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ORIGINAL ARTICLE
Year : 2016  |  Volume : 5  |  Issue : 1  |  Page : 19-23

A clinicopathological study of pheochromocytoma and paraganglioma with review of literature


Department of Pathology, Shri Sathya Sai Medical College and Research Institute, Kanchipuram, Tamil Nadu, India

Date of Web Publication13-Jan-2016

Correspondence Address:
D Manimaran
Department of Pathology, Shri Sathya Sai Medical College and Research Institute, Tiruporur . Guduvanchery Main Road, Ammapettai, Nellikuppam, Chengalpet, Kanchipuram - 603 108, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-344X.173886

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  Abstract 

Background and Aim: Pheochromocytoma and paraganglioma (PPGL) are rare chromaffin cell tumors with variable clinical presentation which are derived from neural crest cells. Pheochromocytomas arising from the adrenal glands are sympathetic, and the paragangliomas arising from extra-adrenal sites are either sympathetic or parasympathetic in origin. These tumors usually come to clinical attention due to the catecholamine secretion or maybe detected as incidentalomas while imaging for unrelated symptoms. Our objective is to study the histopathological and histochemical features of PPGL with clinical correlation. Materials and Methods: PPGLs arising from both sympathetic and parasympathetic nervous systems were retrospectively selected from the records for 5 years, and clinical details were obtained. Routine hematoxylin and eosin (H and E) stain and argentaffin and argyrophilic reactions were employed. Immunohistochemistry for chromogranin was done for cases with doubtful histomorphology in H and E sections. Results: Our study material consisted of 10 cases out of which five cases were adrenal pheochromocytomas; 4, carotid body tumors; and 1, paraganglioma of the organ of Zuckerkandl. Three pheochromocytomas out of five and the paraganglioma of organ of Zuckerkandl were functional and clinically presented with palpitation and hypertension. All the carotid body tumors and two of the pheochromocytomas were nonfunctional. The 24 h urinary levels of vanillylmandelic acid was increased in two cases, and urinary fractionated metanephrine levels was increased in one case of pheochromocytoma. Urinary normetanephrine alone increased in paraganglioma of organ of Zuckerkandl. All pheochromocytomas except one were positive for argentaffin reaction, and all paragangliomas at other sites were positive for argyrophilic reaction. Chromogranin immunohistochemistry stain was done for organ of Zuckerkandl lesion which came out to be positive. Conclusion: Proper clinical evaluation, preoperative preparation, and appropriate early surgical treatment can cure the lesion. Preoperative diagnosis, if not done and if there is a delay in the treatment, will lead to complications such as intraoperative hypertensive attack, persistent hypertension even after removal of the tumor, and progression to malignancy.

Keywords: Carotid body tumor, organ of ZuckerKandl, paraganglioma, pheochromocytoma


How to cite this article:
Manimaran D, Khan DM, Bharathi K, Raman TR, Anuradha S. A clinicopathological study of pheochromocytoma and paraganglioma with review of literature. Int J Health Allied Sci 2016;5:19-23

How to cite this URL:
Manimaran D, Khan DM, Bharathi K, Raman TR, Anuradha S. A clinicopathological study of pheochromocytoma and paraganglioma with review of literature. Int J Health Allied Sci [serial online] 2016 [cited 2019 Oct 14];5:19-23. Available from: http://www.ijhas.in/text.asp?2016/5/1/19/173886


  Introduction Top


Pheochromocytoma and paraganglioma (PPGL) are rare chromaffin cell tumors that are derived from neural crest cells from the adrenal medulla (pheochromocytoma) in 80–85% of patients and from extra-adrenal sites (paraganglioma) in 15–20% of the case.[1],[2] These tumors comprise 10–18% of all chromaffin tumors.[3] According to World Health Organization classification of tumors, paragangliomas can be divided into adrenal and extra-adrenal.[4] The term pheochromocytoma is reserved for intra-adrenal tumors and belongs to sympathetic system. Extra-adrenal tumors arise from either sympathetic or parasympathetic paraganglia. Extra-adrenal parasympathetic paragangliomas include those arising from jugulotympanic, vagal, carotid body, laryngeal, and aorticopulmonary paraganglias and are usually nonfunctional.[5] Extra-adrenal sympathetic paragangliomas can be found anywhere along the sympathetic chain from the base of the skull and neck (5%), thorax (10%), abdomen mostly in organ of Zuckerkandl (75%), and urinary bladder [6],[7] and prostate (10%).[3] Head and neck paragangliomas constitute about 0.012% of cases with estimated clinical incidence of 1/100,000 patients per year. Carotid body tumors are the most common head and neck paragangliomas accounting for 57% of cases, followed by jugulotympanic, 30% and vagal nerve, 13%.[8] Among the sympathoadrenal tumors, pheochromocytoma is the most common. In our study, we are discussing about 10 cases of PPGLs at various sites with clinicopathological findings.


  Materials and Methods Top


Pheochromocytoma and paraganglioma arising from both sympathetic and parasympathetic nervous systems were retrospectively selected from the records for 5 years from January 2000 to September 2004 at Madras Medical College, Chennai. Clinical details were obtained. Data were abstracted by an MD postgraduate student. Routine hematoxylin and eosin (H and E) and special stains such as argentaffin reaction (Singhs modification of the Masson–Hamperl Argentaffin technique) for pheochromocytoma and argyrophilic reaction (Grimelius method) for paragangliomas were employed for the sections obtained from the paraffin blocks. Immunohistochemistry for chromogranin were done for cases with doubtful histomorphology in H and E sections.


  Results Top


In our study, most of the PPGLs were arising from sympathoadrenal system and adrenal medulla was the common site. Age ranged from 20 to 45 years and was predominantly females. Three pheochromocytomas out of five and the paraganglioma of the organ of Zuckerkandl were functional. All the carotid body tumors and two of the pheochromocytomas were nonfunctional clinically.

The 24 h urinary levels of vanillylmandelic acid (VMA) was increased in two cases of pheochromocytomas. The values were 42.5 mg and 61 mg/24 h (normal range 2–7 mg/24 h). Urinary fractionated metanephrine levels increased in one case of adrenal pheochromocytoma and urinary normetanephrine alone increased in paraganglioma of the organ of Zuckerkandl. Plasma free metanephrines and plasma catecholamines were not measured in our study.

Cut section of PPGL of the organ of Zuckerkandl was dark brown due to chromaffin reaction [Figure 1]a and [Figure 2]a. Carotid body tumors were gray-white with areas of hemorrhage on cut section [Figure 3]a. Microscopically, all 10 cases showed similar findings such as Zellballen arrangement of cuboidal cells surrounded by highly vascularized connective tissue [Figure 1]b, [Figure 2]b, and [Figure 3]b, but one of the pheochromocytomas was associated with ganglioneuroma component [Figure 1]c. There was no capsular or vascular invasion in any of our cases. All pheochromocytomas except one were positive for argentaffin stain [Figure 1]d, and all paragangliomas at other sites were positive for argyrophilic reaction [Figure 2]c and [Figure 3]b inset]. Chromogranin immunohistochemistry stain was done for organ of Zuckerkandl lesion which came out to be positive [Figure 2]d. Obvious familial associations were not made out in patient history in our cases. Clinical and histopathological findings of individual cases were shown in [Table 1].
Figure 1: (a) Cut section of pheochromocytoma with chromaffin reaction, (b) photomicrograph show cells with amphophilic cytoplasm and vesicular nucleus arranged in Zellballen pattern separated by vascularized connective tissue (H and E, ×10), (c) show focal ganglioneuroma component in a pheochromocytoma (H and E, ×10), (d) argentaffin granules in the cytoplasm of tumor cells (argentaffin reaction, ×40)

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Figure 2: (a) Cut section of paraganglioma of organ of Zuckerkandl with chromaffin reaction, (b) photomicrograph of paraganglioma of organ of Zuckerkandl with Zellballen arrangement of cells separated by vascular stroma (H and E, ×4), (c) argyrophilic granules in the cytoplasm of tumor cells (argyrophilic reaction, ×40), (d) tumor cells show strong cytoplasmic positivity for chromogranin (×40)

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Figure 3: (a) Cut section of carotid body tumor with gray-white and blackish areas, (b) photomicrograph show Zellballen arrangement of cells separated by thick fibrous stroma (H and E, ×4), inset show argyrophilic reaction positivity with black granules in the cytoplasm (×40)

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Table 1: Clinical and histopathological findings in individual cases

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  Discussion Top


The term pheochromocytoma was coined by Poll in 1905, to express the fact that the tumors darkened after exposure to potassium dichromate due to chromaffin reaction (pheo–dusky, chromo–color).[9] Pheochromocytoma has been called 10% tumor–10% are bilateral, 10% extra-adrenal, 10% occur in children, 10% malignant, and 10% familial. However, current literature depicts that more than 30% cases are associated with familial syndromes such as multiple endocrine neoplasia (MEN) type–II (A and B), Von Hippel-Landau disease, and neurofibromatosis type I with involvement of RET, VHL, and NF1 genes, respectively.[5] Sporadic form occurs in the 4th and 5th decade while familial forms occur in younger age group in the 3rd decade. Succinate dehydrogenase (SDH) subunit D mutation in the head and neck paragangliomas was the first mutation to be identified. Other established genes involved are SDHC and SDHB out of which SDHB gene is associated with metastatic malignant tumors.[1],[10],[11] The newer genes identified are SDHA, SDHAF2, MAX, and TMEM127.[12]

Sweating attacks, palpitation, headache, anxiety, chest pain, weight loss, and paroxysmal hypertension were the common clinical presentation of pheochromocytomas, but some patients may be asymptomatic.[9],[13],[14] The diagnosis depends mainly on biochemical findings followed by radiological investigations such as computed tomography (CT) scan and magnetic resonance imaging. At present, due to increased frequency of imaging for other symptoms, incidentalomas are being diagnosed. Increased urinary and plasma levels of catecholamines and their metabolites (metanephrine, normetanephrine, and VMA) will be seen in functional cases.[11],[15] Endocrine society guidelines for PPGLs include measurements of plasma free metanephrines or urinary fractionated metanephrines for initial workup.[1] Iodine-131 metaiodobenzylguanidine scintigraphy is useful for ruling out metastasis.[14]18 F-fluorodeoxyglucose positron emission tomography CT scanning is recommended by endocrine society in known metastatic PPGLs.[1] These tumors are positive for immunohistochemical markers such as neuron-specific enolase, chromagranin, synaptophysin, S-100, and vasoactive intestinal polypeptide.[9],[11]

Paragangliomas can be sympathetic or parasympathetic in origin. Sympathetic paraganglia are mostly located along the sympathetic nerve chains alongside the vertebra and also in the pelvis including urinary bladder. Most of the chromaffin tissues in fetus are extra-adrenal in location with the most prominent collections residing on either side of the aorta near the origin of inferior mesenteric or renal arteries, down to aortic bifurcation. These paraganglias were described by Zuckerkandl.[8]

Around 0.33% of paragangliomas occur in the head and neck region.[16] Carotid body tumors are the most common among the head and neck paragangliomas. Carotid body tumor is also called chemodectoma, and it was first described by Von Haller in 1743.[17] Usually, they are benign, nonfunctioning, bilateral in 30% of familial cases, and if malignant, the metastatic rate is 10%.[18]

In a study of 10 cases of pheochromocytoma in Indian patients by Krishnappa et al.,[9] 3 cases had elevated urinary VMA. The main clinical features were abdominal pain (90%), hypertension (50%), chest pain (30%), and palpitation and headache (20%). About 40% cases had been reported as malignancy. In our study, out of 5 cases, 2 cases had elevated 24 h VMA in urine, and one case had elevated fractionated metanephrines in urine. Other two cases presented with nonspecific clinical features and diagnosis was suspected in CT scan and confirmed in excision biopsy. No malignancies were reported.

In a study of 169 patients belonging to 19 MEN 2A families by Rodriguez et al.,[14] 54 patients presented with pheochromocytoma. Urinary catecholamines were high in 48 patients with metanephrines in 82% of cases, adrenaline in 76%, normetanephrines in 75%, noradrenaline and VMA in 59%, and dopamine in 53% of cases. Common clinical symptoms were hypertension (13 cases) followed by palpitation and (10 cases). None of our patients presented with clinical features of MEN syndrome and 3 patients showed elevated urinary metabolites of catecholamines (24 h VMA in 2 cases and urinary fractionated metanephrines in one).

Pheochromocytoma/paraganglioma can rarely have a component of ganglioneuroma, ganglioneuroblastoma, neuroblastoma, peripheral nerve sheath tumor, or neuroendocrine carcinoma. It is then called composite pheochromocytoma/paraganglioma. Its biological behavior is variable. Hu et al.[19] reported a case of a 52-year-old female with retroperitoneal composite pheochromocytoma–ganglioneuroma which was functional. In our study, one of the adrenal pheochromocytoma patients was associated with ganglioneuroma and was nonfunctional.

In a study of 45 patients with carotid body tumor by Nazari et al.,[17] 5 patients had bilateral lesions, clinical features were slow-growing cervical mass (100%), pain (16%), vertigo (4%), dysphagia (4%), and tinnitus (2%). On examination, 32 cases (64%) were pulsatile. No patients had neuroendocrine symptoms. Ling et al.[18] reported a case of carotid body tumor in a 51-year-old female with mass in the left side of the neck which was pulsatile on palpation and with an audible bruit on auscultation. There was no systemic symptom. In our study, furthermore, there were no neuroendocrine symptoms in all the carotid body tumors, and the patients came only with mass in the neck as a complaint. On examination, all were pulsatile.

As per Endocrine Society guidelines, PPGL patients with positive family history, syndromic features, and multifocal, bilateral, or metastatic disease are recommended to undergo specific genetic testing prioritized based on clinical features. Paraganglioma patients are suggested to undergo genetic testing for SDH gene mutations and the patients with metastatic disease to undergo testing for SDH-B mutations. Preoperative preparation with α-adrenergic receptor blockade is essential to prevent on table complications during surgery. Postoperatively lifelong yearly biochemical testing is necessary for assessing recurrence and metastasis.[1]


  Conclusion Top


In our study, we have observed that three out of five PPGL of organ of Zuckerkandl were functional with hypertension clinically and urinary excretion of metabolites of catecholamines. All carotid body tumors were nonfunctional. PPGL are rare tumors which come to clinical attention mainly due to secretion of catecholamines. Preoperative diagnosis, if not done, will lead to intraoperative hypertensive attack and its related complications. Delay in the treatment will lead to persistent hypertension even after removal of the tumor and may progress to advanced disease with metastasis. Proper clinical evaluation, preoperative preparation, and appropriate early surgical treatment can cure the lesion.

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Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014;99:1915-42.  Back to cited text no. 1
    
2.
van Berkel A, Lenders JW, Timmers HJ. Diagnosis of endocrine disease: Biochemical diagnosis of phaeochromocytoma and paraganglioma. Eur J Endocrinol 2014;170:R109-19.  Back to cited text no. 2
    
3.
Lee JA, Duh QY. Sporadic paraganglioma. World J Surg 2008;32:683-7.  Back to cited text no. 3
    
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Tischler AS. Pheochromocytoma and extra-adrenal paraganglioma: Updates. Arch Pathol Lab Med 2008;132:1272-84.  Back to cited text no. 4
    
5.
Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab 2006;91:827-36.  Back to cited text no. 5
    
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Lai Y, Chen D, Yu Z, Ni L, Yang S. Non-functioning paraganglioma of the urinary bladder: A case report and review of the literature. Oncol Lett 2014;7:891-893.  Back to cited text no. 6
    
7.
Beilan JA, Lawton A, Hajdenberg J, Rosser CJ. Pheochromocytoma of the urinary bladder: A systematic review of the contemporary literature. BMC Urol 2013;13:22.  Back to cited text no. 7
    
8.
Capatina C, Ntali G, Karavitaki N, Grossman AB. The management of head-and-neck paragangliomas. Endocr Relat Cancer 2013;20:R291-305.  Back to cited text no. 8
    
9.
Krishnappa R, Chikaraddi SB, Arun HN, Deshmane V. Pheochromocytoma in Indian patients: A retrospective study. Indian J Cancer 2012;49:188-93.  Back to cited text no. 9
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Hensen EF, Bayley JP. Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma. Fam Cancer 2011;10:355-63.  Back to cited text no. 10
    
11.
Eisenhofer G, Tischler AS, de Krijger RR. Diagnostic tests and biomarkers for pheochromocytoma and extra-adrenal paraganglioma: From routine laboratory methods to disease stratification. Endocr Pathol 2012;23:4-14.  Back to cited text no. 11
    
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Lefebvre M, Foulkes WD. Pheochromocytoma and paraganglioma syndromes: Genetics and management update. Curr Oncol 2014;21:e8-e17.  Back to cited text no. 12
    
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Noshiro T, Shimizu K, Watanabe T, Akama H, Shibukawa S, Miura W, et al. Changes in clinical features and long-term prognosis in patients with pheochromocytoma. Am J Hypertens 2000;13 (1 Pt 1):35-43.  Back to cited text no. 13
    
14.
Rodriguez JM, Balsalobre M, Ponce JL, Ríos A, Torregrosa NM, Tebar J, et al. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg 2008;32:2520-6.  Back to cited text no. 14
    
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Brain KL, Kay J, Shine B. Measurement of urinary metanephrines to screen for pheochromocytoma in an unselected hospital referral population. Clin Chem 2006;52:2060-4.  Back to cited text no. 15
    
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Nazari I, Aarabi Moghaddam F, Zamani MM, Salimi J. Clinical characteristics and remedies in 45 Iranians with carotid body tumors. Acta Med Iran 2012;50:339-43.  Back to cited text no. 17
    
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Ling FJ, Weinrach DM, Eskandari MK. Carotid body tumor – A case report. Vasc Endovascular Surg 2004;38:185-8.  Back to cited text no. 18
    
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Hu J, Wu J, Cai L, Jiang L, Lang Z, Qu G, et al. Retroperitoneal composite pheochromocytoma-ganglioneuroma: A case report and review of literature. Diagn Pathol 2013;8:63.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]


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