Case Report: Patient with Multiple Paragangliomas Treated with Long Acting Somatostatin Analogue

Endocrine Journal 2003, 50 (5), 507–513

VEDIA TONYUKUK, RIFAT EMRAL, ŞULE TEMIZKAN, AYşE SERTÇELIK*, ILHAN ERDEN** AND DEMET ÇORAPÇIOĞLU

Department of Endocrinology and Metabolic Diseases, Ankara University, School of Medicine, 06100 Ankara, Turkey *Department of Pathology, Ankara University, School of Medicine, 06100 Ankara, Turkey **Department of Radiodiagnostic, Ankara University, School of Medicine, 06100 Ankara, Turkey

Abstract. Paragangliomas of the head and neck are uncommon neoplasms. They are usually benign, but tend to be locally invasive. Although surgical resection remains the definitive treatment, important issues about management arise when such lesions are inoperable. Beneficial effects of octreotide treatment have already been reported in a malign paraganglioma case. Here we report a 24 year old female with familial, bilateral, multiple paraganglioma in the head and neck region, who firstly presented with pulsatile tinnitus and hearing loss in her left ear. After embolization was performed, she underwent operation twice because of the gross tumor mass. No significant change in tumor size was determined after the operations, however there were no distant metastases. Although she experienced hypertension attacks, no hormonal overproduction was found in repeated measurements. As the tumor was unresectable, new alternative therapies were sought. Octreotide scintigraphy was positive in the tumoral tissue, so we began to treat her with somatostatin analogue octreotide. After a 16 month follow up period, an improvement of the performance status, the near normalisation of attacks and stabilization of tumor growth were achieved. However, in the last three visits, she began to experience symptoms more frequently and it had been necessary to increase the octreotide dose. She is now well and being followed up. In conclusion, the beneficial effects of octreotide treatment could be quantified by clinical, tumor and scintigraphic criteria. These data suggest that octreotide can be useful in the treatment of inoperable paragangliomas.

Key Words: Multiple paragangliomas, Long acting somatostatin analogue (Endocrine Journal 50: 507–513, 2003)

PARAGANGLIOMAS of the head and neck are pattern 4. It is estimated that the familial incidence uncommon neoplasms. According to WHO classi- of head and neck paragangliomas is approximately fication all tumors of the paraganglion system are 10% 5. As reported, the family history of paragan- called paraganglioma. Paragangliomas occurring in gliomas did not predict the presence of hyperfunction- the head and neck region (from the carotid and vagal ing tumors, but did predict a high probability of body, from the glomus jugulare and glomus tympani- multiple tumors 6. The incidence of multicentricity cum) are called chemodectomas or glomus tumors 1, for this tumor is 33% 7. 2. They are in general rare, solitary and slow growing The most frequent presenting symptoms for the tumors of neuroendocrine origin [3. They are usually patients with head and neck tumors are palpable benign, but tend to be locally invasive. Head and neck neck mass (55%), tinnitus (18%), and cranial nerve paragangliomas are recognized to occur in two forms: palsies (16%) 6. They may also cause aural fullness a sporadic form and a familial autosomal dominant and hearing loss [8. Symptoms of paraganglioma are hypertension, tachycardia, etc., nevertheless a consid- Received: July 1, 2002 erable number of paragangliomas are asymptomatic. Accepted: May 6, 2003 They may be endocrinologically active or may be Correpondence to: Dr. Vedia TONYUKUK, İbn-i Sina Hospital, found with normal levels of dopamine, catecholamines 10 Floor, D Block, Samanpazarı, 06100 Ankara, Turkey and their metabolites, especially metanephrine and 508 TONYUKUK et al. vanillylmandelic acid (VMA) 9, 10. A small pro- went operation and had to be operated twice because portion (4%) of head and neck paragangliomas are of the gross residual tumor mass. In the first opera- hyperfunctional 6. Even in patients identified with tion, total excision of glomus jugulare and glomus catecholamine-secreting paragangliomas, the sensi- vagale was tried but tumors were subtotally removed. tivities of hormonal determinations are low, and the Unfortunately, they returned to their prior size 15 sensitivities achieved by measurements in the 24-h months after the first operation. As a side effect facial urine collection were 74% for total metanephrines, nerve palsy occurred. 84% for norepinephrine, 16% for dopamine, and 14% Histopathologic examination revealed that the for epinephrine 6. Although surgical resection tumor was a paraganglioma (Fig. 1). Also the neuro- remains the definitive treatment for chemodectomas, endocrine features of the tumor were demonstrated important issues about management arise when such immunohistochemically by S-100, chromagranin A, lesions are inoperable. Approximately one third of synaptophysin, and neuron specific enolase positivity patients have persistent or recurrent paragangliomas (Fig. 2). Control MRI showed no significant change so long-term follow up is important 6. When a in tumor size after the operations; however, there were paraganglioma is suspected, noninvasive techniques no distant metastases. She was referred to the Endo- such as computerized tomography, magnetic reso- crinology Department because of the hypertension nance imaging (MRI) or nuclear medicine imaging attacks with flushing and tachycardia lasting for 10–15 are being used for the localization of the tumor. minutes, two or three times a day. The 24-hour urine Radioiodinated metaiodobenzylguanidine (MIBG) scintigraphy and lately 111-indium-labelled octreotide scintigraphy have been used mainly to localize head and neck chemodectomas 11, 12. In addition, 131- iodine-MIBG therapy is a safe and usually well toler- ated treatment 13. Uptake of radiolabelled somatostatin analogue has already been reported in patients with malignant paragangliomas 14, 15, as well as beneficial effects of octreotide treatment in a malignant paraganglioma case 16. In this presentation, we demonstrated relief of symptoms and stabilization of the disease in a paraganglioma case with positive octreotide scintigraphy who was treated with long acting depot octreotide (Sandostatin LAR®). Fig. 1. Paraganglioma composed of rests of uniform round cells in a delicate vascular stroma (HE × 40)

Case

A 24 year old female was first referred to Oto-Rhino- Laryngology Department with a pulsatile tinnitus in her left ear and she expressed some hearing loss in the left ear as well. MRI of the head and neck showed multiple paragangliomas (bilateral carotid body, bilateral glomus vagale and left glomus jugulare). Embolization was performed through arteria carotis externa and interna for the multiple bilateral lesions but no change in tumor size was achieved although vascularisation of the tumor decreased mini- mally. In addition no symptomatic improvement Fig. 2. Diffuse immunostaining for synaptophysin in tumor occurred after embolization. Afterward, she under- cells (× 40) SOMATOSTATIN TREATMENT IN PARAGANGLIOMA 509

Table 1. Vital signs and hormonal data of the patient during hypertension attacks

Date BP Pulse/min VMA Metanephrine NE Epinephrine Dopamine 5-HIAA NE Epinephrine Dopamine (mmHg) (urine) (urine) (urine) (urine) (urine) (urine) (blood) (blood) (blood) 1.9–9.8 0.01–1 0–90 0–20 65–400 10–31.2 0–600 0–100 0–87 mg/24h mg/24h mg/24h mg/24h ug/24h umol/24h pg/ml pg/ml pg/ml 01.06.00 170/120 120 0.7 0.05 553 25 23.06.00 180/110 125 66.6 4.7 308.9 10.2 23.06.00 170/100 110 412.4 17.9 30.06.00 170/100 118 2.9 0.23 05.06.00 160/100 108 0.4 0.2 06.06.00 220/130 144 0.5 0.05 08.02.01 200/150 125 8.0 0.25 334 22.9 57 15.02.01 180/110 130 6.0 0.47 172 42.8 15.02.01 190/120 128 8.0 0.56 22.02.01 185/115 120 2.6 0.25 01.03.01 170/100 120 0.6 0.034 111 7.3 14.09.01 160/110 116 4.5 0.21 21.09.01 170/100 118 3.2 0.12 N: Normal, BP: Blood pressure, NE: Norepinephrine, 5-HIAA: 5-Hydroxyindole acetic acid, VMA: Vanillylmandelic acid Normal values of the determinations are also given in the Table. dopamine, norepinephrine and VMA determinations, and plasma norepinephrine levels were all negative even during attacks and no hormonal overproduction was found in repeated urinary measurements. Table 1 shows the vital signs and hormonal data of the patient during hypertension attacks. We searched our patient’s pedigree and learned from the hospital records that her father died because of a neck paraganglioma at age 53. Though her blood pressure rose up to 260/140 mmHg during hypertension attacks, in general her blood pressure had a tendency to decrease down to 80/40 mmHg. In order to control hypertension attacks, alpha blocker, with the lowest dose, was started but she could not tolerate it Fig. 3. Whole body and spot images were obtained by a gamma camera at 2 and 24 hr after the i.v. administration of 3.5 as it caused symptomatic hypotension. Calcium chan- mCi In111-octreotide. Bilateral accumulation in the nel blockers and angiotensin converting enzyme inhib- medial regions of the parotis gland and a focal uptake in itors did the same, so they were all discontinued. As the right cervical region, under the right submandibular the tumor was unresectable, new alternative therapies gland are seen in these images. were sought. MIBG uptake was negative. At that point octreotide scintigraphy was performed by using days and then 10 mg long acting depot octreotide for radioactive somatostatin analog 111-indium-diethyl- every 28 days was started. Before the treatment with enetriaminepentaacetic acid (111In-DTPA0) octreotide. octreotide, she experienced long lasting hypertension Octreotide scintigraphy was positive in the regions attacks every day. However, at the end of first month of bilateral cervical ganglions, under submandibular of octreotide therapy, her hypertension attacks nearly gland and near the medial side of parotis gland, as disappeared (one or two times a month) and became shown in Fig. 3, and allowed us to treat her with short lasting (one to three minutes). Her quality of somatostatin analogue octreotide. We began the treat- life improved, and we determined 36% improvement ment with 100 g octreotide three times a day for 15 in her quality of life score according to health ques- 510 TONYUKUK et al.

Fig. 4. Axial T1-weighted (TR 640, TE 12) image with gadolinium shows bilateral, densely opaque mass Fig. 5. The masses are seen beside the carotis arteria at the lesions surrounding the vascular structures, filling the sagittal T1-weighted (TR 400, TE 9) postcontrast carotid space. The lesion on the right side is larger. images. A-Before octreotide treatment A-Before octreotide treatment B-Six months after octreotide treatment B-Nine months after octreotide treatment C-Twenty-two months after octreotide treatment C-Twenty-two months after octreotide treatment SOMATOSTATIN TREATMENT IN PARAGANGLIOMA 511 tionnaire 17. The symptomatic and tumoral responses was determined. There was uptake with radiolabelled before and during long acting depot octreotide (oct- somatostatin analogue (octreoscan) and we observed reotide LAR) therapy, for a follow up period of 26 an improvement in the quality of life, in performance months were recorded. Periodical imaging of tumors status with decrease in hypertensive attacks and stabi- by MRI showed an arrest in tumor growth after the lization of the tumor after treatment with octreotide initiation of octreotide therapy as seen in Fig. 4 and 5. LAR. She probably experienced tachyphylaxis and An improvement of the performance status, the near needed a higher dose during follow up. normalisation of attacks and stabilization of tumor Somatostatin receptors (sst) have been demonstrated growth were achieved. However, in the last three in vitro in 93% of paragangliomas 12. In benign visits, she began to experience symptoms more fre- pheochromocytoma/paraganglioma cases, the sensitiv- quently and it has been necessary to use octreotide ity of octreotide scintigraphy has been reported to be LAR in every three week period. In the latest visit approximately 88% that is similar to that of MIBG the dose changed to 20 mg/month. She is now well scintigraphy even though the experience with these and is being followed up. Fig. 6 shows the attack fre- tumors is quite limited 13. In some reports 111- quency and mean blood pressure of the patient in the indium pentetreotide scintigraphy has been shown follow-up, before and after the initiation of octreotide superior to 123-iodine-MIBG scintigraphy in the diag- therapy. nosis and localization of chemodectomas 12. More- over, 111-indium pentetreotide scintigraphy permits classification of patients with somatostatin receptors Discussion in the chemodectomas, in the application of pharmoco- logical therapy with somatostatin analogues for in- In this report, we describe a familial paraganglioma operable tumors 18. case with multiple, bilateral presentation. She had Both the biochemical and the antiproliferative recurrence after surgery. No hormonal overproduction effects of octreotide are considered to be mediated

Fig. 6. Clinical course including the attack frequency and mean blood pressure of the patient in the follow-up period, before and after the initiation of octreotide therapy. Systolic Blood Pressure + (2x Diastolic Blood Pressure) *Mean Blood Pressure was calculated by the formula = 3 512 TONYUKUK et al. by sst2; octreotide also binds to sst5, which mediates inhibition of angiogenesis in tumor cells 22. On an antitumor response. Tumor growth may continue account of arrest of the tumor growth in our case, it despite ongoing anti-secretory effects, suggesting can be speculated that those indirect effects of these actions may be mediated by different mecha- octreotide might play a role in the clinical improve- nisms. Since sst2 mediates both the biochemical and ment of the patient. Recently, significant improve- antiproliferative effects of octreotide, it is important ment of quality of life has been demonstrated with to perform octreotide scintigraphy as predictive test long-acting depot formulations. There is little or no before initiation of treatment 19. effect on tumor growth during octreotide therapy; Most of the presently available somatostatin ana- tumor shrinkage has been reported in 10%–20% of logues bind to the sst2 and sst5, and in higher doses patients, but stabilization of tumor growth can be to sst3 receptors 20. Clinical improvement during achieved in about half of the patients 19. Eventually, somatostatin analogue therapy is mainly mediated via however, all patients escape from somatostatin ana- a direct inhibitory effect on hormone production from logue therapy with regard both to hormonal production the tumors 19. Due to the lack of any proof for the and tumor growth [23, and the mechanism behind hormonal overproduction in our patient, it is hard to the tachyphylaxis is not yet known. Dose increment say that direct inhibitory effect of octreotide on hor- might be useful in that situation. mone production played a role in this case. Also indi- In conclusion, the beneficial effects of octreotide rect non-tumor mediated effects on peripheral organs treatment could be quantified by clinical, tumor and contribute to the subjective improvement 19. These scintigraphic criteria, which is rarely the case 24. indirect effects includes inhibition of proliferation via These data suggest that octreotide can be useful in decrease in insulin-like growth factor-1 levels 21 and the treatment of inoperable paragangliomas.

References

1. Williams ED, Siebenmann RE, Sobin LH (1980) Covey T (2000) Paragangliomas - A decade of clinical Histological typing of endocrine tumors. In: WHO experience. J Surg Oncology 74: 286–290. International Histological Classification of Tumors. 9. Young WF Jr (1997) Pheochromocytoma: How to World Health Organization, Geneva 33–39. catch a moonbeam in your hand. Eur J Endocrinol 136: 2. Van Gils APG, van Erkel AR, Falke THM, Pauwels 28–29. EKJ (1994) Magnetic resonance imaging or metaiodo- 10. Van Gelder T, Verhoeven GT, de Jong P, Oei HY, benzylguanidine scintigraphy for the demonstration of Krenning EP, Vuzevski VD, van der Meiracker AH paragangliomas? Correlation and disparities. Eur J (1995) Dopamine-producing paraganglioma not visual- Nucl Med 21: 239–253. ized by iodine-123-MIBG scintigraphy. J Nucl Med 36 3. Maier W, Marangos N, Laszig R (1999) Paraganglioma (4): 620–622. as a systemic syndrome: pitfalls and strategies. J 11. Troncone L, Rufini V (1998) Radiolabelled metaiodo- Laryngol Otology 113: 978–982. benzylguanidine in the diagnosis of neural crest 4. Sobol SM, Bailey JC (1990) Familial multiple cervical tumors. In: Murray PC, Ell PJ (eds) Nuclear Medicine paragangliomas: report of a hundred and review of the in Clinical Diagnosis and Therapy. Churchill Living- literature. Otolaryngol Head Neck Surg 102: 382–390. stone, Edinburgh, Vol 2: 843–857. 5. Grufferman S, Gillman MW, Pasternak LR, Peterson 12. Krenning EP, Kwekkeboom DJ, Pauwels S, Kvols LK, CL, Young WG Jr (1990) Familial carotid body Reubi JC (1995) Somatostatin receptor scintigraphy. tumors: case report and epidemiologic review. Cancer In: Freeman LM (ed) Nuclear Medicine Annual. Raven 46: 2116–2122. Press, New York, 1–50. 6. Erickson D, Kudva YC, Ebersold MJ, Thompson BG, 13. Troncone L, Rufini V (1999) Nuclear medicine therapy Grant CS, Heerden JA, Young WF Jr (2001) Benign of pheochromocytoma and paraganglioma. Q J Nucl paragangliomas: Clinical presentation and treatment Med 43: 344–355. outcomes in 236 patients. J Clin Endocrinol Metab 86 14. Kwekkeboom DJ, van Urk H, Pauw BKH, Lamberts (11): 5210–5216. SWJ, Kooij PPM, Hoogma RPLM, Krenning EP 7. Wax M, Briant D (1992) Carotid body tumors: a (1993) Octreotide scintigraphy for the detection of review. J Otolaryngol 21: 4. paragangliomas. J Nucl Med 34: 873–878. 8. Somasundar P, Krouse R, Hostetter R, Vaughan R, 15. Tenenbaum F, Lumbroso J, Schlumberger M, Mure A, SOMATOSTATIN TREATMENT IN PARAGANGLIOMA 513

Plouin PF, Caillou B, Parmentier C (1995) Comparison Future outlook. Ann Oncology 10 (Suppl 2): 31–38. of radiolabelled octreotide and meta-iodobenzylguani- 20. Lamberts SWJ, van der Lely AJ, De Herder WW, dine (MIBG) scintigraphy in malignant pheochromo- Hofland LJ (1996) Octreotide. N Engl J Med 334: 246– cytoma. J Nucl Med 36: 1–6. 254. 16. Tenenbaum F, Schlumberger M, Lumbroso J, 21. Weckbecker G, Stolz B, Susini Ch, Bruns Ch (1999) Parmentier C (1996) Beneficial effects of octreotide Antiproliferative somatostatin analogues with potential in a patient with a metastatic paraganglioma. Eur J in oncology. In: Lamberts SWJ (ed) Octreotide: The Cancer 32A: 737–738. Next Decade. Bioscientifica, Bristol, UK, 339–352. 17. Arraras JI, Arias F, Tejedor M, Pruja E, Marcos M, 22. Barrie R, Woltering EA, Hajarizadeh H, Mueller C, Martinez E, Valerdi J (2002) The EORTC QLQ-C30 Ure T, Fletcher WS (1993) Inhibition of angiogenesis (version 3.0) Quality of Life questionnaire: validation by somatostatin and somatostatin-like compounds is study for Spain with head and neck cancer patients. structurally dependent. J Surg Res 55: 446–450. Psychooncology 11: 249–256. 23. Wynick D, Anderson JV, Williams SJ, Bloom SR 18. Muros MA, Llamas-Elvira JM, Rodriguez A, Ramirez (1989) Resistance of metastatic pancreatic endocrine A, Gomez M, Arraez MA, Valencia E, Vilchez R tumors after long-term treatment with the somatostatin (1998) 111-Indium-pentetreotide scintigraphy is supe- analogue octreotide (SMS 201-995). Clin Endocrinol rior to 123-Iodine-MIBG scintigraphy in the diagnosis 30: 385–388. and location of chemodectoma. Nucl Med Commun 19: 24. Harris AG, Kokoris SP (1993) Therapeutic applica- 735–742. tions of somatostatin and its analogue octreotide. Eur J 19. Eriksson B, Öberg K (1999) Summing up 15 years of Med 2: 97–105. somatostatin analog therapy in neuroendocrine tumors: