Hereditary Paraganglioma-pheochromocytoma Syndrome Research Articles

7204 An Unexpected Cause of Ga-68 Dotatate PET/CT Somatostatin Receptor Avidity in a Pediatric Patient with Hereditary Paraganglioma-Pheochromocytoma Syndrome due to an SDHA Mutation

Abstract Disclosure: K. Leopold: None. S. Polites: None. L. Binkovitz: None. L. Casas: None. A.N. Lteif: None. Title: An Unexpected Cause of Ga-68 Dotatate PET/CT Somatostatin Receptor Avidity in a Pediatric Patient with Hereditary Paraganglioma-Pheochromocytoma Syndrome due to an SDHA Mutation. Introduction: Individuals with Succinate Dehydrogenase (SDHx) gene mutations have an increased risk of paragangliomas and pheochromocytomas beginning in childhood.Clinical Case: A 9 year old male with Cornelia de Lange syndrome and a paternally inherited SDHA pathogenic gene variant (c1534C>T) presented with worsening migraine headaches and skin pallor with activity. 24 hour urine fractionated metanephrines were mildly elevated, with metanephrine 122 mcg/24h (29-92 mcg/24 h), normetanephrine 187 mcg/24 h (34-169 mcg/24 h), and total metanephrine 309 mcg/24 h (47-223 mcg/24 h). Ga-68 DOTATATE PET/CT showed a focus of moderately increased radiotracer activity in the anterior aspect of the distal gastric antrum with a max SUV 8.2 corresponding to a 9x7 mm nodule on CT in the same area, suggestive of underlying somatostatin receptor positive lesion such as a paraganglioma. MRI with contrast completed to further characterize the lesion showed no visible mass corresponding to the focal area of radiotracer uptake on DOTATATE PET/CT. Repeat 24 h urine metanephrines continued to show mild elevation of metanephrine (138 mcg/24h), normetanephrine (200 mcg/24h), and total metanephrines (338 mcg/24h). 24 hour urine catecholamines, 5-Hydroxyindoleacetic acid, and homovanillic acid were normal. An upper endoscopic ultrasound was completed which confirmed the presence of a lesion near the stomach but not arising from the stomach wall and not consistent with a gastrointestinal stromal tumor. CT enterography with IV contrast showed a 6x6 mm enhancing mass within the distal right lateral gastric wall. Due to ongoing symptoms, mild elevations in urine fractionated metanephrines, and a clear mass on US and CT, the patient underwent laparoscopic abdominal exploration where a 14x14x13 mm mass with surrounding gastric and duodenal serosa was excised with primary closure of the bowel. Pathology showed ectopic pancreatic tissue in the wall of the small bowel and stomach. Repeat Ga-68 DOTATATE PET/CT 5 months following surgery showed resolution of the distal gastric somatostatin receptor avidity. Clinical Lesson: This is the first case of ectopic pancreatic tissue mimicking a paraganglioma in a pediatric patient with hereditary paraganglioma-pheochromocytoma syndrome. False positive imaging should be considered in patients with SDHx mutations when the uptake is atypical in location and when the elevation in urine metanephrines is mild. Presentation: 6/3/2024

Advancing Precision Oncology in Hereditary Paraganglioma-Pheochromocytoma Syndromes: Integrated Interpretation and Data Sharing of the Germline and Tumor Genomes.

Standard methods of variant assessment in hereditary cancer susceptibility genes are limited by the lack of availability of key supporting evidence. In cancer, information derived from tumors can serve as a useful source in delineating the tumor behavior and the role of germline variants in tumor progression. We have previously demonstrated the value of integrating tumor and germline findings to comprehensively assess germline variants in hereditary cancer syndromes. Building on this work, herein, we present the development and application of the INT2GRATE|HPPGL platform. INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) is a multi-institution oncology consortium that aims to advance the integrated application of constitutional and tumor data and share the integrated variant information in publicly accessible repositories. The INT2GRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma-pheochromocytoma syndromes (HPPGLs). Using INT2GRATE|HPPGL, we analyzed 8600 variants in succinate dehydrogenase (SDHx) genes and their associated clinical evidence. The integrated evidence includes germline variants in SDHx genes; clinical genetics evidence: personal and family history of HPPGL-related tumors; tumor-derived evidence: somatic inactivation of SDHx alleles, KIT and PDGFRA status in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status for SDHA and SDHB genes. After processing, 8600 variants were submitted programmatically from the INT2GRATE|HPPGL platform to ClinVar via a custom-made INT2GRATE|HPPGL variant submission schema and an application programming interface (API). This novel integrated variant assessment and data sharing in hereditary cancers aims to improve the clinical assessment of genomic variants and advance precision oncology.

Five-Fraction Stereotactic Radiation for Head and Neck Paragangliomas

Paragangliomas of the head and neck (HN) are benign, slow-growing neoplasms that are rarely functional. Treatment is often indicated for patients presenting with mass effect, cranial neuropathies, or pulsatile tinnitus. Radiotherapy, traditionally conventionally fractionated, is often used for primary, post-operative, and salvage therapy, given its excellent control rates and reduced risks to adjacent neurovascular structures. Stereotactic ablative radiation (SAbR) offers shorter treatment time, and modern techniques eliminate margins to improve organ-at-risk avoidance. SAbR may offer additional radiobiological sparing of normal structures over single-fraction SAbR. We aimed to evaluate tumor and symptom response, acute and late toxicity rates, and recurrence patterns in HN paraganglioma patients treated with 25 Gy in 5 fractions. Retrospective chart review collected baseline patient and tumor information, treatment and dosimetry details, acute and long-term toxicity grades (per the CTCAE v. 5.0), symptom and tumor response, and survival. Local control was defined as the absence of local enlargement (per RECIST v. 1.1) or marginal failure and was estimated using the Kaplan-Meier method. Between December 2009-March 2020, 39 patients received 25 Gy in 5 fractions to 43 HN paragangliomas, of which 17 were treated in 11 patients with hereditary paraganglioma-pheochromocytoma syndrome. Fifteen targets were post-operative recurrent or residual tumors. There were 27 jugulotympanic tumors, 4 jugular, 1 tympanic, 8 vagal, 5 carotid body, and 2 jugulotympanic or vagal. Median follow-up time was 3.3 years (range 0-11.4 years), and 21 targets had at least 4 years of follow-up. Tumor volume decreased by a median of 37%. Three-year local control was 100%. One patient, known to harbor an SDHD mutation, had 2 out-of-field recurrences within the post-operative bed at 7.1 years. Two patients experienced 2 marginal recurrences within the post-operative bed at 6.1 and 8.4 years: one had an SDHB mutation and developed metastatic disease, and the other did not have genetic testing. The most common grade 1-2 acute toxicities were headache and fatigue; the most common grade 1-2 late toxicities were dysphagia and otalgia. There were no grade >2 acute toxicities. A late grade 3 aspiration event was seen in 1 patient who presented with paralyzed vocal cord requiring multiple medialization laryngoplasties. Within 6 months of SAbR, 18% of symptoms or toxicities improved or resolved; 34% improved or resolved more than 6 months after SAbR. This is the largest series of HN paragangliomas treated with SAbR, detailing a 10-year experience with a 5-fraction regimen that is well-tolerated and achieves excellent local control. Post-SAbR recurrences occurred outside of the radiation field but within the post-operative bed, suggesting that some post-operative patients may benefit from expanded radiation volumes or close surveillance for salvage therapy.

P060: Spectrum of genetic alterations for hereditary paraganglioma-pheochromocytoma syndrome testing: Eight-year experience from a single diagnostic laboratory

P060: Spectrum of genetic alterations for hereditary paraganglioma-pheochromocytoma syndrome testing: Eight-year experience from a single diagnostic laboratory

An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes.

Genomic profiles of tumors are often unique and represent characteristic mutational signatures defined by DNA damage or DNA repair response processes. The tumor-derived somatic information has been widely used in therapeutic applications, but it is grossly underutilized in the assessment of germline genetic variants. Here, we present a comprehensive approach for evaluating the pathogenicity of germline variants in cancer using an integrated interpretation of somatic and germline genomic data. We have previously demonstrated the utility of this integrated approach in the reassessment of pathogenic germline variants in selected cancer patients with unexpected or non-syndromic phenotypes. The application of this approach is presented in the assessment of rare variants of uncertain significance (VUS) in Lynch-related colon cancer, hereditary paraganglioma-pheochromocytoma syndrome, and Li-Fraumeni syndrome. Using this integrated method, germline VUS in PMS2, MSH6, SDHC, SHDA, and TP53 were assessed in 16 cancer patients after genetic evaluation. Comprehensive clinical criteria, somatic signature profiles, and tumor immunohistochemistry were used to re-classify VUS by upgrading or downgrading the variants to likely or unlikely actionable categories, respectively. Going forward, collation of such germline variants and creation of cross-institutional knowledgebase datasets that include integrated somatic and germline data will be crucial for the assessment of these variants in a larger cancer cohort.

Abstract #1135270: MAX Gene Mutation: A New Marker for Multiple Endocrine Neoplasia Syndrome

The novel germline MAX (MYC-associated factor X) gene mutation is a known cause of hereditary paraganglioma-pheochromocytoma syndrome. Here we describe a novel case suggesting a link between Multiple Endocrine Neoplasia and MAX mutation.

A Four-Generational Report on Hereditary Head and Neck Paraganglioma.

BackgroundThis article investigates the inheritance, penetrance, clinical presentation, and therapeutic outcomes of hereditary head and neck paragangliomas (HNPGLs) by offering a four-generational report of an 18-member family affected by this rare condition.MethodologyInformation was compiled by examination of patients and a review of medical records and correspondence (retrospective case series).ResultsSix members of the 18-member family were diagnosed with HNPGL between 2002 and 2018. A known pathogenic point mutation in subunit D of the succinyl dehydrogenase complex (SDHD, c.317G>T, p.Gly106Val) was responsible for the tumor phenotype. The mutation could be revealed in seven family members, three diseased adults, one healthy adult, and three healthy children, out of the nine who consented to gene testing. The median age at diagnosis was 33.5 years (range: 22-50 years). Five of the eight primary tumors were glomus caroticum, two were glomus jugulare, and one was a glomus vagale tumor. The therapeutic approaches were multimodal and included embolization therapy, surgery, radiation, and watchful waiting. Follow-up was reported for five of the six patients (mean follow-up of 34.8 months after primary therapy); three showed no disease progression or recurrence.ConclusionsThis study exemplifies the autosomal dominant, parent-of-origin-dependent inheritance and the high disease penetrance in hereditary paraganglioma-pheochromocytoma syndromes. Six out of a total of eight adult descendants (75%) of the original SDHD mutation carrier developed tumors, and the morbidity associated with the disease as well as its therapy was especially high in late-diagnosed, advanced cases. This substantiates the necessity for early radiologic surveillance and genetic testing.

Synchronous bilateral pheochromocytomas and extra-adrenal paragangliomas without specific gene mutations

Abstract Introduction/Objective Diagnosis of hereditary paraganglioma-pheochromocytoma syndrome (H-PGL/PCC-S) should be suspected in individuals with pheochromocytoma or paraganglioma, especially those with multifocal lesions, positive family history, or early-onset disease. Recent studies suggest one-third to half of these patients have germline/syndromic associations. We present a challenging case wherein a 44-year-old female with high-risk factors, multiple paragangliomas, and bilateral pheochromocytomas did not have any identifiable syndromic involvement. Methods/Case Report Patient presented seven years ago with epigastric pain, weight loss of 50lbs, and chronic diarrhea. Endoscopic ultrasound revealed 2cm hypoechoic mass behind pancreas, diagnosed as neuroendocrine tumor on fine-needle aspiration. Subsequent SPECT-CT and MRI revealed multiple intra-abdominal lesions, including bilateral adrenal-lesions (right 2cm; left 1.6cm), 2.2cm aortocaval-lesion, and multifocal retroperitoneal lesions, consistent with paragangliomas, gradually increasing in size on follow-up imaging. She also developed intermittent palpitations, flushing, and blood pressure fluctuations. Additionally, multiple thyroid nodules were identified on subsequent ultrasound imaging, suspicious for malignancy on both cytology and Afirma studies. Exploratory laparotomy with left para-adrenal, right infra-renal, and aortocaval nodule-excisions revealed nested tumor cells with abundant granular purple cytoplasm, round central nuclei, prominent nucleoli, diagnosed as moderate to poorly differentiated extra-adrenal paragangliomas with increased metastatic risk based on PASS and GAPP-scoring systems. Additionally, right adrenalectomy revealed pheochromocytoma with 7/20 PASS-score and 4/10 GAPP-score suggesting increased metastatic risk. Results (if a Case Study enter NA) NA Conclusion Young age, strong family-history, multiple high-grade paragangliomas, pheochromocytomas, and suspicious thyroid nodules raise concerns for syndromic association. Multitude of autosomal-dominant syndromes, including paraganglioma-syndromes (PGL1-to PGL5), VHL, MEN2A, MEN2B, and NF1, have been reported. Genes identified in these syndromes include SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX, TMEM127, VHL, NF1, RET, FH, and KIF1B. However, no mutations were identified, thus creating a dilemma in risk-stratification. This leaves out only two considerations: either sporadic PGL/PCC or a yet unidentified genetic-mutation.

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

Abstract #1022216: MAX Gene Mutation: New Marker for Multiple Endocrine Neoplasia Syndrome?

The novel germline MAX (MYC-associated factor X) gene mutation is a known cause of hereditary paraganglioma-pheochromocytoma syndrome. Here we describe a novel case suggesting a link between Multiple Endocrine Neoplasia and MAX mutation.

Presyncope Leading to the Diagnosis of Gastrointestinal Stromal Tumor in a Pediatric Patient.

A 16-year-old African American girl presented after a presyncopal event. Initial evaluation revealed anemia (hemoglobin 5.2 mmol/L) and positive stool hemoccult. Esophagogastroduodenoscopy revealed an ulcerated, bleeding, submucosal mass (Fig. 1). Bleeding was controlled with argon plasma coagulation. Abdominal computed tomography showed a heterogenous 6.8 cm mass at the serosal surface of the lesser curvature. Neck and thorax computed tomography did not show metastases. Endoscopic ultrasound with fine needle biopsy (Fig. 2) revealed histology consistent with a gastrointestinal stromal tumor (GIST). Laparotomy was performed with complete resection of the mass. Pediatric GISTs are rare and they account for about 1% of all GISTs (1). When suspected, endoscopic biopsy, either core needle or forceps biopsy, is the preferred method to prevent tumor spillage which is highly associated with GIST recurrence (2). Pediatric GISTs usually lack KIT or PDGFRA gene mutations, making them wild-type GISTs (3). In this case, genetic testing revealed associations with hereditary paraganglioma-pheochromocytoma syndromes (4). Prognosis is based on the mitotic rate, tumor size, and tumor site; gastric site being the most favorable (5). MRI after surgery showed no residual tumor. The patient will continue close monitoring via annual MRI, which is the preferred modality for surveillance (6).FIGURE 1: Endoscopic photograph showing a bleeding submucosal mass.FIGURE 2: Endoscopic ultrasound of the mass while obtaining fine needle biopsy.

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma–pheochromocytoma syndrome

PurposeMinimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma–pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols. MethodsA multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing. ResultsTwo hundred sixty-three individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n=188/263, 72%), followed by SDHD (n=35/263, 13%) and SDHC (n=28/263, 11%). SDHx-related tumors were found in 17% (n=45/263) of the cohort. Most SDHx-related tumors were identified on baseline imaging screen (n=39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n=14/35, 40%). Of imaging screens identifying SDHx-related paraganglioma/pheochromocytoma, 29% (n=12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n=75/491) of imaging screens. ConclusionCurrent SDHx screening protocols are effective at identifying SDHx-related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.

Tumor detection rates in screening carriers with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome based on prior tumor history.

1545 Background: Patients with germline pathogenic variants (PVs) in the SDHx genes have increased risk for paragangliomas/pheochromocytomas (PGL/PCC), renal cell carcinomas, and gastrointestinal stromal tumors. Expert recommendation suggests individuals with SDHx PVs undergo biennial whole-body imaging and annual biochemical testing. This study aimed to evaluate tumor detection rate using standard biochemical and imaging protocols for individuals with SDHx PVs, particularly in those with and without SDHx-related tumor history, and in those with biochemical testing data. Methods: A retrospective longitudinal observational study at the Universities of Michigan, Pennsylvania, and Utah Huntsman Cancer Institute was conducted from the start of each center’s screening program through March 1, 2018. Individuals with SDHx PVs had clinical imaging with whole body MRI/CT and biochemical testing per expert recommendation. SDHx-related tumors identified during clinical screening were measured. Results: A total of 263 individuals with SDHx PVs completed 491 screens. Individuals with SDHB PVs were the most prevalent (n = 188, 71.5%). The average number of screens per subject was 1.87 (range 1-7). A majority (n = 194, 73.7%) of individuals did not have a prior history of PGL/PCC. Overall, SDHx-related tumors were detected in 17.1% (n = 45) of the cohort. Of the 46 scans that identified an SDHx-related tumor, 85% of them (n = 39) were baseline scans. SDHx-related tumors were identified in 18.6% (n = 36/194) of individuals that did not have a prior history of PGL/PCC, whereas they were identified in 13.0% (n = 9/69) of individuals that did have a prior history of PGL/PCC (p = 0.39). Biochemical testing was available for 70% (n = 343) of imaging screens, of which 18% (n = 61) had positive biochemistry. Of those with positive biochemistry, 19 tumors were identified on imaging (6%). Sixteen tumors were identified on imaging with negative biochemistry (5%) with a sensitivity of 54% and a specificity of 94%. Utilizing a cut-off of two times the upper limit of normal, 9.91% (n = 34) biochemical tests were positive, and 15 (44.12%) had an SDHx-related tumor on corresponding imaging. Conclusions: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumors were detected in subjects with a prior history of PGL/PCC and those with no prior history. This suggests life-long screening is important for all SDHx carriers. Imaging is a crucial piece of SDHx screening given biochemical testing’s sensitivity and specificity.

MON-249 SDHD Mutation: Nonfunctional Paragangliomas Presenting as Bilateral Carotid Body Tumors with Syncope

SDHD Mutation: Nonfunctional paragangliomas presenting as bilateral carotid body tumors with syncopeBackground:A mutation of the SDHD gene is associated with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes which most commonly originate in the head and neck region, and usually form in the carotid body. Paragangliomas (PGL) can be secretory or non-secretory with about 95% of head and neck PGL being non-secretory. They can rarely present with symptoms due to compression, however, as in this case of a 29 year-old female presenting with syncope.Clinical Case:A 29 year-old female presented for evaluation after syncope. She had a syncopal event and fell down while walking in her home. Syncope was preceded by about 15 minutes of flushing, nausea and palpitations. She reported similar episodes once weekly in the preceding months, which generally lasted an hour. Initial workup included normal vital signs at presentation, normal ECG and echocardiogram, normal TFT, CBC, complete metabolic panel. Subsequent head/neck CT revealed bilateral masses in the carotid bifurcations consistent with carotid body tumors. Further history revealed a family history of bilateral carotid body tumors in her father which had never been evaluated. Plasma and urine metanephrines were normal. She underwent carotid body tumor excision. The left carotid body tumor was successfully excised and pathology revealed a paraganglioma with positive synaptophysin and chromogranin stains. Genetic testing revealed an SDHD (succinate dehydrogenase complex subunit D) gene mutation. Repeat biochemical assessment 4 months later was again negative and patient remained asymptomatic postoperatively.Conclusion:Paragangliomas can be secretory or non-secretory with about 95% of head and neck paragangliomas being non-secretory, as in this case. Symptoms can arise from catecholamine hypersecretion, which generally presents as hypertension, headaches, diaphoresis, flushing, anxiety or palpitations, and can be episodic or sustained, or mass effect. Syncope as a presenting symptom is rare, however, and has not been quantified but only reported in case reports. The exact etiology of syncope in our patient is not clear. Hereditary PGL/PCC syndromes should be suspected in any individual with multiple, recurrent, early-onset (age less than 45 years) or family history of PGL/PCC, as these syndromes are inherited in an autosomal dominant manner.

MON-377 Hereditary Paraganglioma Pheochromocytoma Syndrome in the Setting of End Stage Renal Disease

Pheochromocytomas and Paragangliomas represent rare catecholamine producing tumors of the adrenal gland or sympathetic/parasympathetic nervous system respectively. These can arise de novo or can result from genetically inherited mutations that predispose their origin. Overall these are rare tumors that can range from being asymptomatic to have symptoms related to excess catecholamines (including labile hypertension). While labile blood pressure is often associated with end stage renal disease (ESRD), pheochromocytoma/paragangliomas as cause of this are very rare with only 30 cases being reported in the literature. We report the case of a hereditary paraganglioma in a patient with ESRD. The patient is a 19 year old man with a history of ESRD secondary to hypoplastic kidneys and hypertension. He had initial presented to the hospital with shortness of breath in the setting of missing hemodialysis (HD). He received a session of HD in the emergency department without improvement and was placed on BIPAP. As part of his admission workup he had a CT of his chest which was negative for PE but did show a 5.3 by 3.5 by 4.7 cm left periaortic mass. Suspicion for possible paraganglioma was raised in the setting of difficult to control blood pressure along with his reported symptoms of palpitations and periodic sweats. Plasma metanephrines drawn after HD revealed an elevated normetanephrine of 28 nmol/L (<0.90 nmol/L) and plasma catecholamines were elevated with a norepinephrine of 17,928 pg/ml ( 70-750 pg/ml while supine or 200-1700 pg/ml while standing) and dopamine of 123 pg/ml (<30 pg/ml). He underwent metaiodobenzylguanidine (MIBG) scanning that showed abnormal radiotracer uptake in the left periaortic mass concerning for a paraganglioma. He was started on alpha-blockade and arrangements were made for surgery in several weeks time. While awaiting surgery genetic testing for hereditary paraganglioma pheochromocytoma syndrome returned positive for a variant mutation in SDHB. He underwent successful resection of his paraganglioma and was able to come off of his blood pressure medications. Postoperative testing showed normalization of his plasma metanephrines and catecholamines and arrangements were made for his siblings to undergo genetic testing. This case represents a relatively rare presentation of a paraganglioma in a patient with ESRD. The typical diagnostic workup for a paraganglioma can often not be pursued as 24 hour urine catecholamines can often not be collected as patients are often anuric/oliguric so plasma catecholamines must be pursued. Clinicians must be aware that those on HD can naturally have elevated catecholamines as a result of sympathetic nervous system activation from fluid shifting. Studies have shown that these values never exceed more than 3 times the upper limit of normal as a result of HD and values beyond that should raise suspicion for a paraganglioma or pheochromocytoma.

Whole-body magnetic resonance imaging (WB-MRI) in oncology: recommendations and key uses.

The past decade has witnessed a growing role and increasing use of whole-body magnetic resonance imaging (WB-MRI). Driving these successes are developments in both hardware and software that have reduced overall examination times and significantly improved MR imaging quality. In addition, radiologists and clinicians have continued to find promising new applications of this innovative imaging technique that brings together morphologic and functional characterization of tissues. In oncology, the role of WB-MRI has expanded to the point of being recommended in international guidelines for the assessment of several cancer histotypes (multiple myeloma, melanoma, prostate cancer) and cancer-prone syndromes (Li-Fraumeni and hereditary paraganglioma-pheochromocytoma syndromes). The literature shows growing use of WB-MRI for the staging and follow-up of other cancer histotypes and cancer-related syndromes (including breast cancer, lymphoma, neurofibromatosis, and von Hippel-Lindau syndromes). The main aim of this review is to examine the current scientific evidence for the use of WB-MRI in oncology.

Abstract 1247: Hereditary paraganglioma-pheochromocytoma syndrome: Patterns of presentation in a Brazilian oncogenetics clinic

Abstract Introductory Sentence: More than 35% of pheochromocytomas and paragangliomas (PPGL) are thought to occur due to an underlying genetic predisposition, which explain approximately 30% of familial cases. Methods: We analyzed data of four families with clinical and molecular diagnosis of PPGL followed at Oncogenetics Department of A.C. Camargo Cancer Center, from 2010 to 2017. Results: The proband of Family 1 is a 40-year-old woman with glomus jugulare paraganglioma and confirmed SDHB mutation. Her two children have the same mutation in SDHB gene and her son had the diagnosis of retroperitoneal paraganglioma at the age 13. The brother of the index case had a pheochromocytoma and her nephew had an abdominal paraganglioma at the age of 8. In the Family 2 the index case is a 33-year-old woman with paraganglioma of the carotid body bilateral and had a molecular diagnosis with SDHB mutation. There are no other paraganglioma cases in the members of this family. Family 3 initiated counseling in our clinics with a woman with paraganglioma of the carotid body bilateral at 25-year-old with recurrence at 35-year-old and it was found in genetic test a SDHD mutation. She had two cousins with bilateral cervical paraganglioma, but without genetic testing. Our fourth family: Man with pheochromocytoma at 28-year-old and mutation in the SDHD gene. A son with metastatic phaeochromocytoma in the retroperitoneum, mediastinum and lung at 11-year-old and bilateral carotid paraganglioma at 12-year-old. Sister of the index case with glomus jugulare paraganglioma at the age of 38. Conclusions: Although PPGL are rare tumors, it is estimated that up to 30-40% of cases are hereditary, based on this it is relevant to raise the PPGL syndrome suspicion and refer a paraganglioma or pheochromocytoma patient to a cancer genetic counseling. There are clear follow-up guidelines for the early detection of these tumors in carriers and the genotype-phenotype correlation can direct the diagnosis and in some cases the management of these patients. Citation Format: Diogo C. Soares, Ana Milena G. Camacho, Maria Isabel Achatz, Maria Nirvana C. Formiga. Hereditary paraganglioma-pheochromocytoma syndrome: Patterns of presentation in a Brazilian oncogenetics clinic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1247.

The utility of SDHB and FH immunohistochemistry in patients evaluated for hereditary paraganglioma-pheochromocytoma syndromes

A significant portion of paragangliomas (PGL) and pheochromocytomas (PCC) occur in patients with hereditary PGL/PCC syndromes, including those with germline mutations in succinate dehydrogenase (SDHx) subunit genes. Recently, germline fumarate hydratase (FH) mutations have been identified in a subset of PGL/PCC, and patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) may have an increased risk of developing PGL/PCC. SDHB immunohistochemistry (IHC) has previously been shown to be useful for identifying SDHx-deficient PGL/PCC, however, FH IHC has never been explored in these tumors. Thus, we characterized SDHB and FH IHC in a large cohort of PGL/PCC patients (n = 41) at our institution who were evaluated for hereditary PGL/PCC syndromes. Overall, there was strong, positive correlation between germline SDHx subunit gene mutation status and SDHB IHC status (rφ = 0.77; P < .0001), with high corresponding sensitivity, specificity, positive predictive value, and negative predictive value (95.0%, 81.8%, 82.6%, and 94.7%, respectively). Although SDHB loss by IHC was highly correlated with germline SDHx gene mutations, its utility in this population was dependent on clinicopathologic context: while all head and neck PGL patients with SDHB-deficient tumors had germline SDHx gene mutations, only a small subset (25.0%) of PCC patients with SDHB-deficient tumors harbored a germline SDHx gene mutation. Finally, although our cohort contained only one HLRCC patient, their tumor was FH-deficient by IHC, and all other PGL/PCC showed retained FH IHC. Thus, in the appropriate clinical setting, SDHB and FH IHC may be useful for identifying PGL/PCC patients for Medical Genetics evaluation.

SY-6-1 - What should we do for better management of hereditary tumor syndromes? In the case of hereditary endocrine tumors

About 5-10％ of cancers are thought to be hereditary of which a single gene mutation is responsible for cancer development. Hereditary cancers often show different clinical courses from those of sporadic cancers. Accordingly, different clinical management can be chosen for hereditary- and sporadic cancers. Appropriate diagnosis of hereditary cancer is thus important as it enables to offer patients better and personalized management of their cancers. Also, it enables identify at-risk family members and if they have the same genetic defect as the proband, early intervention including early, and specialized surveillance and prophylactic treatment for some tumors. There are a number of hereditary endocrine tumor syndromes such as multiple endocrine neoplasia type 1 (MEN1), MEN2, von-Hippel Lindau disease, and hyperparathyroidism-jaw tumor syndrome, which manifest various endocrine- and non-endocrine tumors. Besides these, non-syndromic hereditary single tumor such as hereditary paraganglioma-pheochromocytoma syndrome, familial isolated hyperparathyroidism and familial isolated pituitary adenoma are also known. These syndromes based on the pathological germline mutation of the responsible gene and the mutation can be transmitted to the offspring. In the case of MEN2, nearly all patients develop medullary thyroid carcinoma (MTC) as early as in childhood, As about 30% of patients with MTC have MEN2 as their genetic background, all patients with MTC is strongly recommended to have genetic testing for MEN2 (RET mutation analysis). Once pathological germline mutation is detected, surgical procedure for MTC, surveillance for pheochromocytoma, and presymptomatic genetic testing for at-risk relatives are considered. In 2016, RET mutation analysis was added to the list of insurance-covered genetic testing in Japan. This will facilitate to perform testing at clinical practice which will reduce proportion of undiagnosed patients, while it could cause some complex problems related genetic counseling and family matters. All clinicians should be aware the power and impact of genetic information on clinical management and that on patients and family members.

Combined Treatment With 131I-MIBG and Sunitinib Induces Remission in a Patient With Metastatic Paraganglioma Due to Hereditary Paraganglioma-Pheochromocytoma Syndrome From an SDHB Mutation

A 22-year-old woman with rapidly progressing metastatic paraganglioma due to hereditary paraganglioma-pheochromocytoma syndrome from an SDHB mutation, who recurred after neoadjuvant chemotherapy, was found to be MIBG avid. She was treated with 2 I-MIBG treatments and concurrent sunitinib, achieving a complete response. She was in full remission for 9 months before developing bone metastases.