Pheochromocytoma Of The Adrenal Gland Scaled Score Research Articles

Long-term outcomes and prognostic factors of metastatic or recurrent pheochromocytoma and paraganglioma: a 20-year review in a single institution

Pheochromocytoma and paraganglioma (PPGL) represent a group of rare neuroendocrine tumors known for their potential to metastasize. This study provides a comprehensive retrospective evaluation of 15 patients diagnosed with metastatic or recurrent PPGL at our institution over a two-decade span (2000–2020). Our primary objectives were to delineate the long-term clinical outcomes and pinpoint key prognostic determinants. Median duration from initial PPGL diagnosis to the onset of metastasis or recurrence stood at 5.8 years. Predominant sites for metastasis included the bone, lung, lymph nodes, and peritoneum. A salient finding was that surgical interventions targeting metastatic lesions significantly improved prognosis. Further analysis revealed that a Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) exceeding 7 closely associated with unfavorable outcomes. These insights not only underscore the clinical variability of PPGL’s progression but also highlight the pivotal role of surgical management for metastatic or recurrent cases. The value of the PASS score as an informative prognostic tool was evident, suggesting its utility in shaping future therapeutic approaches. Given the intricacies of PPGL, collaborative studies involving larger patient cohorts will be crucial to optimize management strategies and prognostication.

Case report of laparoscopic adrenalectomy for a giant pheochromocytoma: medical and surgical challenge

Pheochromocytomas are rare adrenal tumors that can pose significant clinical challenges due to their potential for catecholamine release and hypertensive crises. We present a case of a large pheochromocytoma managed successfully through a laparoscopic adrenalectomy. A 66-year-old male presented with adrenal incidentaloma. Imaging revealed a sizable left adrenal mass (9.5 cm) consistent with a pheochromocytoma. Preoperative alpha- and beta-adrenergic blockade was initiated to optimize hemodynamic control. The patient underwent a laparoscopic adrenalectomy, with meticulous dissection and adrenal vein ligation to minimize catecholamine release during surgery. Post operatively, blood pressure and catecholamine levels normalized. Histopathological evaluation confirmed the diagnosis of pheochromocytoma with high pheochromocytoma of the adrenal gland scaled score (PASS) and grading of adrenal pheochromocytoma and paraganglioma (GAPP) scoring. Laparoscopic adrenalectomy proved to be a safe and effective approach for managing this large pheochromocytoma, resulting in improved blood pressure control and quality of life for the patient. This case underscores the importance of a multidisciplinary approach, including preoperative medical optimization and close postoperative monitoring, in the management of pheochromocytomas, and contributes to the growing body of evidence supporting laparoscopic techniques for these adrenal tumors.

7537 Composite Pheochromocytoma-Ganglioneuroma Secreting Vasoactive Intestinal Peptide: A Case Report

Abstract Disclosure: B. Brochu: None. Y. Collin: None. R. Temmar: None. F. Bernier: None. K. Dandurand: None. M. St-Jean: None. M. Massicotte: None. Background: Composite pheochromocytoma-ganglioneuroma is a rare tumor combining features of both pheochromocytoma/paraganglioma (PPGL) and neurogenic tumors. Cosecretion of vasoactive intestinal peptide (VIP) is even less common and highlights the diverse secretory potential of these tumors. Clinical Case: An 80-year-old woman presented with severe chronic diarrhea that had been progressively worsening over the past 10 years. The diarrhea was associated with chronic hyponatremia between 128 and 132 mmol/L. She also had mild hypertension, with a mean blood pressure of 145/90 mm Hg. An abdominal CT scan revealed a right adrenal mass of 68 mm x 44 mm x 50 mm with a density of 19 HU without contrast. A 24-hour urinary collection demonstrated normetanephrines (NM) levels at 3.5 times the upper limit of normal. A 68Ga-DOTATATE PET/CT demonstrated significant uptake only in the adrenal mass. Because of the ongoing severe diarrhea, that is unusual in the context of NM secreting PPGL, serum VIP level was measured and came back at nearly three times the upper limit of normal. A provisional diagnosis of pheochromocytoma with VIP and catecholamines cosecretion was made and surgical resection by laparotomy was performed without complication. Pathology demonstrated a composite tumor combining a pheochromocytoma and a ganglioneuroma, with a Pheochromocytoma of the Adrenal gland Scaled Score (PASS) score of 3. Tumor immunohistochemical staining was positive for VIP in both pheochromocytoma and ganglioneuroma cells. After surgery, diarrhea and hyponatremia resolved and blood pressure normalized. Conclusion: This is one of the very rare cases described in the current literature of a composite pheochromocytoma coproducing catecholamines and VIP. While the two tumors might have developed synchronously, the finding of VIP secretion in the pheochromocytoma and the ganglioneuroma suggest that both tumors might originate from the same cell. Presentation: 6/1/2024

Usefulness of the Primary Tumor Standardized Uptake Value of Iodine-123 Metaiodobenzylguanidine for Predicting Metastatic Potential in Pheochromocytoma and Paraganglioma.

To examine the usefulness of semi-quantitative analysis using the standardized uptake value (SUV) of iodine-123 metaiodobenzylguanidine ([123I]-MIBG) for predicting metastatic potential in patients with pheochromocytoma (PHEO) and paraganglioma (PGL). This study included 18 PHEO and 2 PGL patients. [123I]-MIBG visibility and SUV-related parameters (SUVmax, SUVmean, tumor volume of [123I]-MIBG uptake [TV_MIBG], and total lesion [123I]-MIBG uptake) were compared with the pathological grading obtained using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP), which are used to predict metastatic potential. The PASS scores were categorized as < 4 and ≥ 4. Based on the GAPP scores, PHEOs/PGLs were categorized as follows: well, moderately, and poorly differentiated tumors. The Mann-Whitney U test or Spearman's rank correlation was used to assess differences or associations between two quantitative variables. All PHEOs/PGLs were visualized on [123I]-MIBG scintigraphy. There were 16 PASS < 4 and 4 PASS ≥ 4 tumors. Moreover, 11 and 9 tumors were well and moderately differentiated, respectively. The uptake scores and SUV-related parameters significantly differed between tumors with a PASS score of < 4 and those with a PASS score of ≥ 4 (each, p > 0.05). Moderately differentiated tumors had significantly higher uptake scores and SUV-related parameters except TV_MIBG than well-differentiated tumors (each, p < 0.05). The GAPP score was positively correlated with the uptake scores and SUV-related parameters (each, p < 0.05) except TV_MIBG. The primary tumor [123I]-MIBG uptake assessed using SUV-related parameters can be an imaging tool for predicting metastatic potential in patients with PHEO/PGL.

Validation and Evaluation of 5 Scoring Systems for Predicting Metastatic Risk in Pheochromocytoma and Paraganglioma.

Currently, 5 scoring systems have been proposed in the literature for predicting metastatic risk in pheochromocytoma and paraganglioma (PPGL): Pheochromocytoma of the Adrenal Gland Scaled Score (PASS), Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP), Composite Pheochromocytoma/paraganglioma Prognostic Score (COPPS), Age, Size, Extra-adrenal location, Secretion type (ASES) score, and Size, Genetic, Age, and PASS (SGAP) model. To validate and evaluate these 5 scoring systems, we conducted a retrospective review of cases diagnosed as PPGL at the Department of Pathology, West China Hospital of Sichuan University, between January 2012 and December 2019. A total of 185 PPGL cases were included, comprising 35 cases with metastasis and 150 cases remained metastasis-free for over 8 years after surgery. The criteria of the 5 scoring systems were used for scoring and risk classification. The predictive performance of the 5 scoring systems was validated, compared, and evaluated using concordance index (C-index) and decision curve analysis (DCA). The C-indices for PASS, GAPP, and SGAP were 0.600, 0.547, and 0.547, respectively, indicating low discriminative ability. In contrast, COPPS and ASES had C-indices of 0.740 and 0.706, respectively, indicating better discriminative performance. DCA also showed that the predictive capability of COPPS was superior to that of ASES, with both outperformed PASS, while PASS had better predictive ability than GAPP and SGAP. Our analysis indicated that pathology-based scoring systems cannot accurately predict metastatic risk of PPGL. Establishing a precise prediction system requires integrating clinical, pathologic, and molecular information, using a scientific methodology for predictive factor selection and weight assessment.

Identification of Predictors of Metastatic Potential in Paragangliomas to Develop a Prognostic Score (PSPGL).

Paragangliomas (PGLs) are rare tumors in adrenal and extra-adrenal locations. Metastasis are found in approximately 5% to 35% of PGLs, and there are no reliable predictors of metastatic disease. This work aimed to develop a prognostic score of metastatic potential in PGLs. A retrospective analysis was conducted of clinical data from a cohort with PGLs and tumor histological assessment. Patients were divided into metastatic PGL (presence of metastasis) and nonmetastatic PGL (absence of metastasis ≥96 months of follow-up) groups. Univariate and multivariable analysis were performed to identify predictors of metastatic potential. A prognostic score was developed based on coefficients of multivariable analysis. Kaplan-Meier curves were generated to estimate disease-specific survival (DSS). Out of 263 patients, 35 patients had metastatic PGL and 110 patients had nonmetastatic PGL. In multivariable analysis, 4 features were independently related to metastatic disease and composed the Prognostic Score of Paragangliomas (PSPGL): presence of central or confluent necrosis (33 points), more than 3 mitosis/10 high-power field (HPF) (28 points), extension into adipose tissue (20 points), and extra-adrenal location (19 points). A PSPGL of 24 or greater showed similar sensitivity with higher specificity than the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP). PSPGL less than or equal to 20 was associated with a risk of metastasis of approximately 10%, whereas a PSPGL of 40 or greater was associated with approximately 80%. The presence of metastasis and Ki-67 of 3% or greater were related to lower DSS. The PSPGL, composed of 4 easy-to-assess parameters, demonstrated good performance in predicting metastatic potential and good ability in estimating metastasis risk.

The Utility of Phosphohistone-H3 Immunohistochemistry (PHH3) in Pheochromocytomas

Abstract Introduction/Objective Most pheochromocytomas (PCC) are sporadic; ~40% present as part of familial syndromes and some cases are associated with germline mutations of succinate dehydrogenase (SDH) genes. Few cases are malignant. The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) is a scoring system to predict behavior that includes evaluation of mitotic count, among other parameters. PHH3 has been used to assess mitosis in breast and glial tumors. The aim of this study was to assess the potential utility of PHH3 in pheochromocytomas. Methods/Case Report 50 cases of PCC diagnosed between 2016 and 2020 at our institution were included in the study. Clinicopathologic data was recorded. One hematoxylin and eosin (H&amp;E) slide was selected per case and mitotic count was evaluated at 40x high power-fields (HPF). PHH3 was performed on the same block to assess mitoses. Cells with dark and coarsely clumped staining were considered positive for PHH3. PHH3-positive cells were counted also at 40x HPF. In one case with bilateral pheochromocytomas, the largest tumor was evaluated. Follow-up was available in 39 cases and recorded as no evidence of disease (NED), alive with disease (AWD), or dead of disease (DOD). Results (if a Case Study enter NA) 21 patients were female, 29 were males. Age ranged from 24 to 95 (mean: 56). Tumor size ranged from 1.1 to 16.0 cm (mean: 5.6 cm). Mean follow-up was 13.6 months (1-32 months range). Mitotic count ranged from 0 to 7 and 0 to 21 per 10 HPFs, on H&amp;E and PHH3, respectively. PHH3 showed higher mitotic count in 33 cases compared to H&amp;E. In 11 cases, mitotic count was equal on H&amp;E and PHH3, and in the remaining cases, mitotic count was higher on H&amp;E than PHH3. In cases with PASS score ≥ 4, 50% and 27% of cases had mitotic count &amp;gt;3/10HPF on PHH3 and H&amp;E, respectively. Follow-up showed two patients AWD and one DOD, all of whom had PASS score ≥ 4, with mitotic count on H&amp;E 7, 1 and 6 and mitotic count on PHH3 8, 4, and 21 respectively. Conclusion This is the first study evaluating the use of PHH3 in pheochromocytomas. Overall, mitotic count was higher on PHH3 than on H&amp;E. This indicates PHH3 is a helpful tool in counting mitosis. Since the PASS score is an imperfect system to predict outcome, additional studies are needed to evaluate the use of PHH3 in prognostic scoring systems for PCC.

SAT308 An Assessment Of Prognostic Markers To Predict Metastatic Pheochromocytoma/Paraganglioma

Abstract Disclosure: M.D. Lundholm: None. E. Berber: None. P.P. Rao: None. Introduction: Pheochromocytoma/paraganglioma (PCC/PGL, or PPGL) are rare neuroendocrine tumors arising from chromaffin cells. Early identification of PPGL with metastatic potential is a diagnostic challenge. More data are needed on features and scoring markers used to predict PPGL metastasis. Methods: A single-center, retrospective observational study was performed of consecutive patients with pathology-confirmed PPGL from 2005 to 2022. Features associated with metastasis were identified and Pheochromocytoma of the Adrenal gland Scaled Score (PASS), Age, Size, Extra-adrenal location and Secretory type (ASES) score, and Size, Genetic, Age, and PASS (SGAP) score were calculated. Results: We identified 371 patients with PPGL (251 PCC, 120 PGL), age 52.2±15.4yrs, 60.6% female, 69.8% incidental. Metastatic disease was reported in 13.2% (N=49; 30 PCC, 19 PGL) associated with younger age (47.3 vs 53.0yrs, p=0.029), larger tumor size (6.3 vs 4.0cm, p&amp;lt;0.001), histologic findings of necrosis (26% vs 2.5%, p&amp;lt;0.001) and vascular invasion (42.1% vs 19.6% p=0.038), hyperadrenergic symptoms at diagnosis (38.8% vs 22.0%, p=0.038), norepinephrine-only secreting tumors (59.6% vs 30.1%, p&amp;lt;0.001), extra-adrenal location (51.0% vs 32.0%, p=0.009), presence of genetic mutations (72.4% vs 38.5%, p&amp;lt;0.001), particularly SDHx (31.0% vs 12.2%, p=0.020) and VHL mutations (24.1% vs 3.8%, p=0.001). There were no significant differences by gender, race, other histologic criteria from PASS, or other mutations such as RET or NF-1. ASES was positive (≥2) in 27.2% (N=100/371) with sensitivity (SN) 79.6%, specificity (SP) 81.1%, positive predictive value (PPV) 39.0%, and negative predictive value (NPV) 96.3% for predicting metastatic disease. PASS and SGAP could only be applied to patients with PCC: PASS was positive (≥4) in 29.7% (N=55/185) with SN 60.0%, SP 73.9%, PPV 21.8%, and NPV 93.8%. SGAP was positive (≥5) in 27.6% (N=32/116) with SN 56.3%, SP 77.0%, PPV 28.1%, and NPV 91.7%. Discussion: Metastatic PPGL is associated with age, tumor size and location, select histologic findings, symptomatic presentation, hormone-secreting pattern, and select genetic mutations. PPGL scoring markers ASES, PASS, and SGAP were all effective at identifying cases with low likelihood of metastasis, but had poor PPV. ASES outperformed PASS and SGAP in test metrics and practicality as the only clinically-derived marker which could be applied to all cases of PPGL. ASES can also be used pre-operatively. Most histologic features and genetic mutations included in PASS and SGAP were not strongly correlated with metastasis, though limited by lower prevalence in the study population. Conclusion: Our data supports the use of ASES alongside data on necrosis, vascular invasion, SDHx and VHL mutations where available to fine-tune our prediction of metastatic potential for PPGL. Presentation: Saturday, June 17, 2023

Expression of endocan and vascular endothelial growth factor and their correlation with histopathological prognostic parameters in pheochromocytoma.

Endocan and vascular endothelial growth factor (VEGF) are markers expressed in various cancer types that are highly vascular, and they have prognostic significance for these cancers. In this study, we aimed to show the expression of endocan and VEGF in pheochromocytoma tumor tissues and to evaluate their correlations with histopathological parameters. Thirty-eight patients who had been operated for pheochromocytoma were included in the study. As the control group, 28 subjects whose specimens contained normal adrenal medulla tissue were included. The formalin-fixed paraffin-embedded specimens of pheochromocytoma patients were evaluated for Pheochromocytoma of the Adrenal gland Scaled Score (PASS). Sections were then stained for immunohistochemical analysis. The degree of endocan and VEGF positivity was determined by the proportion of stained cells on a negative to strong scale. Endocan (p < 0.001) and VEGF (p = 0.004) expressions were found to be significantly higher in the pheochromocytoma group than in the control group. In the pheochromocytoma group, total PASS score (r = 0.714; p < 0.001) and most of the PASS score components were positively correlated with the level of endocan expression. Median Ki-67 index (p = 0.010), total PASS score (p < 0.001), tumor cell spindling (p = 0.048), and nuclear pleomorphism (p = 0.030) were higher in pheochromocytoma with VEGF expression than in those without. If our findings are supported by studies with a larger sample size, we think that endocan has the potential to be used both as a tumor marker and in predicting malignancy potential in patients with pheochromocytoma, and that the detection of VEGF expression in these tumors is also associated with an increase in malignancy potential.

Lesion-based indicators predict long-term outcomes of pheochromocytoma and paraganglioma- SIZEPASS.

We seek a simple and reliable tool to predict malignant behavior of pheochromocytoma and paraganglioma (PPGL). This single-center prospective cohort study assessed size of primary PPGLs on preoperative cross-sectional imaging and prospectively scored specimens using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS). Multiplication of PASS points with maximum lesion diameter (in mm) yielded the SIZEPASS criterion. Local recurrence, metastasis or death from disease were surrogates defining malignancy. 76 consecutive PPGL patients, whereof 58 with pheochromocytoma and 51 female, were diagnosed at a mean age of 52.0 ± 15.2 years. 11 lesions (14.5%) exhibited malignant features at a median follow-up (FU) of 49 months (range 4-172 mo). Median FU of the remaining cohort was 139 months (range 120-226 mo). SIZEPASS classified malignancy with an area under the curve (AUC) of 0.97 (95%CI 0.93-1.01; p<0.0001). Across PPGL, SIZEPASS >1000 outperformed all known predictors of malignancy, with sensitivity 91%, specificity 94%, and accuracy 93%, and an odds ratio of 72 fold (95%CI 9-571; P<0.001). It retained an accuracy >90% in cohorts defined by location (adrenal, extra-adrenal) or mutation status. The SIZEPASS>1000 criterion is a lesion-based, clinically available, simple and effective tool to predict malignant behavior of PPGLs independently of age, sex, location or mutation status.

Locally invasive recurrence or metastasis of pheochromocytoma into the liver?—clinicopathological challenges

Pheochromocytomas (PCC) are rare and functional neuroendocrine tumors developing from adrenal chromaffin cells. Predicting malignant behavior especially in the absence of metastasis can be quite challenging even in the era of improved understanding of the molecular mechanisms involved in PCCs. Currently, two histopathological grading systems Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading of Adrenal Pheochromocytoma and Paraganglioma (GAPP) score are used in clinical practice, but these are subject to significant interobserver variability. Some of the most useful clinical factors associated with malignancy are large size ([4–5 cm), and genetic features such as presence of SDHB germline mutations. Local invasion is uncommon in PCC and metastasis seen in 10 to 17% but higher in germline mutations and when this occurs management can be challenging. Here, we report on a case with challenges faced by the pathologist and clinicians alike in diagnosis and management of PCC recurrence.

ODP042 Hereditary Pheochromocytoma with a Novel Mutation in the Succinate Dehydrogenase Subunit A gene

Abstract Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumorswith a diverse clinical presentation. Pathogenic variants in the genes encoding different subunits of the succinate dehydrogenaseenzyme complex that plays a central role in energy metabolism,have been linked to hereditary PPGL syndromes. Here wereport a rare case of hereditary pheochromocytoma with a novel mutation in the succinate dehydrogenase subunit A (SDHA) gene. A middle aged woman presented with left sided abdominal pain and was incidentally found to have bilateral adrenal lesions on abdominal imaging. She denied any symptoms of catecholamine excess but her plasma metanephrines level was elevated. Family history was significant for breast cancer in her motherand sister. Computed tomography (CT) scan of the abdomen showed bilateralbulky adrenal glands with a lesion in theleft adrenal gland. Magnetic resonance imaging (MRI) abdomen was performed for further characterization, the lesion measured approximately 2.8×2.6 cm with imaging characteristics suggestive of pheochromocytoma. Iodine-131 Metaiodobenzylguanidine (MIBG) whole body scan showed abnormal focal radiotracer uptake at the left adrenal gland, and she then underwentleft sided robotic adrenalectomy. Following surgery, the patient had symptomatic relief. Histopathology confirmed the diagnosis of pheochromocytoma measuring 2×2×1.5 cm with PASS (Pheochromocytoma of the Adrenal gland Scaled Score) score of 1/10, due to cellular monotony. Genetic testing revealed that she was positive for a pathogenic mutation in the SDHA gene consistent with the diagnosis of hereditary PPGL syndrome. Genetic testing was performed for the patient due to her presentation with bilateral adrenal masses and family history of cancers. Guidelines recommend genetic testing for patients with features that indicate a high likelihood of a hereditary cause for PPGL, including positive family history, syndromic features, and multifocal, bilateral, or metastatic disease. SDHA mutated PPGLs have diverse phenotypes and may be at high risk of metastasis. They are also associated with extra-adrenal tumors, include gastrointestinal stromal tumours (GIST), pituitary adenomas, papillary thyroid carcinoma, renal carcinoma and breast carcinoma. The detection of susceptibility genes for hereditary PPGL syndromes has key implications, for surveillance to detectextra-adrenal disease and recurrent tumors, as well as for consideration of genetic testing forfamily members. Presentation: No date and time listed

PSAT015 A Rare Case of Incidental Massive Pheochromocytoma with Ectopic Parathyroid Hormone Secretion

Abstract Background Pheochromocytoma (PC) is a rare neuroendocrine tumor with an annual incidence of 2 to 8 cases per million that can secrete excess catecholamines precipitating hyper-adrenergic symptoms. In rarer instances, PCs can also secrete substances other than catecholamines. Case A 51-year-old female underwent MRI lumbar spine that demonstrated an incidental 13 cm right adrenal mass. History was significant for newly diagnosed hypertension and a five-year history of episodic headaches, diaphoresis, palpitations and anxiety. A previous cardiac evaluation including Holter monitor, echocardiogram, and stress test was unrevealing. Physical exam was significant only for chronic back pain and BMI 20.4. Labs revealed elevated serum catecholamines with metanephrines and normetanephrines &amp;gt;40x and &amp;gt;65x the upper limit of normal respectively, elevated urine catecholamines and elevated chromogranin A suggestive of PC. Labs also demonstrated mild hypercalcemia &amp;gt;10.3 mg/dL (8.6-10.4 mg/dL) with elevated PTH 78 pg/mL (14-64 pg/mL) and low vitamin D 25-OH 25 ng/mL (30-100 ng/mL). Calcitonin, albumin and phosphorus were normal. She was treated with non-competitive alpha and beta-blockade and metyrosine before undergoing successful right adrenalectomy. Post-operative labs demonstrated normalization of catecholamines, PTH and calcium. Surgical pathology confirmed the diagnosis of PC and demonstrated tumor cells which stained for PTH confirming ectopic PTH secretion, a rare phenomenon. The PC was very large with an elevated PASS (Pheochromocytoma of the Adrenal Gland Scaled Score) indicating increased risk for malignancy/recurrence; however, there was low Ki-67 activity and no capsular involvement, which suggested benign behavior. Furthermore, an MIBG scan was negative for metastatic disease, and an extensive genetic workup for familial PC/PGL (including MEN, RET, SDHx) was negative. Conclusion PC is a rare neuroendocrine tumor that can secrete excess catecholamines precipitating hyper-adrenergic symptoms and potentially fatal complications including hypertensive crises, cardiovascular disease, ischemia and multi-organ failure if untreated. Consequently, early recognition of PCs is imperative. The patient in this case had a five-year history of symptoms seen with PC and newly diagnosed hypertension despite normal BMI and negative cardiac workup. However, she had no evaluation for secondary causes of hypertension. Despite the large tumor size and significantly elevated catecholamines, she functioned without significant morbidity potentially due to adrenergic receptor desensitization. This case also highlights the rare phenomenon of ectopic secretion in PCs, specifically ectopic PTH secretion. A 2019 systemic review identified only 150 cases of pheochromocytomas/paragangliomas with ectopic hormone secretion – of those, only 17 secreted PTH or PTH-related peptide [1]. It is important to consider ectopic secretion in patients with PCs as they may have additional clinical manifestations associated with the hormone or substance secreted. Fortunately, this patient had no overt manifestations of hyperparathyroidism or hypercalcemia.

Pheocromocytoma of Adrenal gland - A Rare Tumor: Case Series

Pheochromocytoma is a rare neoplasm arises from adrenal medulla composed of chromaffin cells that produce catecholamines. Most are sporadic tumors that present in the fourth and fifth decade of life. Classic triad of episodic headaches, sweating and tachycardia present in about 30%, while hypertension is present in almost 90 % of cases. Clinical suspicion with laboratory testing and imaging for confirmation. Histopathological examination is gold standard, but no single biomarker or histologic feature predicts malignancy. Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) provides prognosis based on histologic features. Five patients of pheochromocytoma with PASS score are described with the aim to represent a rare neoplasm. They are positive for chromogranin, synaptophysin and S100. Keywords: Pheochromocytoma, Adrenal gland, PASS

Computerized tomography texture analysis of pheochromocytoma: relationship with hormonal and histopathological data

ObjectivesPheochromocytomas are rare tumors which can present with heterogeneous secretion profiles, clinical manifestations, and radiologic appearance. Under a histopathological point of view, they can be characterized as more or less aggressive with the Pheochromocytoma of the Adrenal gland Scaled Score (PASS) and the Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP) score. The aim of this study is to analyze the texture analysis characteristics of pheochromocytoma and identify whether the texture analysis can yield information aiding in the diagnosis and the characterization of those tumors.MethodsRadiological, biochemical, and histopathological data regarding 30 consecutive patients with histologically confirmed pheochromocytoma were analyzed. Images obtained in the unenhanced, late arterial, venous, and delayed phases were used for the texture analysis.ResultsUrinary epinephrine and metanephrine levels showed a significant correlation (R2 = 0.946; R2 = 699) in the multivariate linear model with texture features, as well as Ki-67 (R2 = 0.397), PASS score (R2 = 0.182), GAPP score (R2 = 0.705), and cellularity showed a significant correlation (R2 = 0.389). The cluster analysis based on radiomic features resulted in 2 clusters, with significative differences in terms of systolic and diastolic blood pressure values at the time of diagnosis (p = 0.025), GAPP score (4 vs 6, p = 0.05), histological pattern (1–2, p = 0.039), and comedonecrosis (0% vs 50%, p = 0.013).ConclusionIn conclusion, our study provides the proof of concept for the use of texture analysis on contrast-enhanced CT images as a noninvasive, quantitative tool for helping in the characterization of the clinical, biochemical, and histopathological features of pheochromocytoma.

Development and internal validation of a predictive model for the estimation of pheochromocytoma recurrence risk after radical surgery.

Various features have been identified as predictors of relapse after complete resection of pheochromocytoma, but a comprehensive multivariable model for recurrence risk prediction is lacking. The aim of this study was to develop and internally validate an integrated predictive model for post-surgical recurrence of pheochromocytoma. The present research retrospectively enrolled 177 patients affected by pheochromocytoma and submitted to radical surgery from 1990 to 2016, in nine referral centers for adrenal diseases. Cox regression analysis was adopted for model development, and a bootstrapping procedure was used for internal validation. Variables independently associated with recurrence were tumor size (hazard ratio (HR): 1.01, 95% CI: 1.00-1.02), positive genetic testing (HR: 5.14, 95% CI: 2.10-12.55), age (HR: 0.97, 95% CI: 0.94-0.99), and Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) (HR: 1.16, 95% CI: 1.04-1.29). The predictive performance of the overall model, evaluated by Somers' D, was equal to 0.594, and was significantly higher than the ones of any single predictor alone (P = 0.002 compared to tumor size; P = 0.004 compared to genetic testing; P = 0.048 compared to age; P = 0.006 compared to PASS). Internal validation by bootstrapping techniques estimated an optimistic bias of 6.3%, which reassured about a small tendency towards overfit. We proposed a multivariable model for the prediction of post-surgical recurrence of pheochromocytoma, derived by the integration of genetic, histopathological, and clinical data. This predictive tool may be of value for a comprehensive tailoring of post-surgical follow-up in radically operated pheochromocytoma patients.

Histopathological Analysis of Tumor Microenvironment and Angiogenesis in Pheochromocytoma.

Pheochromocytomas (PHEOs) are relatively rare catecholamine-producing tumors derived from adrenal medulla. Tumor microenvironment (TME) including neoangiogenesis has been explored in many human neoplasms but not necessarily in PHEOs. Therefore, in this study, we examined tumor infiltrating lymphocytes (CD4 and CD8), tumor associated macrophages (CD68 and CD163), sustentacular cells (S100p), and angiogenic markers (CD31 and areas of intratumoral hemorrhage) in 39 cases of PHEOs in the quantitative fashion. We then compared the results with pheochromocytoma of the adrenal gland scaled score (PASS), grading system for pheochromocytoma and paraganglioma (GAPP) and the status of intra-tumoral catecholamine-synthesizing enzymes (TH, DDC, and PNMT) as well as their clinicopathological factors. Intratumoral CD8 (p = 0.0256), CD31 (p = 0.0400), and PNMT (p = 0.0498) status was significantly higher in PHEOs with PASS <4 than PASS ≧4. In addition, intratumoral CD8+ lymphocytes were also significantly more abundant in well-than moderately differentiated PHEO according to GAPP score (p = 0.0108) and inversely correlated with tumor size (p = 0.0257). Intratumoral CD68+ cells were significantly higher in PHEOs with regular or normal histological patterns than those not (p = 0.0370) and inversely correlated with tumor size (p = 0.0457). The status of CD163 was significantly positively correlated with that of CD8 positive cells (p = 0.0032). The proportion of intratumoral hemorrhage areas was significantly higher in PHEOs with PASS ≧4 (p = 0.0172). DDC immunoreactivity in tumor cells was significantly positively correlated with PASS score (p = 0.0356) and TH status was significantly higher in PHEOs harboring normal histological patterns (p = 0.0236) and cellular monotony (p = 0.0219) than those not. Results of our present study did demonstrate that abundant CD8+ and CD68+ cells could represent a histologically low-scored tumor. In particular, PHEOs with increased intratumoral hemorrhage should be considered rather malignant. In addition, abnormal catecholamine-producing status of tumor cells such as deficient PNMT and TH and increased DDC could also represent more aggressive PHEOs.

Predicting Metastatic Potential in Pheochromocytoma and Paraganglioma: A Comparison of PASS and GAPP Scoring Systems.

The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP) are scoring systems to predict metastatic potential in pheochromocytomas (PCC) and paragangliomas (PGLs). The goal of this study is to assess PASS and GAPP as metastatic predictors and to correlate with survival outcomes. The cohort included PCC/PGL with ≥5 years of follow-up or known metastases. Surgical pathology slides were rereviewed. PASS and GAPP scores were assigned. Univariable and multivariable logistic regression, Kaplan-Meier survival analysis, and Cox proportional hazards were performed to assess recurrence-free survival (RFS) and disease-specific survival (DSS). From 143 subjects, 106 tumors were PCC and 37 were PGL. Metastases developed in 24%. The median PASS score was 6.5 (interquartile range [IQR]: 4.0-8.0) and median GAPP score was 3.0 (IQR: 2.0-4.0). Interrater reliability was low-moderate for PASS (intraclass correlation coefficient [ICC]: 0.6082) and good for GAPP (ICC 0.7921). Older age (OR: 0.969, P = .0170) was associated with longer RFS. SDHB germline pathogenic variant (OR: 8.205, P = .0049), extra-adrenal tumor (OR: 6.357, P < .0001), Ki-67 index 1% to 3% (OR: 4.810, P = .0477), and higher GAPP score (OR: 1.537, P = .0047) were associated with shorter RFS. PASS score was not associated with RFS (P = .1779). On Cox regression, a GAPP score in the moderately differentiated range was significantly associated with disease recurrence (HR: 3.367, P = .0184) compared with well-differentiated score. Higher GAPP scores were associated with aggressive PCC/PGL. PASS score was not associated with metastases and demonstrated significant interobserver variability. Scoring systems for predicting metastatic PCC/PGL may be improved by incorporation of histopathology, clinical data, and germline and somatic tumor markers.

Long-term outcomes of abdominal paraganglioma

PurposeParagangliomas (PGL) are rare neuroendocrine tumors derived from chromaffin cells of the autonomic nervous system. We aim to describe our experience and the long-term outcome of abdominal PGL over the last decade.MethodsA retrospective review of patients diagnosed with PGL in our hospital between November 2005 and June 2017 was conducted. All nonabdominal PGL were excluded and the clinicopathological features and long-term outcomes of the patients were analyzed.ResultsA total of 46 patients were diagnosed with abdominal PGL. The average age of diagnosis was 55.4 years and there was no sex predilection. The average tumor size was 5.85 cm and they were predominantly located in the infrarenal position (50%). The mean follow-up period was 42 months (range, 1.8–252 months). All patients with metastases had Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) of ≥4. One patient presented with synchronous metastases while 2 developed local recurrence and distant metastases. One presented with only local recurrence. One patient died 5 years after diagnosis.ConclusionAbdominal PGL is a rare tumor with excellent long-term prognosis. Recurrence although uncommon, can occur decades after initial diagnosis. Long-term follow-up is therefore recommended for all patients with PGL, especially in patients with PASS of ≥4.

Retrospective application of the pathologic tumor-node-metastasis classification system for pheochromocytoma and abdominal paraganglioma in a well characterized cohort with long-term follow-up

BackgroundA pathologic tumor-node-metastasis staging algorithm for pheochromocytoma and sympathetic paraganglioma was introduced recently in the 8th Edition of the cancer staging manual of the American Joint Committee on Cancer. There is no information, however, as to how this staging correlates to well-established clinical cohorts of pheochromocytoma and sympathetic paraganglioma with extensive follow-up. MethodsWe applied the pathologic tumor-node-metastasis staging retrospectively to a cohort of 118 patients with pheochromocytoma and sympathetic paraganglioma, in which the majority has been characterized for susceptibility gene mutations and global mRNA expressional patterns as well as histologic risk criteria using the pheochromocytoma of the adrenal gland scaled score (PASS). ResultsThe overall tumor stage correlated with the presence of metastases, disease-related death, and PASS scores as well as established mutational and expressional clusters. ConclusionStage III to IV pheochromocytomas and sympathetic paragangliomas are associated with increased mortality, increased PASS scores, and mutational and expressional aberrancies in the pseudo-hypoxia pathway cluster. These findings validate the stratification proposed by the American Joint Committee on Cancer staging manual by linking malignancy-associated pheno- and genotypes to more advanced stages. Moreover, because few pheochromocytomas and sympathetic paragangliomas are metastatic at the time of the original presentation, the staging relies heavily on identifying histologic signs of extra-adrenal invasion.