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Endocrine Pathology Jun 2021Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although... (Review)
Review
Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although few pathologists outside of endocrine tertiary centers will ever diagnose such a lesion, the tumors are well known through the medical community-possible due to a combination of the sheer rarity, their often-spectacular presentation due to excess catecholamine secretion as well as their unrivaled coupling to constitutional susceptibility gene mutations and hereditary syndromes. All PPGLs are thought to harbor malignant potential, and therefore pose several challenges to the practicing pathologist. Specifically, a responsible diagnostician should recognize both the capacity and limitations of histological, immunohistochemical, and molecular algorithms to pinpoint high risk for future metastatic disease. This focused review aims to provide the surgical pathologist with a condensed update regarding the current strategies available in order to deliver an accurate prognostication of these enigmatic lesions.
Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Humans; Immunohistochemistry; Paraganglioma; Pathology, Molecular; Pheochromocytoma
PubMed: 33768452
DOI: 10.1007/s12022-021-09675-0 -
Clinical Cancer Research : An Official... Jan 2023Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer-associated renal cell...
PURPOSE
Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations.
PATIENTS AND METHODS
Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed.
RESULTS
Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18-57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1-17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed.
CONCLUSIONS
Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.
Topics: Male; Female; Adult; Humans; Child; Adolescent; Young Adult; Middle Aged; Succinate Dehydrogenase; Carcinoma, Renal Cell; Pheochromocytoma; Gastrointestinal Stromal Tumors; Leukocytes, Mononuclear; Paraganglioma; Adrenal Gland Neoplasms; Kidney Neoplasms; Biological Products
PubMed: 36302175
DOI: 10.1158/1078-0432.CCR-22-2168 -
Frontiers in Endocrinology 2023Resection of pheochromocytoma and paraganglioma (PPGL) carries risks with perioperative hemodynamic instability. Phenoxybenzamine (PXB) is a commonly used α-blockade to...
Influence of duration of preoperative treatment with phenoxybenzamine and secretory phenotypes on perioperative hemodynamics and postoperative outcomes in pheochromocytoma and paraganglioma.
OBJECTIVES
Resection of pheochromocytoma and paraganglioma (PPGL) carries risks with perioperative hemodynamic instability. Phenoxybenzamine (PXB) is a commonly used α-blockade to prevent it. It is unclear whether lengthening the preoperative duration of PXB is better for hemodynamic stability and postoperative outcomes. Furthermore, different types of catecholamines have varying effects on perioperative hemodynamics. Thus, our study aimed to investigate the impact of the duration of preoperative preparation with PXB and secretory phenotypes of the patients on intraoperative hemodynamic stability and postoperative complications in PPGL.
METHODS
Between Dec 2014 and Jan 2022, 166 patients with PPGL were operated on by the same team at Sun Yat-sen Memorial Hospital. They were divided into group A(1-14d), Group B(15-21d), and Group C(>21d) based on the duration of management with PXB and into the adrenergic and the noradrenergic phenotype group based on secretory profiles. Data on intraoperative hemodynamics and postoperative outcomes were collected and compared among groups.
RESULTS
A total of 96 patients occurred intraoperative hemodynamic instability, and 24 patients had 29 postoperative complications related to the surgery. Among the 145 patients treated with PXB, no significant differences were found in the cumulative time outside the target blood pressure(6.67%[0-17.16%] 5.97%[0-23.08%] 1.22%[0-17.27%], =0.736) or in the median total HI-score(42.00[30.00-91.00] 89.00[30.00-113.00] 49.00[30.00-93.00], =0.150) among group A(n=45), B(n=51) and C(n=49). Multivariate analysis demonstrated that the level of plasma-free metanephrine(MN) was an independent risk factor for intraoperative hemodynamic instability. And the median cumulative time outside of the target blood pressure in the adrenergic phenotype group was significantly greater than that in the noradrenergic phenotype group(8.17%[0-26.22%] 1.86%[0-11.74%], =0.029). However, the median total HI-score(99.50[85.00-113.25] 90.00[78.00-105.00], =0.570) and postoperative outcomes showed no differences between the two groups.
CONCLUSIONS
A preoperative duration of nearly 14 days with PXB is sufficient for ensuring intraoperative hemodynamic stability in PPGL. And lengthening the preparation duration may not provide additional benefits in the era of widespread application and advanced techniques of laparoscopic surgery. Additionally, patients with the adrenergic phenotype are more prone to intraoperative hemodynamic instability than the noradrenergic phenotype. Thus, more attention should be given to the adrenergic phenotype during surgery.
Topics: Humans; Phenoxybenzamine; Pheochromocytoma; Paraganglioma; Hemodynamics; Metanephrine; Postoperative Complications; Norepinephrine; Adrenal Gland Neoplasms; Adrenergic Agents
PubMed: 37152936
DOI: 10.3389/fendo.2023.1139015 -
Frontiers in Endocrinology 2021To study the characteristics, risk factors, and outcomes of local-regional recurrence of pheochromocytoma and paraganglioma (PPGL).
OBJECTIVE
To study the characteristics, risk factors, and outcomes of local-regional recurrence of pheochromocytoma and paraganglioma (PPGL).
METHODS
Clinical data of 96 PPGL patients with local-regional recurrence and 112 patients without recurrence were retrospectively analyzed.
RESULTS
Recurrent patients exhibited a median recurrence time of 6.0 (4.0, 9.0) years after resection of the primary tumor. mutation [HR 4.1 (1.7, 9.5), p=0.001), primary tumor size ≥5cm [HR 2.3 (1.1, 4.7), p=0.028], and average Ki-67 count ≥3% in the primary tumor [HR 2.6 (1.4, 4.9), p=0.003] were independent predictors for recurrence of PPGL. Primary tumor sizes ≥5cm [HR 5.1 (1.7, 15.3), p=0.003] and average Ki-67 counts ≥3% of the primary tumor [HR 2.4 (1.1, 5.2), p=0.035] were independent predictors for recurrence of pheochromocytoma, while mutation [HR 4.6 (1.5, 13.9), p=0.007] was a predictor for paraganglioma recurrence. Among recurrent patients, 47% (45/96) had multiple nodules in recurrent sites, and 58% (56/96) had metastases, with 20% (19/96) being implantation metastases. The risk of metastases (42% vs. 25%, p=0.030) and death (15% vs. 8%, p=0.003) was significantly increased in untreated patients after recurrence compared with treated patients.
CONCLUSION
Long-term follow-up is necessary for all PPGL patients. Risk factors for recurrence of pheochromocytoma and paraganglioma differ, with primary tumor size and average Ki-67 count representing independent predictors for pheochromocytoma patients and mutations predicting paraganglioma recurrence. Although the treatment of recurrence can be difficult, patients should be treated once recurrence is detected as it decreases the risk of metastases and death.
Topics: Adrenal Gland Neoplasms; Adult; Female; Humans; Male; Mutation; Neoplasm Recurrence, Local; Paraganglioma; Pheochromocytoma; Retrospective Studies; Risk Factors; Succinate Dehydrogenase
PubMed: 34899602
DOI: 10.3389/fendo.2021.762548 -
Journal of Endocrinological... Jan 2022Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors releasing catecholamines. Metastatic pheochromocytomas/paragangliomas (PPGLs) occur in...
BACKGROUND
Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors releasing catecholamines. Metastatic pheochromocytomas/paragangliomas (PPGLs) occur in about 5-26% of cases. To date, the management of patients affected by metastatic disease is a challenge in the absence of guidelines.
AIM
The aim of this study was to evaluate the overall survival (OS) and the progression-free survival (PFS) in metastatic PPGLs.
METHODS
Clinical data of 20 patients referred to the Careggi University Hospital (Florence, Italy) were retrospectively collected. Follow-up ranged from 1989 to 2019. Site and size of primary tumor, biochemical activity, genetic analysis and employed therapies were considered. Data were analyzed with SPSS version 27.
RESULTS
Nine PHEOs (45%) and 11 PGLs (55%) were enrolled. Median age at diagnosis was 43.5 years [30-55]. Mean follow-up was 104.6 ± 89.3 months. Catecholamines were released in 70% of cases. An inherited disease was reported in 50% of patients. OS from the initial diagnosis (OSpt) and from the metastatic appearance (OSmtx) were lower in older patients (OSpt p = 0.028; OSmtx p < 0.001), abdominal PGLs (OSpt p = 0.007; OSmtx p = 0.041), larger tumors (OSpt p = 0.008; OSmtx p = 0.025) and sporadic disease (OSpt p = 0.013; OSmtx p = 0.008).
CONCLUSION
Our data showed that older age at the initial diagnosis, sympathetic extra-adrenal localization, larger tumors and wild-type neoplasms are related to worse prognosis. Notably, the employed therapies do not seem to influence the survival of our patients. At present, effective treatments for metastatic PPGLs are missing and a multidisciplinary approach is indispensably required.
Topics: Adrenal Gland Neoplasms; Adult; Female; Humans; Italy; Male; Middle Aged; Neoplasm Metastasis; Paraganglioma; Pheochromocytoma; Prognosis; Retrospective Studies; Survival Analysis; Treatment Outcome; Watchful Waiting
PubMed: 34227051
DOI: 10.1007/s40618-021-01629-x -
Endocrine-related Cancer Jun 2023Metabolites represent the highest layer of biological information. Their diverse chemical nature enables networks of chemical reactions that are critical for maintaining...
Metabolites represent the highest layer of biological information. Their diverse chemical nature enables networks of chemical reactions that are critical for maintaining life by providing energy and building blocks. Quantification by targeted and untargeted analytical methods using either mass spectrometry or nuclear magnetic resonance spectroscopy has been applied to pheochromocytoma/paraganglioma (PPGL) with the long-term goal to improve diagnosis and therapy. PPGLs have unique features that provide useful biomarkers and clues for targeted treatments. First, high production rates of catecholamines and metanephrines allow for specific and sensitive detection of the disease in plasma or urine. Secondly, PPGLs are associated with heritable pathogenic variants (PVs) in around 40% of cases, many of which occur in genes encoding enzymes, such as succinate dehydrogenase (SDH) and fumarate hydratase (FH). These genetic aberrations lead to the overproduction of oncometabolites succinate or fumarate, respectively, and are detectable in tumors and blood. Such metabolic dysregulation can be exploited diagnostically, with the aim to ensure appropriate interpretation of gene variants, especially those with unknown significance, and facilitate early tumor detection through regular patient follow-up. Furthermore, SDHx and FH PV alter cellular pathways, including DNA hypermethylation, hypoxia signaling, redox homeostasis, DNA repair, calcium signaling, kinase cascades, and central carbon metabolism. Pharmacological interventions targeted toward such features have the potential to uncover treatments against metastatic PPGL, around 50% of which are associated with germline PV in SDHx. With the availability of omics technologies for all layers of biological information, personalized diagnostics and treatment is in close reach.
Topics: Humans; Paraganglioma; Pheochromocytoma; Metabolomics; Succinate Dehydrogenase; Adrenal Gland Neoplasms; Catecholamines
PubMed: 36897220
DOI: 10.1530/ERC-22-0376 -
Current Opinion in Endocrinology,... Jun 2022Many publications review perioperative management of pheochromocytomas/paragangliomas (PPGLs); however, a large population, including 10-20% of metastatic PPGL patients,... (Review)
Review
PURPOSE OF REVIEW
Many publications review perioperative management of pheochromocytomas/paragangliomas (PPGLs); however, a large population, including 10-20% of metastatic PPGL patients, have inoperable disease. This has necessitated the development of noninvasive treatments (e.g., radio/chemotherapy), which, in affording disease-modification, have led to an ever-growing population of surviving patients with inoperable PPGL. These patients experience debilitating symptoms arising from discomforts related to the masses themselves (e.g., pain from osseous metastasis) and symptoms from tumoral catecholamine production and release. Unfortunately, management of these conditions is not yet well-defined. Adding further insult-to-injury, these noninvasive treatments can trigger catecholamine release, worsening catecholamine-induced symptoms. Herein, we detail these ailments and their management, especially while patients receive these noninvasive treatments.
RECENT FINDINGS
Improved diagnostic evaluations have allowed for earlier detection of PPGL, prolonging survival in patients with inoperable PPGLs. Accordingly, noninvasive treatment strategies have rapidly evolved alongside state-of- the-art theranostics and genetic testing, which inform ongoing management and therapeutic response.
SUMMARY
While treatments afford improved survival, there must be a corresponding attention to quality-of-life. This is ensured by employing supportive management, which mitigates debilitating symptoms. This is best accomplished with a multidisciplinary approach and familiarity with genetic and biochemical determinants which guide patient education and management.
Topics: Adrenal Gland Neoplasms; Catecholamines; Genetic Testing; Humans; Paraganglioma; Pheochromocytoma
PubMed: 35621181
DOI: 10.1097/MED.0000000000000724 -
The Israel Medical Association Journal... Jan 2020Primary retroperitoneal neoplasms (PRN) arise from diverse retroperitoneal tissues. Soft tissue sarcomas (STS) comprise the majority and are well studied. Other...
BACKGROUND
Primary retroperitoneal neoplasms (PRN) arise from diverse retroperitoneal tissues. Soft tissue sarcomas (STS) comprise the majority and are well studied. Other non-sarcomatous PRN are very rare and less familiar.
OBJECTIVES
To evaluate the clinicopathologic and radiologic features of non-sarcomatous PRN, as well as the outcome of complete tumor resection (TR).
METHODS
Retrospective data were collected on consecutive patients (June 2006 to January 2015) who underwent resection of retroperitoneal lesions at our department. Final pathology of non-sarcomatous PRN was included.
RESULTS
The study population included 36 patients (26% with PRN). PRN were neurogenic (17%), fat-containing (3%), and cystic (6%). The preoperative diagnosis was correct in only 28%. All patients underwent TR via laparotomy (72%) or laparoscopy (28%), for mean operative time of 120 ± 46 minutes. En bloc organ resection was performed in 11%. Complete TR was achieved in 97%. Intra-operative spillage occurred in 8%. Intra-operative, 90-day postoperative complications, and mortality rates were 11%, 36%, and 0%, respectively. The mean length of stay was 6.5 ± 5.5 days. The median overall survival was 53 ± 4.9 months.
CONCLUSIONS
Familiarity with radiologic characteristics of PRN is important for appropriate management. Counter to STS, other PRN are mostly benign and have an indolent course. Radical surgery is not required, as complete TR confers good prognosis. Expectant management is reserved for small, asymptomatic, benign neoplasms.
Topics: Aged; Female; Ganglioneuroma; Humans; Lipoma; Male; Middle Aged; Neurilemmoma; Neurofibroma; Paraganglioma; Retroperitoneal Neoplasms; Retrospective Studies; Tomography, X-Ray Computed
PubMed: 31927807
DOI: No ID Found -
Human Pathology Apr 2021The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit to develop evidence-based, internationally agreed-upon standardized data sets for each... (Review)
Review
Data set for the reporting of pheochromocytoma and paraganglioma: explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting.
BACKGROUND AND OBJECTIVES
The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit to develop evidence-based, internationally agreed-upon standardized data sets for each anatomic site, to be used throughout the world. Providing global standardization of pathology tumor classification, staging, and other reporting elements will lead to improved patient management and enhanced epidemiological research.
METHODS
Pheochromocytoma and paraganglioma are uncommon and are frequently overlooked in registry data sets. Malignant criteria have previously been defined only when there was metastatic disease.
RESULTS
With recent recognition of a significant inheritance association and the development of risk stratification tools, this data set was created in order to obtain more meaningful outcomes and management data, using similar criteria across the global pathology community. Issues related to key core and non-core elements, especially clinical hormonal status, familial history, tumor focality, proliferative fraction, adverse or risk stratification features, and ancillary techniques, are discussed in the context of daily application to these types of specimens.
CONCLUSIONS
The ICCR data set, developed by an international panel of endocrine organ specialists, establishes a pathology-standardized reporting guide for pheochromocytoma and paraganglioma.
Topics: Adrenal Gland Neoplasms; Carcinoma; Humans; Paraganglioma; Pathology, Clinical; Pheochromocytoma; Research Design
PubMed: 32407815
DOI: 10.1016/j.humpath.2020.04.012 -
Endocrine Journal Jun 2021Cytotoxic chemotherapy, including cyclophosphamide, vincristine, and dacarbazine (CVD) therapy, is widely used to treat metastatic pheochromocytoma and paraganglioma....
Cytotoxic chemotherapy, including cyclophosphamide, vincristine, and dacarbazine (CVD) therapy, is widely used to treat metastatic pheochromocytoma and paraganglioma. Because these diseases are rare, studies are needed to establish treatment strategies. This was a single-center and retrospective study to analyze the efficacy of chemotherapy for patients with metastatic pheochromocytoma and paraganglioma diagnosed in 1983-2020. Clinical characteristics, tumor volume response, biochemical response based on catecholamine level, overall survival, and progression-free survival were evaluated. Patients with a complete response or partial response in tumor volume or catecholamine level were classified as responders. Sixteen patients were administered chemotherapy for a median of 16.5 cycles (interquartile range, 10-42). The tumor volume response was classified as follows: partial response (N = 4), stable disease (N = 9), and progressive disease (N = 3) (disease control rate = 81%). The biochemical responses were as follows: complete response (N = 2), partial response (N = 5), no change (N = 3), and progressive disease (N = 1) (disease control rate = 91%). The 5-year survival rate was 50% (95% confidence interval [CI], 21-74%) and median overall survival was 4.4 years (95% CI, 2.4 years-not reached). Overall survival and progression-free survival between responders and nonresponders were not statistically different. One patient developed myelodysplastic syndrome during CVD therapy. In conclusion, chemotherapy achieved disease control among more than half of patients, although survival did not differ between responders and nonresponders. Further fundamental research and prospective trials are needed to analyze the efficacy of CVD therapy.
Topics: Adrenal Gland Neoplasms; Adult; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Paraganglioma; Pheochromocytoma; Retrospective Studies; Survival Rate; Treatment Outcome
PubMed: 33518616
DOI: 10.1507/endocrj.EJ20-0762