JCDR Clinical Case Report Based Study Pheochromocytoma with inferior vena cava thrombosis: An unusual association Sunil K. Kota, Siva K. Kota1, Sruti Jammula2, Lalit K. Meher3, Kirtikumar D. Modi Departments of Endocrinology, Medwin Hospital, Hyderabad, Andhra Pradesh, 2Pharmaceutics, Roland Institute of Pharmaceutical Sciences, 3Medicine, MKCG Medical College, Berhampur, Orissa, India, 1Anaesthesia, Central Security Hospital, Riyadh, Saudi Arabia Address for correspondence: Dr. Sunil Kumar Kota, Department of Endocrinology, Medwin Hospitals, Chirag Ali Lane, Nampally, Hyderabad - 500 001, Andhra Pradesh, India. E-mail: [email protected] ABSTRACT Pheochromocytomas have been described in association with vascular abnormalities like renal artery stenosis. A 48-year-old man was admitted to our hospital with the complaints of headache, sweating, anxiety, dizziness, nausea, vomiting and hypertension. For last several days, he was having a dull aching abdominal pain. Abdominal computed tomography (CT) revealed the presence of a left adrenal pheochromocytoma. An inferior vena cava (IVC) venogram via the right jugular vein demonstrated occlusion of the IVC inferior to the right atrium. Surgical removal of pheochromocytoma was done, followed by anticoagulant treatment for IVC thrombosis, initially with subcutaneous low molecular weight heparin, and then with oral warfarin, resulting in restoration of patency. To the best of our knowledge, the occurrence of pheochromocytoma in IVC thrombosis has not been reported so far from India. Possible mechanisms of such an involvement are discussed. Key words: Anticoagulant, hypertension, inferior vena cava thrombosis, pheochromocytoma INTRODUCTION scans.[4] Surgical resection of the tumor mass is the definitive treatment.[5] Pheochromocytomas are rare catecholamine producing tumors arising from chromaffine cells in the sympatho Thrombosis of the inferior vena cava (IVC) has comparable adrenal system. Its prevalence is estimated at 0.1% to etiological factors to lower limb deep venous thrombosis.[6] 0.6%.[ 1] They secrete various catecholamines, predominantly Hypercoagulability related to hematological or neoplastic norepinephrine, and epinephrine to small extent.[2] These abnormalities, venous stasis secondary to extraluminal pressure from tumors or inflammatory processes, and vessel catecholamines are responsible for the manifestations injury due to trauma have all been implicated as primary with sustained or paroxysmal symptoms.[2] Diagnosis is mechanism in the pathophysiology of IVC thrombosis.[6] established by measuring metanephrines in the urine or However, its association with pheochromocytoma in Indian blood.[3] Localization of the tumor is done using computed subjects has not been reported till date. We report the case tomography (CT) or magnetic resonance imaging (MRI) of a patient who presented with pheochromocytoma and IVC thrombosis. Access this article online Quick Response Code: Website: CASE REPORT www.jcdronline.com A 48-year-old man was admitted to our hospital with complaints of headache, sweating, anxiety, dizziness, nausea DOI: and vomiting. He also had dull aching abdominal pain. 10.4103/0975-3583.95375 He was a nonsmoker with no significant family history. 160 Journal of Cardiovascular Disease Research Vol. 3 / No 2 Kota, et al.: Pheochromocytoma with IVC thrombosis There was no history of risk factors for hypercoagulable [Figure 3]. There was simultaneous enlargement of distal state. The patient was 164 cm tall and weighed 57 kg. On part of IVC. physical examination, there were no café au lait spots or neurofibromas. His resting pulse rate was 100 beats/min. The patient’s blood pressure was 240/150 mmHg. Bilateral lower limb arterial and venous examination was normal. There was no redness over feet, pedal edema or collateral formation over abdomen. Abdominal examination revealed mild lower abdominal tenderness without any hepatomegaly and ascitis. Rest of the systemic examination was unremarkable. Hematological analysis confirmed normocytic anemia with hemoglobin 11.3 gm/dl, a raised erythrocyte sedimentation rate (ESR) (130 mm fall in the first hour), while the total Figure 1: Computed tomography of the abdomen- showing a and differential leukocyte counts were normal. C-reactive well defined, heterogeneously enhancing mass lesion of size protein was elevated at 130 mg/L. Urine examination was 7.6 × 5.3 × 4.8 cm at the upper pole of right kidney without any calcifications. The left adrenal gland appeared to be normal normal. Biochemical parameters such as liver and kidney functions, and serum electrolytes, calcium, phosphorous, alkaline phosphatase and D-dimer were within normal limits. Electrocardiogram revealed left ventricular hypertrophy. The chest radiograph and echocardiogram were normal. The Endocrinological evaluation revealed increased urine catecholamines and urinary vanillyl mandelic acid (VMA) [Table 1]. Plasma cortisol and Adrenocorticotropic hormone (ACTH) were within normal limits. Abdominal CT revealed a well defined, heterogenous mass lesion of size 7.6 × 5.3 × 4.8 cms with attenuation score of 35 HU at the upper pole of right kidney without any calcifications [Figure 1]. Ultrasound (USG) abdomen revealed normal renal and hepatic parenchyma. There was Figure 2: T2-weighted axial magnetic resonance imaging demonstrating no involvement of renal vein, hepatic veins and veins of the mass (predominantly high signal) between the inferior vena cava lower limbs demonstrated by doppler ultrasound. Magnetic and right kidney (black arrow) compressing the overlying inferior vena resonance imaging (MRI) revealed intraluminal thrombus cava (white arrow) extending proximally up to the confluence of hepatic veins immediately inferior to the right atrium without distal extension to femoral veins bilaterally [Figure 2]. MRI also revealed compression of IVC. An IVC venogram via the right jugular vein demonstrated multiple filling defects indicating occlusion of the IVC inferior to the right atrium Table 1: Baseline biochemical parameters of the patient Parameters Values Normal range Plasma rennin activity (ng/ml/h) 8.2 0.7-1.4 Plasma aldosterone (ng/dl) 61.2 2-20 24 hour urine fractionated 53 <1.3 metanephrines (mg/24 hrs) 24 hour urine VMA (mg/24 hrs) 69 1-8 Plasma metanephrines (µg/dl) 285 <60 8.00 AM Plasma cortisol (µg/dl) 17.2 5-25 Figure 3: IVC venogram showing multiple filling defects indicating Plasma ACTH (pg/ml) 27.8 10-60 occlusion of the inferior vena cava inferior to the right atrium. There is VMA: Vanillyl mandelic acid; ACTH: Adrenocorticotropic hormone distal enlargement of inferior vena cava Journal of Cardiovascular Disease Research Vol. 3 / No 2 161 Kota, et al.: Pheochromocytoma with IVC thrombosis A diagnosis of IVC thrombosis with pheochromocytoma was established, and surgical treatment was planned. Alpha receptor blocking therapy with prazosin was instituted, followed by β blocker, after testing for adequacy of α blockade. The patient was treated conservatively with subcutaneous low molecular weight heparin followed by oral warfarin. After 2 weeks, hypertension was well controlled and the remaining symptoms disappeared. With adequate blood pressure control, patient was subjected to laparoscopic adrenalectomy. There was no evidence of perilesional or distant invasions. Biopsy of the specimen revealed a typical organoid or zellballen pattern with no cytoplasmatic inclusion, pleomorphism, cytological alterations or necrosis; and, the mitotic index was low Figure 4: The typical growth pattern of nests of tumor cells (zellballen) [Figure 4]. During the postoperative period, the blood surrounded by a discontinuous layer of sustentacular cells and pressure was normal, and the patient’s convalescence was fibrovascular stroma in the biopsy specimen of the patient in the study. Blood vessels surrounding tumor nests are composed of round uncomplicated. He was discharged on the 11th postoperative to oval cells day. During the next 16 months, the patient’s blood pressure remained normal. A 24-hour urine specimen collected for metanephrine and VMA, revealed levels within normal limits. At present, the patient is asymptomatic, requires no medications, and is employed as an engineer. MRI imaging demonstrated resolution of the thrombosis and return of patency of the IVC at 4 months [Figure 5]. DISCUSSION Two aspects render our case unusual: 1) the coexistence of pheochromocytoma with IVC thrombosis 2) Though there are case reports citing the association between malignant pheochromocytoma and IVC thrombus,[7,8] to our sincere belief; this is the first such report citing this uncommon Figure 5: T2-weighted axial magnetic resonance imaging comparable association from India. in position and image acquisition to Figure 2 demonstrating complete resolution of inferior vena cava thrombosis (white arrow) after 4-months Although the lifetime incidence of venous thrombosis is of oral anticoagulation therapy 0.1%, it still remains a rare condition especially in patients pyrexic at presentation, with an associated elevation in below 30 years of age.[9] Predisposing factors include D-dimer levels and inflammatory markers (white cell count, alterations in blood flow [stasis], injury to the vascular C-reactive protein).[12] Our patient had no lower limb, liver endothelium and abnormalities in the constitution of or kidney involvement, and this might be ascribed to the blood hypercoagulability (Virchow’s Triad).[10] Endothelial partial occlusion of IVC. He only had elevated inflammatory damage is invariably an acquired phenomenon, whereas markers. We could not explain normal D-dimer levels in the hypercoagulability may result from both congenital and backdrop of such a large thrombus in our patient. acquired risk factors (especially in the peri-operative period). The classical presentation of IVC thrombus CT scan with contrast enhanced images and MRI scan varies according to the level of the thrombosis with up to are used to localize adrenal pheochromocytoma.[13] meta- 50% of patients presenting with bilateral lower extremity iodobenzylguanidine (MIBG) and Positron emission swelling and dilatation of superficial abdominal vessels. tomography (PET) scanning (Gallium- DOTA-toc/noc Whilst some patients remain asymptomatic, lower back and DOPA-PET perform better than FDG- PET) are pain, nephrotic syndrome, hepatic engorgement, cardiac largely reserved for extraadrenal paraganglioma, or very failure and pulmonary embolus have also been described.[ 11] large tumors to rule out metastasis. Heterogeneity, high Tsuji et al. reported a series of 10 patients where 40% were hounsfield density on CT (>HU), marked enhancement 162 Journal of Cardiovascular Disease Research Vol. 3 / No 2 Kota, et al.: Pheochromocytoma with IVC thrombosis with intravenous contrast and delayed contrast washout these 2 conditions. In our case, local compression due to (<60 % at 10 minutes), high signal intensity on T coexisting pheochromocytoma might have been causative. 2 weighted MRI, cystic and hemorrhagic changes point to pheochromocytoma, adrenocortical carcinoma or Recent advances in the utilization of ultrasound, CT metastasis. However, pheochromocytoma with lipid and MRI imaging as well as endovascular procedures degeneration can result in low attenuation scores (<10 HU) have resulted in an increase in detection rates of IVC and >60% washout at delayed CT scanning.[14] Benign anomalies, as well as an increase in the incidental discovery adrenal incidentalomas are characterized by size <5 cm, of such abnormalities during unrelated investigations, sharp margins, smooth contours, lack of demonstrable therapeutic endovascular or surgical procedures.[12] growth on serial examinations, attenuation scores Contrast venography remains the standard for diagnosis <10 HU, and >60% washout at delayed CT scanning.[ 13,15] of IVC thrombosis with a low false-positive rate, and the In our patient, CT scan revealed nonhomogenous mass advantage of access for immediate treatment if required. of HU 35 without any calcification. Histologically, However, it is an invasive procedure associated with a pheochromocytomas are capsulated and are composed 2%-10% incidence of post-procedural Deep venous of round or polygonal epithelioid/chief cells arranged in thrombosis (DVT).[6] Duplex ultrasound scanning has characteristic compact cell nests (Zellballen) or trabecular become an accurate non-invasive method of diagnosing patterns. The chief cells have centrally located nuclei IVC thrombosis and is often the first-line investigative with finely clumped chromatin, and a moderate amount modality.[6] However, duplex USG is operator dependant of eosinophilic, granular cytoplasm. Spindle shaped and can be limited by body habitus or the presence of sustentacular or supporting cells are located peripherally. bowel gas and may occasionally fail to identify any IVC Tumors of higher grade are characterized by a progressive anomaly.[19] CT imaging is a rapid non-invasive method loss in the relationship between chief cells and sustentacular which can accurately diagnose and assess the extent of cells, and a decrease in the number of sustentacular cells. In thrombus as well as delineate any associated abdominal our patient, typical zellballen pattern was found. Presence or pelvic abnormality.[6] MRI imaging is now replacing CT of markers like chromogranin A (CGA), neuron specific as the optimal investigative tool avoiding radiation and enloase, synaptophsyin serve as additional tools to confirm giving more accurate delineation of thrombus as well as the neuroendocrine nature of the chief cells.[16] any IVC anomaly. MRI is also used to follow-up patients to determine morphological changes in the thrombus Malignant pheochromocytomas are histologically and following therapy.[20] biochemically similar to benign ones. The only reliable clue to the presence of a malignant pheochromocytoma Management of patients with coexisting pheochromocytoma is local invasion or distant metastases, which may occur and IVC thrombosis needs operative resection of the as long as 20 years after resection.[17] Thus, even when adrenal mass and medical/interventional management pheochromocytomas or paragangliomas are considered of IVC thrombosis. The goals of operation include 1) “benign” on pathologic examination, long term follow-up removal of the tumor with postoperative normotension, is indicated in all patients to confirm that impression. Other and 2) IVC luminal restoration and anticoagulation. markers for malignancy are absent or weak expression of Minimally invasive techniques are being increasingly used inhibin/activin- beta B subunit,[18] and presence of succinate for resection of adrenal tumors and to treat renal artery dehydrogenase B (SDH B) subunit is seen. In absence of any lesions. Laparoscopic adrenalectomy is performed by invasion, we considered the mass in our patient to be benign. either the transperitoneal or retroperitoneal approach.[21] Our patient was subjected to laparoscopic adrenalectomy The simultaneous occurrence of pheochromocytoma and after adequate preoperative blood pressure control by α IVC thrombosis is reported sporadically. IVC thrombosis blockers, followed by β blockers. Treatment options in the in this case could be because of: 1) local compression case of IVC thrombus without anatomical variance include leading to alteration in blood flow and stasis 2) sustained anticoagulation, mechanical thrombectomy, systemic hypertension leading to vascular endothelial injury and thrombolytic therapy, transcatheter regional thrombolysis, hypercoagulability, 3) association of pheochromocytoma pulse-spray pharmacomechanical thrombolysis and with systemic lupus erythematous and Behcet’s disease angioplasty.[22] There is no specific literature describing might explain the triggering of an autoimmune the ideal duration of anticoagulation in these instances; phenomenon leading to a hypercoagulable state, and however, case evidence identifies a trend toward treatment 4) an underlying anatomic abnormality or coagulation for a minimum of one year with the interplay of disorder. It also could be a chance association between hypercoagulability disorders needing to be factored into any Journal of Cardiovascular Disease Research Vol. 3 / No 2 163 Kota, et al.: Pheochromocytoma with IVC thrombosis decision. Surgical reconstruction of the IVC and bypass of pheochromocytomas, but not in extra-adrenal pheochromocytoma. J Clin Endocrinol Metab 1990;70:996-9. an aberrant section are both recognized modalities reserved 3. Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, for the most severe cases and are associated with morbidity et al. Biochemical diagnosis of Pheochromocytoma which test is best? JAMA and mortality risk.[23] Endovascular stent placement in 2002;287:1427-34. 4. Szolar DH, Korobkin M, Reittner P, Berghold A, Bauernhofer T, Trummer H, combination with angioplasty is recommended in the cases et al. Adrenocortical carcinomas and adrenal pheochromocytomas: Mass and of residual stenosis and chronic IVC occlusion.[23] enhancement loss evaluation at delayed contrast enhanced CT. Radiology 2005;234:479-85. In the case of IVC thrombus associated with an aberrant 5. Assalia A, Gagner M. Laparoscopic adrenalectomy. Br J Surg 2004;91:1259-74. 6. Giordano P, Weber K, Davis M, Carter E. Acute thrombus of the inferior IVC, with no other predisposing factors, treatment vena cava. Am J Emerg Med 2006;24:640-6. involves anti-coagulation. The duration of this treatment 7. Shigemura K, Tanaka K, Arakawa S, Hara I, Kawabata G, Fujisawa M. is widely debated with no extensive literature to provide Malignant pheochromocytoma with IVC thrombus. Int Urol Nephrol 2007;39:103-6. an evidence based approach. Dean et al. took a view, which 8. Dossett LA, Rudzinski ER, Blevins LS, Chambers EP Jr. Malignant is quite similar to that of ours, that a caval anomaly is a pheochromocytoma of the organ of Zuckerkandl requiring aortic and vena permanent risk factor for venous stasis and thrombosis and caval reconstruction. Endocr Pract 2007;13:493-7. 9. Rosendaal FR. Thrombosis in the young: Epidemiology and risk factors, a that anticoagulant treatment should be lifelong.[24] Since focus on venous thrombosis. Thromb Haemost 1997;78:1-6. our patient had no anatomic abnormality or any other 10. Chee YL, Culligan DJ, Watson HG. Inferior vena cava malformation as predisposing factors, we decided to give the treatment a risk factor for deep venous thrombosis in the young. Br J Haematol 2001;114:878-80. for 4 months only and stopped it then after documenting 11. Jackson BT, Thomas ML. Post-thrombotic inferior vena caval obstruction. radiologic luminal restoration. A review of 24 patients. Br Med J 1970;1:18-22. 12. Tsuji Y, Inoue T, Murakami H, Hino Y, Matsuda H, Okita Y. Deep vein thrombosis caused by congenital interruption of the inferior vena cava – CONCLUSION A case report. Angiology 2001;52:721-5. 13. Szolar DH, Korobkin M, Reittner P, Berghold A, Bauernhofer T, Trummer H, et al. Adrenocortical carcinomas and adrenal pheochromocytomas: Mass and Pheochromocytoma is known to be associated with vascular enhancement loss evaluation at delayed contrast enhanced CT. Radiology abnormalities. Though cases of renal artery stenosis, renal 2005;234:479-85. artery aneurysm and inferior vena cava thrombosis have 14. Blake MA, Krishnamoorthy SA, Boland GW, Sweeney AT, Pitman MB, Harisinghani M, et al. Low-density Pheochromocytoma on CT. A mimicker been described, we found the uncommon association with of Adrenal Adenoma. AJR Am J Roentgenol 2003;181:1663-8. IVC thrombosis in an Indian patient. IVC thrombosis is 15. Boraschi P, Braccini G, Grassi L, Campatelli A, Di Vito A, Mosca F, associated with a significant acute and chronic morbidity. et al. Incidentally discovered adrenal masses: Evaluation with gadolinium enhancement and fat-suppressed MR imaging at 0.5 T. Eur J Radiol 1997;24: A high index of suspicion is warranted for IVC thrombus. 245-52. CT or preferably MRI imaging are required to delineate IVC 16. Kliewer KE, Wen DR, Cancilla PA, Cochran AJ. Paragangliomas: Assessment of prognosis by histologic, immunohistochemical, and ultrastructural anatomy and ascertain proximal extent of the thrombus. techniques. Hum Pathol 1989;20:29-39. Although invasive therapeutic modalities exist, long-term 17. Goldstein RE, O’Neill JA Jr, Holcomb GW 3rd, Morgan WM 3rd, and commonly life-long anticoagulation is often required. Neblett WW 3rd, Oates JA, et al. Clinical experience over 48 years with pheochromocytoma. Ann Surg 1999;229:755-66. Pheochromocytoma does not seem to have any effect on 18. Salmenkivi K, Arola J, Voutilainen R, Ilvesmäki V, Haglund C, Kahri AI, the outcome of the coexisting IVC thrombosis. Our article et al. Inhibin/activin betaB-subunit expression in pheochromocytomas calls for more research to confirm or refute the proposed favors benign diagnosis. J Clin Endocrinol Metab 2001;86:2231-5. 19. Park JH, Lee JB, Han MC, Choi BI, Im CK, Chang KH, et al. Sonographic hypothetical association. evaluation of inferior vena caval obstruction: Correlative study with vena cavography. AJR Am J Roentgenol 1985;145:757-62. 20. Soler R, Rodriguez E, Lopez MF, Marini M. MR imaging in inferior vena ACKNOWLEDGMENT cava thrombosis. Eur J Radiol 1995;19:101-7. 21. Del Pizzo JJ, Schiff JD, Vaughan ED. Laparoscopic adrenalectomy for All the authors would like to express their heartfelt thanks to Dr. pheochromocytoma. Curr Urol Rep 2005;6:78-85. Jagadeesh Tangudu, M Tech, MS, PhD, and Sowmya Jammula, 22. Yamada N, Ishikura K, Ota S, Tsuji A, Nakamura M, Ito M, et al. 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J Cardiovasc Dis Res 2012;3:160-4. corticotropin-releasing hormone, growth hormone-releasing hormone, somatostatin, and peptide histidine methionine are present in adrenal Source of Support: Nil, Conflict of Interest: None declared. 164 Journal of Cardiovascular Disease Research Vol. 3 / No 2