external anal sphincter and anorectal manometry in ovariectomized rats with spinal cord injury. METHODS: Adult ovariectomized rats were divided in three groups: (a) sham of spinal cord injury, (b) spinal cord injury treated with saline solution, and (c) spinal cord injury treated with leuprolide acetate. The spinal cord injury was induced by clamping at level T9. Leuprolide acetate dosage of 10 µg/kg was proctored intramuscular for 5 weeks, commencing the day after the lesion. Electromyography of the external anal sphincter, anorectal manometry, and volume of the cecum were evaluated in all groups. RESULTS: The electromyographic study of the external anal sphincter activity showed a significant improvement in injured rats treated with leuprolide acetate. Manometric analysis and cecum volume data obtained in animals with leuprolide acetate were very similar to those found in the sham group. CONCLUSIONS: These results demonstrate that leuprolide acetate treatment improves the neurogenic colon in ovariectomized rats with spinal cord injury.

Pituitary pathology in traumatic brain injury: a review.

PURPOSE: Traumatic brain injury most commonly affects young adults under the age of 35 and frequently results in reduced quality of life, disability, and death. In long-term survivors, hypopituitarism is a common complication. RESULTS: Pituitary dysfunction occurs in approximately 20-40% of patients diagnosed with moderate and severe traumatic brain injury giving rise to growth hormone deficiency, hypogonadism, hypothyroidism, hypocortisolism, and central diabetes insipidus. Varying degrees of hypopituitarism have been identified in patients during both the acute and chronic phase. Anterior pituitary hormone deficiency has been shown to cause morbidity and increase mortality in TBI patients, already encumbered by other complications. Hypopituitarism after childhood traumatic brain injury may cause treatable morbidity in those survivors. Prospective studies indicate that the incidence rate of hypopituitarism may be ten-fold higher than assumed; factors altering reports include case definition, geographic location, variable hospital coding, and lost notes. While the precise pathophysiology of post traumatic hypopituitarism has not yet been elucidated, it has been hypothesized that, apart from the primary mechanical event, secondary insults such as hypotension, hypoxia, increased intracranial pressure, as well as changes in cerebral flow and metabolism may contribute to hypothalamic-pituitary damage. A number of mechanisms have been proposed to clarify the causes of primary mechanical events giving rise to ischemic adenohypophysial infarction and the ensuing development of hypopituitarism. CONCLUSION: Future research should focus more on experimental and clinical studies to elucidate the exact mechanisms behind post-traumatic pituitary damage. The use of preventive medical measures to limit possible damage in the pituitary gland and hypothalamic pituitary axis in order to maintain or re-establish near normal physiologic functions are crucial to minimize the effects of TBI.

Ectopic cushing's syndrome due to corticotropin releasing hormone.

Cushing's syndrome (CS) secondary to corticotropin releasing hormone (CRH) producing tumors is rare. In this paper we present an Iranian patient who was admitted to our hospital with classic signs and symptoms of CS. Laboratory evaluation revealed high serum and urine cortisol which could not be suppressed with dexamethasone. Abdominal CT scan revealed a mass in abdominal cavity. A percutaneous needle biopsy was performed and histopathologic evaluation revealed that the mass was a neuroendocrine tumor. A multi-disciplinary approach including resection of the mass, bilateral adrenalectomy somatostatin analogue and chemotherapy was applied for management of the disease. Extensive review of English literature focusing on the topic from 1971 to 2018 revealed that there have been only 75 similar cases. Clinical, laboratory, imaging, histopathologic characteristics and managements of these patients will also be discussed in this paper.

Pathology of GH-producing pituitary adenomas and GH cell hyperplasia of the pituitary.

INTRODUCTION: Histologic, immunohistochemical and electron microscopic studies have provided conclusive evidence that a marked diversity exists between tumors which secrete growth hormone (GH) in excess. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH-releasing hormone secreting tumors or in familial pituitary tumor syndromes. MATERIALS AND METHODS: A literature search was performed for information regarding pathology, GH-producing tumors and acromegaly. RESULTS: This review summarizes the current knowledge on the morphology of GH-producing and silent GH adenomas, as well as GH hyperplasia of the pituitary. CONCLUSION: The importance of morphologic classification and identification of different subgroups of patients with GH-producing adenomas and their impact on clinical management is discussed.

Prognostic significance of human tissue kallikrein-related peptidases 11 and 15 in gastric cancer.

Human tissue kallikrein-related peptidases (KLK) are a group of 15 serine proteases which have been investigated as potential cancer biomarkers. This study determined the prognostic significance of KLK 11 and 15 expression levels in gastric carcinoma specimens. Expression of KLK11 and KLK15 was assessed by immunohistochemistry staining on a tissue microarray constructed from 113 gastrectomy specimens from patients with gastric carcinoma. To minimize inter-observer variability, expression levels were quantified using an automated algorithm. Epithelial and stromal staining were assessed separately. Both KLK11 and KLK15 were expressed in gastric carcinoma. There was no significant correlation between either KLK11 or KLK15 expression and the presence of lymph node metastases or Lauren classification (intestinal vs. diffuse). Higher levels of KLK11 expression in gastric carcinoma were associated with significantly worse overall survival (p = 0.008), and a multivariate analysis showed that it had prognostic value independent of tumor stage and differentiation (p = 0.004). Variations in KLK15 expression were not significantly associated with prognosis. KLK11 shows promise as a potential independent prognostic marker for gastric carcinoma.

miR-221/222 Are Involved in Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma.

Sunitinib is a multitargeting tyrosine kinase inhibitor used for metastatic renal cancer. There are no biomarkers that can predict sunitinib response. Such markers are needed to avoid administration of costly medication with side effects to patients who would not benefit from it. We compared global miRNA expression between patients with a short (≤12 months) versus prolonged (>12 months) progression-free survival (PFS) under sunitinib as first-line therapy for metastatic renal cell carcinoma. We identified a number of differentially expressed miRNAs and developed miRNA statistical models that can accurately distinguish between the two groups. We validated our models in the discovery set and an independent set of 57 patients. Target prediction and pathway analysis showed that these miRNAs are involved in vascular endothelial growth factor (VEGF), TGFß, and mammalian target of rapamycin (mTOR)-mediated signaling and cell-cell communication. We tested the effect of these miRNAs on cellular proliferation and angiogenesis. We validated the negative correlation between miR-221 and its target, VEGFR2.miR-221 overexpression was associated with a poor PFS while its target, VEGFR2 was associated with longer survival. Gain of function experiments showed that miR-221 and miR-222 decreased angiogenesis and cellular proliferation in human umbilical vein endothelial cells (HUVEC) while increasing cellular proliferation in ACHN cells. miRNAs represent potential predictive markers for sunitinib response.

Arginine vasopressin (AVP): a review of its historical perspectives, current research and multifunctional role in the hypothalamo-hypophysial system.

INTRODUCTION: This publication reviews the function of arginine vasopressin and focuses on the morphologic and functional correlation between the hormone and its effect on stress, the hypophysial-adrenocortical axis, neuroimmune responses, renal function and corticotroph pituitary tumors. MATERIALS AND METHODS: A literature review was performed using various search engines for information regarding the morphology and the multifunctional role of arginine vasopressin. RESULTS: Although a large number of studies were published discussing these interactions, there are several important areas that are still obscure. CONCLUSION: The questions of how does arginine vasopressin affect the morphology and function of these various areas, and how does the secretion of ACTH and adrenocortical hormones influence the morphology of arginine vasopressin-producing cells and their hormone secretion requires further investigation.

Current status on histological classification in Cushing's disease.

INTRODUCTION: Managing Cushing's disease remains a challenge. Surgery is the first option of treatment and it offers a high success rate. Even in cases where biochemical remission is not achieved, it is crucial to obtain surgical tissue for morphological diagnosis because the therapeutic approach can be modified according to the findings. MATERIALS AND METHODS: A literature search was performed using PubMed for information regarding pathology and Cushing's disease. RESULTS: The histopathological features found in the pituitary gland of patients with Cushing's disease are presented. CONCLUSION: Different subtypes of ACTH-producing pituitary tumors are recognized and characterized. The significance of finding a normal pituitary gland with or without Crooke's changes is also discussed.

Lactate dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma.

BACKGROUND: Over 90% of cancer-related deaths in clear cell renal cell carcinoma (RCC) are caused by tumor relapse and metastasis. Thus, there is an urgent need for new molecular markers that can potentiate the efficacy of the current clinical-based models of prognosis assessment. The objective of this study is to evaluate the potential significance of lactate dehydrogenase A (LDHA), assessed by immunohistochemical staining, as a prognostic marker in clear cell renal cell carcinoma in relation to clinicopathological features and clinical outcome. METHODS: We assessed the expression of LDHA at the protein level, by immunohistochemistry, and correlated its expression with multiple clinicopathological features including tumor size, clinical stage, histological grade, disease-free and overall survival in 385 patients with primary clear cell renal cell carcinoma. We also correlated the LDHA expression with overall survival, at mRNA level, in an independent data set of 170 clear cell renal cell carcinoma cases from The Cancer Genome Atlas databases. Cox proportional hazards models adjusted for the potential clinicopathological factors were used to test for associations between the LDHA expression and both disease-free survival and overall survival. RESULTS: There is statistically significant positive correlation between LDHA level of expression and tumor size, clinical stage and histological grade. Moreover, LDHA expression shows significantly inverse correlation with both disease-free survival and overall survival in patients with clear cell renal cell carcinoma. Our results are validated by examining LDHA expression, at the mRNA level, in the independent data set of clear cell renal cell carcinoma cases from The Cancer Genome Atlas databases which also shows that higher lactate dehydrogenase A expression is associated with significantly shorter overall survival. CONCLUSION: Our results indicate that LDHA up-regulation can be a predictor of poor prognosis in clear cell renal cell carcinoma. Thus, it represents a potential prognostic biomarker that can boost the accuracy of other prognostic models in patients with clear cell renal cell carcinoma.

Prognostic significance of human tissue kallikrein-related peptidases 6 and 10 in gastric cancer.

The prognosis of patients following surgery for gastric cancer is often poor and is estimated using traditional clinicopathological parameters, which can be inaccurate predictors of future survival. Kallikreins are a group of serine proteases, which are differentially expressed in many human tumors and are being investigated as potential cancer biomarkers. This study assessed the prognostic utility of human tissue kallikrein-like peptidases 6 and 10 (KLK6 and KLK10) and correlated their expression with histopathological and clinical parameters in gastric cancer. We constructed a gastric tumor tissue microarray from 113 gastrectomy specimens and quantified KLK6 and KLK10 expression using immunohistochemistry. To overcome the problem of inter-observer variability and subjectivity in immunohistochemistry interpretation, a whole-slide scanned image of the tissue microarray was analyzed using an automated algorithm to quantify staining intensity. KLK6 expression was positively correlated with nodal involvement (p=0.002) and was predictive of advanced-stage disease (p<0.05). Kaplan-Meier survival curves revealed that tumors expressing high levels of KLK6 were significantly associated with significantly lower overall survival (p=0.04). KLK10 overexpression was also a predictor of advanced-stage disease (p<0.01), but was not significantly correlated with lymph node involvement or survival period. Our results show the potential ability of KLK6 as a prognostic marker for gastric cancer.

Integrative bioinformatics analysis reveals new prognostic biomarkers of clear cell renal cell carcinoma.

BACKGROUND: The outcome of clear cell renal cell carcinoma (ccRCC) is still unpredictable. Even with new targeted therapies, the average progression-free survival is dismal. Markers for early detection and progression could improve disease outcome. METHODS: To identify efficient and hitherto unrecognized pathogenic factors of the disease, we performed a uniquely comprehensive pathway analysis and built a gene interaction network based on large publicly available data sets assembled from 28 publications, comprising a 3-prong approach with high-throughput mRNA, microRNA, and protein expression profiles of 593 ccRCC and 389 normal kidney samples. We validated our results on 2 different data sets of 882 ccRCC and 152 normal tissues. Functional analyses were done by proliferation, migration, and invasion assays following siRNA (small interfering RNA) knockdown. RESULTS: After integration of multilevel data, we identified aryl-hydrocarbon receptor (AHR), grainyhead-like-2 (GRHL2), and KIAA0101 as new pathogenic factors. GRHL2 expression was associated with higher chances for disease relapse and retained prognostic utility after controlling for grade and stage [hazard ratio (HR), 3.47, P = 0.012]. Patients with KIAA0101-positive expression suffered worse disease-free survival (HR, 3.64, P < 0.001), and in multivariate analysis KIAA0101 retained its independent prognostic significance. Survival analysis showed that GRHL2- and KIAA0101-positive patients had significantly lower disease-free survival (P = 0.002 and P < 0.001). We also found that KIAA0101 silencing decreased kidney cancer cell migration and invasion in vitro. CONCLUSIONS: Using an integrative system biology approach, we identified 3 novel factors as potential biomarkers (AHR, GRHL2 and KIAA0101) involved in ccRCC pathogenesis and not linked to kidney cancer before.

Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

STRESS IN THE CLASSIFICATION OF PITUITARY TUMORS. FOCUS ON AGGRESSIVE PITUITARY ADENOMAS.

After a brief summary of the stress concept and the contribution of Dr. Hans Selye, this publication focuses on the classification of pituitary neoplasms and the difficulties to provide conclusive information on the prognosis of various pituitary tumor types. The term "aggressive pituitary tumors" was introduced. These tumors have a rapid cell proliferation rate. At present, the assessment of Ki-67 nuclear labeling index appears to be the simplest and most reliable method to evaluate tumor cell multiplication. Further studies on pituitary tumor biomarkers are needed.

Microvascular morphometrics of the hypophysis and pituitary tumors: from bench to operating theatre.

The idea that microvasculature might be a histopathological biomarker in the prognosis and treatment of tumors is garnering even more attention in the scientific community. The roles of neovascularity in tumor progression and metastasis, have become a hot-topic of investigation in cancer research. A number of methods of quantitatively analyzing pituitary adenoma microvasculature have been applied, and fractal analysis is emerging as a potential effective model for this aim. Additionally, new and more specific immunological techniques have been developed for the detection of microvessels. CD105 (Endoglin) has been proposed as a valuable antigen that marks only newly formed vessels, rather than the entire tumor microvascular system. The combination of different types of immunostaining techniques for the detection of microvessels in pituitary adenomas with fractal analysis as an objective and computer-aided technique to quantify and describe morphological aspects of microvessels has potential implications in future clinical and surgical applications. Tumor treatments, such as anti-angiogenic therapy, as well as intraoperative tools, stand to be enhanced by increasing advances in microvascular research. We here review the methods used for the quantitative analysis of microvessels of the pituitary in its physiopathological states, with the aim to show the pituitary adenoma as a model for the study of neoplastic angioarchitecture and the importance of the introduction of new techniques for the study of angiogenesis, with the relative scientific, medical and surgical implications.

ACTH-secreting Crooke cell carcinoma of the pituitary.

PURPOSE: While pituitary adenomas are common, pituitary carcinomas are rare. It is unclear whether pituitary carcinomas arise de novo or evolve from adenomas. METHODS: We studied the clinical characteristics and tissue samples from eight pituitary surgeries and the autopsy from a patient with pituitary carcinoma. A 16-year-old female patient was diagnosed with an aggressive Crooke cell macroadenoma. Following transsphenoidal surgery, clinical signs of Cushing disease quickly reappeared. During the 14-year course of the illness, eight pituitary surgeries, three courses of extracranial irradiation and two (90) Yttrium-DOTATOC treatments were undertaken. A bilateral adrenalectomy was performed. The patient died of metastatic disease and uncontrolled hypercortisolism due to an adrenal remnant. A systematic morphologic study (histologic staining, electron microscopy) of all available surgical and autopsy specimens was undertaken. RESULTS: Brisk mitotic activity, high Ki-67 and p53 immunolabelling were present in the pituitary samples from the onset. High proportion of tumour cells showed irregular nuclei and large nucleoli, and gradual increase in MGMT staining was observed. The tumour remained of Crooke cell type throughout the course. Autopsy disclosed a postirradiation sarcoma in the pituitary area. CONCLUSIONS: The question whether pituitary carcinomas arise de novo or transform from an adenoma cannot be answered at present with certainty.

Pituitary stem cells: candidates and implications.

The pituitary is the master endocrine gland of the body. It undergoes many changes after birth, and these changes may be mediated by the differentiation of pituitary stem cells. Stem cells in any tissue source must display (1) pluripotent capacity, (2) capacity for indefinite self-renewal, and (3) a lack of specialization. Unlike neural stem cells identified in the hippocampus and subventricular zone, pituitary stem cells are not associated with one specific cell type. There are many major candidates that are thought to be potential pituitary stem cell sources. This article reviews the evidence for each of the major cell types and discuss the implications of identifying a definitive pituitary stem cell type.

Melanoma of the sellar region mimicking pituitary adenoma.

We report here the case of an 82-year-old woman who presented with visual disturbance. MRI demonstrated a sellar mass. The diagnosis of pituitary adenoma was made. She underwent transnasal surgery. Histologic, immunohistochemical and ultrastructural studies indicated that the tumor was a melanoma. Despite an exhaustive search for a primary lesion elsewhere, none was found. The sellar tumor was considered a primary lesion, although extrasellar primary tumor imaging cannot be excluded with 100% certainty. Reported examples of melanoma affecting the sellar region are few. They exhibit morphologic features identical to those of melanomas arising elsewhere. Although very rare, primary melanomas enter into the differential diagnosis of sellar lesions.