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Najjar ME, Naous E, Blake C, Bulut A, Perepletchikov A, Sweeney AT. Two Cases of Composite Pheochromocytoma-Ganglioneuromas With Plasma Metanephrine Levels in the Subclinical Range Pheochromocytoma-Ganglioneuroma. AACE Clin Case Rep 2025; 11:45-48. [PMID: 39896949 PMCID: PMC11784617 DOI: 10.1016/j.aace.2024.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/13/2024] [Accepted: 10/14/2024] [Indexed: 02/04/2025] Open
Abstract
Background/Objective In <10% of cases, pheochromocytomas coexist with other tumors, most commonly ganglioneuromas, and are termed composite pheochromocytoma-ganglioneuromas. We present 2 cases of composite pheochromocytoma-ganglioneuromas and review the diagnosis and management of these rare tumors. Case Report Patient 1 and patient 2 were 35-year-old and 45-year-old woman, respectively. Patient 1 presented with a history of controlled hypertension and symptoms of anxiety along with palpitations, diaphoresis, and flushing. Patient 2 complained of abdominal pain and underwent abdominal computed tomography (CT) imaging. Patient 1 and patient 2 had metanephrine levels of 76 pg/mL and 61 pg/mL (normal <57 pg/mL), respectively, and normetanephrine levels of 161 pg/mL and 116 pg/mL (normal < 148 pg/mL), respectively. CT scans depicted right adrenal masses in both cases: patient 1 had a 2.3 × 2.6 cm mass measuring 36 Hounsfield units on noncontrast CT imaging and patient 2 had a 4.5 × 3.5 cm right adrenal mass measuring 73 Hounsfield units on contrast CT imaging. Both patients underwent laparoscopic robotic adrenalectomies without complications. The pathologic analyses of both cases revealed composite pheochromocytoma-ganglioneuroma tumors. Surveillance at 1 year in both patients demonstrated no evidence of recurrence. Discussion The clinical and radiological presentation of composite pheochromocytoma-ganglioneuromas mirrors pheochromocytomas. The diagnosis relies on histopathological analysis. Treatment of pheochromocytoma-ganglioneuromas is complete surgical excision in a high-volume center with adrenal expertise and is associated with an overall excellent prognosis. The probability of recurrence is low, and distant metastases have rarely been reported. Conclusion Pheochromocytoma-ganglioneuromas may present with plasma metanephrine levels in the subclinical range. As with isolated pheochromocytomas, lifetime surveillance is critical for composite pheochromocytoma-ganglioneuromas.
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Affiliation(s)
- Mayssam El Najjar
- Department of Medicine, St Elizabeth’s Medical Center, Brighton, Massachusetts
| | - Elie Naous
- Department of Medicine, St Elizabeth’s Medical Center, Brighton, Massachusetts
| | - Caroline Blake
- Department of Medicine, St Elizabeth’s Medical Center, Brighton, Massachusetts
| | - Aysegul Bulut
- Department of Medicine, Division of Endocrinology, Boston Medical Center, Boston, Massachusetts
| | - Alexander Perepletchikov
- Professional Pathology Services, Professional Corporation, Hilton Head Hospital, Hilton Head Island, South Carolina
| | - Ann T. Sweeney
- Department of Medicine, Division of Endocrinology, St Elizabeth’s Medical Center, Brighton, Massachusetts
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Mete O, Juhlin CC. Recent progress in the pathologic classification of pheochromocytomas and paragangliomas. Best Pract Res Clin Endocrinol Metab 2024; 38:101958. [PMID: 39609157 DOI: 10.1016/j.beem.2024.101958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
Pheochromocytomas and paragangliomas (PPGLs) represent a unique subset of neuroendocrine neoplasms (NENs) characterized by their genetic diversity and potential for catecholamine secretion. Similar to epithelial NENs, all PPGLs are classified as malignant neoplasms that are associated with a variable risk of metastatic spread. PPGLs arise from neuroendocrine cells of the adrenal medulla (intra-adrenal paraganglia) or extra-adrenal paraganglia. Advances over the past two decades have significantly enhanced our understanding of the biological and genetic underpinnings of these neoplasms, resulting in robust genotype-phenotype (e.g., morphology, anatomic distribution, catecholamine profile, biomarker profile, risk of metastasis) correlations that guide diagnosis and prognostication. The 2022 WHO classification of PPGLs emphasizes a shift away from morphology-only diagnostic approaches by ensuring the integration of morphology with functional, structural and pathogenesis-related biomarker studies into routine pathology practice when assessing PPGLs. This paradigm is critical in distinguishing metastatic disease from multifocal primary tumors, particularly in patients with germline mutations - a hallmark of PPGLs, with germline susceptibility observed in at least 40 % of cases. This review provides practicing pathologists with a concise update on modern diagnostic and risk assessment strategies for PPGLs, focusing on the integration of biomarkers, genetic profiling, and morphological features. It also addresses emerging challenges, such as identifying metastatic potential and distinguishing these from synchronous lesions, to improve multidisciplinary care of these patients.
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Affiliation(s)
- Ozgur Mete
- Department of Pathology, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Temerty Faculty of Medicine, Toronto, ON, Canada; Endocrine Oncology Site, Princess Margaret Cancer Centre, Toronto, ON, Canada.
| | - C Christofer Juhlin
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
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Senthilnathan S, Reddy KSS, Ravipati C. Acute Quadriparesis: A Rare Presenting Manifestation of an Adrenal Tumor. Cureus 2024; 16:e68395. [PMID: 39355460 PMCID: PMC11444809 DOI: 10.7759/cureus.68395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 08/29/2024] [Indexed: 10/03/2024] Open
Abstract
Acute quadriparesis is caused by severe and sudden weakness of all four limbs, which is a distressing clinical presentation that demands immediate and comprehensive investigation. This case report presents a unique instance of acute quadriparesis secondary to an adrenal tumor. A 54-year-old female presented with acute weakness in her upper and lower limbs over six hours without a prior history of fever, convulsions, or other systemic symptoms. Laboratory evaluations revealed significant hypokalemia, prompting further investigation. Differential diagnoses such as Guillain-Barré syndrome, demyelinating lesions, and myopathy were systematically ruled out through clinical evaluation and diagnostic testing. The patient's hypokalemia was aggressively managed with intravenous potassium replacement, leading to significant improvement in muscle strength. Radiological imaging revealed a hyperenhancing lesion in the left adrenal gland, consistent with an adrenal tumor. Elevated serum aldosterone levels supported the diagnosis of hyperaldosteronism. The patient's condition stabilized with intravenous potassium and antihypertensive medications, and a laparoscopic adrenalectomy was performed to remove the adrenal tumor. Postoperatively, the patient's blood pressure and electrolyte levels normalized, and she experienced a full recovery of muscle strength. This case highlights the importance of considering endocrine disorders in the differential diagnosis of acute quadriparesis and underscores the need for a comprehensive diagnostic approach, including routine electrolyte assessments, hormonal evaluations, and thorough imaging studies. Effective management involving prompt identification and treatment of underlying causes is critical for optimal patient outcomes. This case contributes valuable insights into the diverse clinical manifestations of adrenal tumors and the importance of early and accurate diagnosis.
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Affiliation(s)
- Subbiah Senthilnathan
- Internal Medicine, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Keesari Sai Sandeep Reddy
- Internal Medicine, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Chakradhar Ravipati
- Radiodiagnosis, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
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Razack R, Butt JL, Coetzee L, Hostein I, Croce S, De Wet DR, McCluggage WG. Cervical Small Cell Variant of Paraganglioma With Sarcomatous Transformation: Report of a Unique Case. Int J Gynecol Pathol 2022; 41:370-377. [PMID: 34570014 DOI: 10.1097/pgp.0000000000000823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
We report a unique primary cervical neoplasm in a 44-yr-old woman which we believe, based on the morphology and immunophenotype, represents an extremely unusual small cell variant of paraganglioma. This represents the first report of a primary cervical paraganglioma. Following chemoradiation treatment, the tumor underwent malignant transformation into an S100 and SOX10 positive sarcoma, morphologically and immunohistochemically resembling a malignant peripheral nerve sheath tumor, which we believe represents a sarcoma derived from the sustentacular cells of the paraganglioma. Mutational analysis detected a nonsense mutation of NF1 gene in the sarcoma. This further supports the diagnosis as both somatic and germline NF1 mutations have been associated with paragangliomas and malignant peripheral nerve sheath tumors. Targeted RNA sequencing (ARCHER, expanded sarcoma panel) covering many known genes implicated in sarcoma development, did not reveal any other molecular alteration (fusion or internal tandem duplication).
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Yee SK, Meyer JH, Wong LL. VIP-secreting Pheochromocytoma: A Case Report and Review of Literature. AACE Clin Case Rep 2022; 8:158-162. [PMID: 35959082 PMCID: PMC9363508 DOI: 10.1016/j.aace.2022.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 03/17/2022] [Accepted: 03/28/2022] [Indexed: 02/03/2023] Open
Abstract
Objective To describe a case of composite vasoactive intestinal peptide (VIP)-secreting pheochromocytoma and review literature to provide insight into the various presentations and potential management of these rare tumors. Case Report A 64-year-old male patient presented with hypertensive emergency and coronary demand ischemia with development of watery diarrhea, hypokalemia, and achlorhydria syndrome. Serum and urine studies demonstrated elevated metanephrine and VIP levels. Definitive surgical resection resolved symptoms and normalized laboratory values. Pathologic examination of the specimen revealed pheochromocytoma with a Pheochromocytoma of the Adrenal gland Scaled Score of 4 and patchy expression of VIP. Discussion Given the different actions of hormones that can be secreted by these composite tumors, we suggest that pheochromocytomas with diversified secretory capabilities may be an underrecognized clinical entity. Localized disease is often amenable to surgical resection, although management of metastatic disease is not well established due to the rarity of these tumors and lack of randomized trials. Conclusion In patients presenting with diarrhea of unclear etiology or the suggestion of secondary hypertension, assessment for a possible neuroendocrine tumor may be prudent. If an adrenal mass is discovered but the patient exhibits atypical symptoms of catecholamine excess, a diagnosis of composite pheochromocytoma with multisecretory properties should be considered.
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Affiliation(s)
- Shelby K. Yee
- University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii
| | - John H. Meyer
- Department of Endocrinology, University of Hawaii, John A. Burns School of Medicine, Honolulu, Hawaii
| | - Linda L. Wong
- Department of Surgery, University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii
- Address correspondence to Correspondence to: Dr Linda L. Wong, Department of Surgery, University of Hawaii John A. Burns School of Medicine, 550 South Beretania Street, Suite 403, Honolulu, HI 96813.
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Mete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A. Overview of the 2022 WHO Classification of Paragangliomas and Pheochromocytomas. Endocr Pathol 2022; 33:90-114. [PMID: 35285002 DOI: 10.1007/s12022-022-09704-6] [Citation(s) in RCA: 173] [Impact Index Per Article: 57.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/15/2022] [Indexed: 12/12/2022]
Abstract
This review summarizes the classification of tumors of the adrenal medulla and extra-adrenal paraganglia as outlined in the 5th series of the WHO Classification of Endocrine and Neuroendocrine Tumors. The non-epithelial neuroendocrine neoplasms (NENs) known as paragangliomas produce predominantly catecholamines and secrete them into the bloodstream like hormones, and they represent a group of NENs that have exceptionally high genetic predisposition. This classification discusses the embryologic derivation of the cells that give rise to these lesions and the historical evolution of the terminology used to classify their tumors; paragangliomas can be sympathetic or parasympathetic and the term pheochromocytoma is used specifically for intra-adrenal paragangliomas that represent the classical sympathetic form. In addition to the general neuroendocrine cell biomarkers INSM1, synaptophysin, and chromogranins, these tumors are typically negative for keratins and instead have highly specific biomarkers, including the GATA3 transcription factor and enzymes involved in catecholamine biosynthesis: tyrosine hydroxylase that converts L-tyrosine to L-DOPA as the rate-limiting step in catecholamine biosynthesis, dopamine beta-hydroxylase that is present in cells expressing norepinephrine, and phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine and therefore can be used to distinguish tumors that make epinephrine. In addition to these important tools that can be used to confirm the diagnosis of a paraganglioma, new tools are recommended to determine genetic predisposition syndromes; in addition to the identification of precursor lesions, molecular immunohistochemistry can serve to identify associations with SDHx, VHL, FH, MAX, and MEN1 mutations, as well as pseudohypoxia-related pathogenesis. Paragangliomas have a well-formed network of sustentacular cells that express SOX10 and S100, but this is not a distinctive feature, as other epithelial NENs also have sustentacular cells. Indeed, it is the presence of such cells and the association with ganglion cells that led to a misinterpretation of several unusual lesions as paragangliomas; in the 2022 WHO classification, the tumor formerly known as cauda equina paraganglioma is now classified as cauda equina neuroendocrine tumor and the lesion known as gangliocytic paraganglioma has been renamed composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). Since the 4th edition of the WHO, paragangliomas have no longer been classified as benign and malignant, as any lesion can have metastatic potential and there are no clear-cut features that can predict metastatic behavior. Moreover, some tumors are lethal without metastatic spread, by nature of local invasion involving critical structures. Nevertheless, there are features that can be used to identify more aggressive lesions; the WHO does not endorse the various scoring systems that are reviewed but also does not discourage their use. The identification of metastases is also complex, particularly in patients with germline predisposition syndromes, since multiple lesions may represent multifocal primary tumors rather than metastatic spread; the identification of paragangliomas in unusual locations such as lung or liver is not diagnostic of metastasis, since these may be primary sites. The value of sustentacular cells and Ki67 labeling as prognostic features is also discussed in this new classification. A staging system for pheochromocytoma and extra-adrenal sympathetic PGLs, introduced in the 8th Edition AJCC Cancer Staging Manual, is now included. This paper also provides a summary of the criteria for the diagnosis of a composite paragangliomas and summarizes the classification of neuroblastic tumors. This review adopts a practical question-answer framework to provide members of the multidisciplinary endocrine oncology team with a most up-to-date approach to tumors of the adrenal medulla and extra-adrenal paraganglia.
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Affiliation(s)
- Ozgur Mete
- Department of Pathology, University Health Network, Toronto, ON, Canada.
- Endocrine Oncology Site, Princess Margaret Cancer Centre, Toronto, ON, Canada.
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
| | - Sylvia L Asa
- Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - Anthony J Gill
- Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
- Department of Anatomical Pathology, NSW Health Pathology, Royal North Shore Hospital, St Leonards, NSW, Sydney, Australia
| | - Noriko Kimura
- Department of Clinical Research, Division of Diagnostic Pathology, National Hospital Organization Hakodate Hospital, Hakodate, Japan
| | - Ronald R de Krijger
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Arthur Tischler
- Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA
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Araujo PB, Carvallo MS, Vidal AP, Nascimento JB, Wo JM, Naliato EO, Cunha Neto SH, Conceição FL, Fontes R, de Lima VV, Carvalho DP, Soares P, Lima J, Lourenço DM, Violante AHD. Case Report: Composite pheochromocytoma with ganglioneuroma component: A report of three cases. Front Endocrinol (Lausanne) 2022; 13:903085. [PMID: 36187102 PMCID: PMC9515550 DOI: 10.3389/fendo.2022.903085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
Composite pheochromocytoma (CP) is a very rare tumor originating from neural crest cells, predominantly composed of pheochromocytoma (PCC), a chromaffin cell tumor arising in adrenal medulla, and ganglioneuroma, a tumor derived from autonomic ganglion cells of the nervous system. Moreover, CP may be present in the hereditary syndromes of which pheochromocytoma is part. Literature offers scarce data on this subject, and particularly about its biological behavior, clinical evolution, and molecular profile. We report the phenotype and outcome of three cases of CP (PCC and ganglioneuroma components), followed up at the Endocrine Service of the Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, UFRJ, Rio de Janeiro, Brazil. Two nonsyndromic patients (cases 1 and 2) were negative to germline mutations in genes VHL, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX, while the third case (case 3) had clinical diagnosis of neurofibromatosis syndrome. Cases 1, 2, and 3 were diagnosed at 29, 39, and 47 years old, respectively, and were followed up for 3, 17, and 9 years without no CP recurrence. All cases had apparent symptoms of catecholaminergic excess secreted by PCC. Ganglioneuroma, the neurogenic component present in all three cases, had a percentage representation ranging from 5% to 15%. Tumors were unilateral and large, measuring 7.0 cm × 6.0 cm × 6.0 cm, 6.0 cm × 4.0 cm × 3.2 cm, and 7.5 cm × 6.0 cm × 4.5 cm, respectively. All cases underwent adrenalectomy with no recurrence, metastasis, or development of contralateral tumor during follow-up. Genetic testing has been scarcely offered to CP cases. However, a similar frequency of genetic background is found when compared with classic PCC, mainly by the overrepresentation of NF1 cases in the CP subset. By literature review, we identified a notorious increase in cases reported with CP in the last decade, especially in the last 3 years, indicating a recent improvement in the diagnosis of this rare disorder in clinical practice.
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Affiliation(s)
- Paula B. Araujo
- Medical Board of Clinical Analysis Department, Dasa, Rio de Janeiro, Brazil
- Medical School, Endocrine Service, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mirna S. Carvallo
- Medical School, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ana P. Vidal
- Pathology Service Clementino Fraga Filho University Hospital, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - João B. Nascimento
- Medical School, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Julia M. Wo
- Medical School, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Erika O. Naliato
- Ricardo Castilho Center of Studies Teresopolis Medical Association, Teresopolis, Rio de Janeiro, Brazil
| | - Silvio H. Cunha Neto
- Endocrine Surgery Service, Hospital Universitario Clementino Fraga Filho, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Flavia L. Conceição
- Medical School, Endocrinology Unit, Hospital Universitario Clementino Fraga Filho, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rosita Fontes
- Medical Board of Clinical Analysis Department, Dasa, Rio de Janeiro, Brazil
| | - Vinicius V. de Lima
- Laboratorio de Fisiologia Endocrina Doris Rosenthal, Instituto de Biofísica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Denise P. Carvalho
- Laboratorio de Fisiologia Endocrina Doris Rosenthal, Instituto de Biofísica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Paula Soares
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Institute of Research and Innovation in Health of the University do Porto, Porto, Portugal
- Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Jorge Lima
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Institute of Research and Innovation in Health of the University do Porto, Porto, Portugal
- Department of Medicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Delmar M. Lourenço
- Endocrine Genetic Unit, Endocrinology Division, Hospital das Clínicas, University of Sao Paulo School of Medicine, University of Sao Paulo, São Paulo, Brazil
- Endocrine Oncology Division, Institute of Cancer of the State of Sao Paulo, University of Sao Paulo School of Medicine, University of Sao Paulo, São Paulo, Brazil
| | - Alice Helena D. Violante
- Medical School, Endocrinology Unit, Hospital Universitario Clementino Fraga Filho, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- *Correspondence: Alice Helena D. Violante,
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Dhanasekar K, Visakan V, Tahir F, Balasubramanian SP. Composite phaeochromocytomas-a systematic review of published literature. Langenbecks Arch Surg 2021; 407:517-527. [PMID: 33651160 PMCID: PMC8933353 DOI: 10.1007/s00423-021-02129-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/09/2021] [Indexed: 01/09/2023]
Abstract
Introduction Composite phaeochromocytoma is a tumour containing a separate tumour of neuronal origin in addition to a chromaffin cell tumour. This study reports on two cases from a single centre’s records and presents a systematic literature review of composite phaeochromocytomas. Methods In addition to describing 2 case reports, a systematic search of the Medline database from inception up to April 2020 was done for human case reports on composite phaeochromocytomas. Relevant titles and/or abstracts were screened, and full texts were reviewed to identify appropriate studies. Data was extracted and a descriptive analysis of presentation, clinical features, management strategies and outcomes was performed. The quality of included studies was assessed using a critical appraisal checklist. Results There were 62 studies included, with a total of 94 patients. Of 91 patients where data was available, the median (range) age of patients was 48 (4–86) years. Of 90 patients where information was provided, 57% were female. In at least 28% of patients, a genetic cause was identified. Common presenting features include abdominal pain, palpable mass, cardiovascular and gastrointestinal symptoms. The most common tumour component with phaeochromocytoma is ganglioneuroma; other components include ganglioneuroblastoma, neuroblastoma and malignant peripheral nerve sheath tumours. In patients with follow-up data (n=48), 85% of patients were alive and well at a median (range) follow-up time of 18 (0.5–168) months. Conclusion Composite phaeochromocytoma is a rare tumour, with a significant genetic predisposition. This review summarises available epidemiological data, which will be useful for clinicians managing this rare condition.
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Affiliation(s)
| | - V Visakan
- Newcastle University, Newcastle upon Tyne, UK
| | - F Tahir
- Sheffield Teaching Hospitals NHS Trust UK, Sheffield, UK
| | - S P Balasubramanian
- University of Sheffield, Sheffield, UK.,Sheffield Teaching Hospitals NHS Trust UK, Sheffield, UK
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Abstract
Since Felix Fränkel's account of pheochromocytoma in 1886, great discoveries and vast advancements in the diagnosis, genetics, anatomical and functional imaging techniques, and surgical management of pheochromcytoma and paraganglioma (P-PGL) have been made. The improved insight in the pathophysiology of P-PGL and more accurate detection methods enable physicians to tailor the treatment plan to an individual based on the genetic profile and tumor behavior. This review will cover briefly the clinical features, diagnosis, genetic mutations, and imaging modalities that are used to guide current surgical management of these rare and interesting endocrinopathies.
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Affiliation(s)
- Douglas Wiseman
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mustapha El Lakis
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Naris Nilubol
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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10
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Suenaga S, Ichiyanagi O, Ito H, Naito S, Kato T, Nagaoka A, Kato T, Yamakawa M, Obara Y, Tsuchiya N. Expression of Extracellular Signal-regulated Kinase 5 and Ankyrin Repeat Domain 1 in Composite Pheochromocytoma and Ganglioneuroblastoma Detected Incidentally in the Adult Adrenal Gland. Intern Med 2016; 55:3611-3621. [PMID: 27980262 PMCID: PMC5283962 DOI: 10.2169/internalmedicine.55.7293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 04/03/2016] [Indexed: 01/07/2023] Open
Abstract
Composite pheochromocytoma (cPC) is extremely rare, arising in the adrenal medulla as a mixture of PC and other tumors of neural origin. We herein report on a case of adrenal incidentaloma post-operatively diagnosed as cPC with ganglioneuroblastoma (GNBL). The PC component had 7 points on the PASS, a Ki-67 index of 5.1%, a focal absence of sustentacular cells, and no genetic aberrations in succinate dehydrogenase subunit B. The GNBL component exhibited no N-myc amplification. Tumor cells of both components were stained positively for extracellular signal-regulated kinase 5 and ankyrin repeat domain 1. The aberrant activation of growth signaling may play a role in the marginal malignancy of cPC.
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Affiliation(s)
- Shinta Suenaga
- Department of Urology, Yamagata University Faculty of Medicine, Japan
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Monclair T, Ruud E, Holmstrøm H, Aagenæs I, Asplin M, Beiske K. Extra-adrenal composite phaeochromocytoma/neuroblastoma in a 15-month-old child. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2015. [DOI: 10.1016/j.epsc.2015.06.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Shida Y, Igawa T, Abe K, Hakariya T, Takehara K, Onita T, Sakai H. Composite pheochromocytoma of the adrenal gland: a case series. BMC Res Notes 2015; 8:257. [PMID: 26104921 PMCID: PMC4477526 DOI: 10.1186/s13104-015-1233-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 06/16/2015] [Indexed: 12/19/2022] Open
Abstract
Background Composite pheochromocytoma is a rare pathological condition characterized by elements of both pheochromocytoma and neurogenic tumors. However, detailed clinical outcomes of this tumor have not been fully shown. From 2007 to 2013, we experienced three cases of adrenal composite pheochromocytoma. In this report, we investigate the clinicopathological features of these three cases of composite pheochromocytoma and compare them with previously reported cases. Case presentations Cases 1 and 2 were a 29-year-old Japanese woman and a 59-year-old Japanese man, respectively. They underwent laparoscopic left adrenalectomy, and pathological examination revealed composite pheochromocytoma–ganglioneuroma. Case 3 was a 53-year-old Japanese man who had been receiving hemodialysis for 17 years. He underwent laparoscopic right adrenalectomy, and pathological examination revealed composite pheochromocytoma–ganglioneuroblastoma. Although the Ki67-positive rates varied from 1.0 to 6.2% among the three cases, no clinical recurrences occurred. Despite the relatively high rate of Ki67 positivity, complete tumor resection resulted in favorable clinical outcomes. Conclusion We experienced three cases of adrenal composite pheochromocytoma. Although the clinical findings and treatment outcomes of composite pheochromocytoma were similar to those of ordinary pheochromocytoma, further studies of the biological behavior and genetic profiles of composite pheochromocytoma are necessary to achieve a better understanding of this tumor.
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Affiliation(s)
- Yohei Shida
- Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Tsukasa Igawa
- Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Kuniko Abe
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Tomoaki Hakariya
- Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Kousuke Takehara
- Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Toru Onita
- Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Hideki Sakai
- Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
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Gupta G, Saran RK, Godhi S, Srivastava S, Saluja SS, Mishra PK. Composite pheochromocytoma masquerading as solid-pseudopapillary neoplasm of pancreas. World J Clin Cases 2015; 3:474-478. [PMID: 25984524 PMCID: PMC4419113 DOI: 10.12998/wjcc.v3.i5.474] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 11/10/2014] [Accepted: 02/12/2015] [Indexed: 02/05/2023] Open
Abstract
Pheochromocytoma and ganglioneuroma form rare composite tumours of the adrenal medulla comprising less than 3% of all sympathoadrenal tumours. We present a case of intraoperatively detected adrenal medullary tumour of composite pheochromocytoma and ganglioneuroma diagnosed on histopathology, in a normotensive patient. A 50-year-old male with a past history of chronic obstructive pulmonary disease presented with abdominal pain and significant weight loss since one month. Ultrasound and contrast-enhanced computed tomography abdomen revealed a large lobulated lesion in the distal body and tail of pancreas suggestive of solid and papillary neoplasm of body and tail of pancreas. Intra-operatively, a 15 cm × 10 cm solid lesion with cystic areas was seen arising from the left lower pole of the adrenal gland pushing the pancreas which appeared unremarkable. In our case, exploratory laparotomy with tumour excision was done. Extensive sectioning and microscopic examination of this adrenal tumour confirmed a diagnosis of composite Pheochromocytoma with Ganglioneuroma on histopathology. Immunophenotyping with S-100 further supported the diagnosis. The goal of this report is to increase the awareness of this rare disease and to further identify its variable presentation.
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14
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Shawa H, Elsayes KM, Javadi S, Sircar K, Jimenez C, Habra MA. Clinical and radiologic features of pheochromocytoma/ganglioneuroma composite tumors: a case series with comparative analysis. Endocr Pract 2014; 20:864-9. [PMID: 24641930 DOI: 10.4158/ep14010.or] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To describe and compare the clinical, biochemical, radiologic, and pathologic features of adrenal pheochromocytoma-ganglioneuroma (PC-GN) composites with the features of isolated pheochromocytomas (PCs) and adrenal ganglioneuromas (AGNs). METHODS We reviewed data for PC-GN composite cases seen at a single tertiary center between 1993 and 2012 and compared them with cases of isolated AGN and relatively similar median-size PCs. RESULTS Nine PC-GN composites were included. The median age at diagnosis was 52 years (range, 28 to 83 years) for PC-GN compared with 55 years (range, 24 to 78 years) for PC patients and 40 years (range, 18 to 64 years) for AGN patients. Similar to PCs, all PC-GN composites were associated with catecholamine overproduction, whereas AGNs were nonfunctioning. On pathology, the median tumor sizes were 7 cm (range, 2.5 to 13 cm) for PC-GN tumors, 6.5 cm (range, 3.5 to 7 cm) for PCs, and 8 cm (range, 3.2 to 20 cm) for AGNs. On computed tomography (CT) imaging, PC-GN composites and PCs were heterogeneous, with both having significantly higher postcontrast density values than AGNs, which typically looked homogeneous and had a progressive enhancement pattern without contrast washout in most cases. CONCLUSION The presence of a PC component significantly increases tumor heterogeneity and postcontrast density values. CT imaging could be very helpful in distinguishing AGNs from both PC-GN and PC tumors, but only pathologic examination can yield the diagnosis. Clinically and radiologically, PC-GN composites are indistinguishable from PCs and need to be managed similarly.
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Affiliation(s)
- Hassan Shawa
- Department of Endocrinology, Albany Medical Center, Albany, New York
| | - Khaled M Elsayes
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sanaz Javadi
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kanishka Sircar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Camilo Jimenez
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mouhammed Amir Habra
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
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15
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Papathomas TG, de Krijger RR, Tischler AS. Paragangliomas: update on differential diagnostic considerations, composite tumors, and recent genetic developments. Semin Diagn Pathol 2013; 30:207-23. [PMID: 24144290 DOI: 10.1053/j.semdp.2013.06.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Recent developments in molecular genetics have expanded the spectrum of disorders associated with pheochromocytomas (PCCs) and extra-adrenal paragangliomas (PGLs) and have increased the roles of pathologists in helping to guide patient care. At least 30% of these tumors are now known to be hereditary, and germline mutations of at least 10 genes are known to cause the tumors to develop. Genotype-phenotype correlations have been identified, including differences in tumor distribution, catecholamine production, and risk of metastasis, and types of tumors not previously associated with PCC/PGL are now considered in the spectrum of hereditary disease. Important new findings are that mutations of succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 (collectively "SDHx") are responsible for a large percentage of hereditary PCC/PGL and that SDHB mutations are strongly correlated with extra-adrenal tumor location, metastasis, and poor prognosis. Further, gastrointestinal stromal tumors and renal tumors are now associated with SDHx mutations. A PCC or PGL caused by any of the hereditary susceptibility genes can present as a solitary, apparently sporadic, tumor, and substantial numbers of patients presenting with apparently sporadic tumors harbor occult germline mutations of susceptibility genes. Current roles of pathologists are differential diagnosis of primary tumors and metastases, identification of clues to occult hereditary disease, and triaging of patients for optimal genetic testing by immunohistochemical staining of tumor tissue for the loss of SDHB and SDHA protein. Diagnostic pitfalls are posed by morphological variants of PCC/PGL, unusual anatomic sites of occurrence, and coexisting neuroendocrine tumors of other types in some hereditary syndromes. These pitfalls can be avoided by judicious use of appropriate immunohistochemical stains. Aside from loss of staining for SDHB, criteria for predicting risk of metastasis are still controversial, and "malignancy" is diagnosed only after metastases have occurred. All PCCs/PGLs are considered to pose some risk of metastasis, and long-term follow-up is advised.
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Affiliation(s)
- Thomas G Papathomas
- Department of Pathology, Josephine Nefkens Institute, Erasmus MC-University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
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