Rare Cause of Severe Hypertension in a Young Woman
Presentation of Case
An asymptomatic 20-year-old woman was seen at a preoperative assessment clinic before elective orthopedic surgery. She had a blood pressure of 240/110 mm Hg in both arms and was referred for urgent medical opinion. On examination, her phenotype was unremarkable. She had bilateral papilledema with normal cardiovascular examination other than her blood pressure. Renal function and urinalysis were normal.
The patient had a normal renal ultrasound, plain computed tomography of brain, and computed tomography cerebral venogram. Renin and aldosterone were normal with a normal ratio and potassium was within the normal range. She commenced amlodipine and an angiotensin-converting enzyme inhibitor with blood pressure falling to 151/112 mm Hg.
Dr Colin Perry: I would ask our experts, what would they do next?
Dr Ernesto Schiffrin: I think in a young person you have to consider secondary hypertension. And of course, with very severe elevated blood pressure I would have liked to know whether she is very pale, does she not have headaches? One would start to think of pheochromocytoma in a young person like this.
Dr Perry: That is why I think the history is very important at this stage, because she did not complain of recent headaches when seen initially in the emergency department. She was always rather pale.
Dr Schiffrin: I think that is important because I always tell the medical students that if the patient has a flushed face it is not pheochromocytoma. Pallor is almost an inevitable element.
Dr Marie Freel: Would there have been an argument that an MR angiogram of renal vessels might still have been appropriate in a young girl with malignant-phase hypertension because you can still have a fairly normal aldosterone renin ratio in that circumstance?
Dr Perry: I think that is entirely justifiable.
Discussion of Investigation
Dr Perry: Can I ask then, what test would you do for pheochromocytoma?
Dr Schiffrin: We usually measure urinary metanephrines.
Prof Garry Jennings: This lady did not have it, but when you have episodic hypertension with a pheochromocytoma, that is when your plasma measurement can be absolutely definitive. If they are not elevated and their blood pressure is up, they have not got a pheochromocytoma.
Dr. Schiffrin: Just going back to the history, simply because I have seen some of these patients, I would have inquired about family history, about thyroid surgery in the family.
Dr. Perry: I agree, however at this stage, she has not been to the specialist center. So, in fact you are correct. She does have headaches and if you really explore the history, she gives a good story of headaches. Eighty percent of patients with pheochromocytoma will give a history of headaches when asked specifically.
Twenty-four–hour urinary metanephrines and catecholamines were measured and were reported as elevated, with 24-hour urinary norepinephrine 11 374 nmol/24 hour (normal range <900 nmol/24 hour) and 24-hour urinary free normetanephrine 16 365 nmol/24 hour (normal range <650 nmol/24 hour).
Computed tomography scan of chest, abdomen, and pelvis revealed a left para-aortic mass and a smaller mass on the right, along with sclerotic vertebral and rib deposits (Figure 1). 123I metaiodobenzylguanidine (mIBG) scintigraphy confirmed widespread 123I mIBG avid disease (Figure 2).
Dr. Perry: At this stage, what would you suggest in terms of treatment given the extensive nature of this young woman’s disease?
Dr. Schiffrin: Debulking.
Dr. Perry: Would anyone not operate at this point? Or do you think the right thing to do is to debulk as much disease as we can?
All heads nod.
After α- and β-blockade she underwent debulking surgery where a 80×40×22 mm tumor adjacent to left adrenal was resected along with affected lymph nodes.
Dr. Schiffrin: Perhaps for those who are not used to treating these patients, can you explain why you proceed with the phenoxybenzamine first and introduce the β-blocker shortly after?
Dr. Perry: So, the danger in a patient like this would be that if they are given unopposed β-blockade you may have profound α-mediated vasoconstriction and precipitate a crisis and that can be fatal. So, there is a real danger of giving the wrong agent in the wrong order. The options would be phenoxybenzamine and doxazosin. Phenoxybenzamine is long-acting and noncompetitive and is only inactive once the receptor becomes internalized. So that may be a safer approach to α-blockade preoperatively than doxazosin, although there are more symptoms associated with it and long-term phenoxybenzamine is not a particularly pleasant medication to take.
Prof Patrick O’Dwyer: We did a laparoscopic resection. We removed all her para-aortic and paracaval lymph nodes from the iliacs right up to the diaphragmatic crus, removing this, as you can see, with the vein. We divided the left renal vein. We removed it all laparoscopically and she was in hospital for 24 hours postoperatively with a noneventful recovery.
Dr. Schiffrin: During the manipulation of the tumor, were there any arrhythmias?
Prof O’Dwyer: No. We have done >100 pheochromocytomas or paragangliomas and we have not had a serious event in anyone. No arrhythmias. This is because the laparoscopy is so gentle on these tissues
Prof Anna Dominiczak: Even in old times when we did open surgery, medically well-prepared patients, well α-blocked patients, did not have any tachycardias, arrhythmias, or blood pressure rises. Because if you give enough phenoxybenzamine nothing happens.
Prof. O’Dwyer: We did have 1 arrest, Anna, at open surgery on the table.
Prof Dominiczak: That was not my patient.
Pathological examination of the resected tumor revealed infiltrating islands of solid cellular sheets of tumor cells, which had round vesicular nuclei and eosinophilic granular cytoplasm. The tumor’s immunohistochemical staining was positive for chromogranin and synaptophysin. The Ki-67 proliferation index was variable, being <1% in some areas and between 2% and 3% in others. Infiltration into fat, vascular invasion, and involvement of local lymph nodes was evident.
The panel were asked about their suggestions for further treatment, with the patient having undergone debulking surgery though with disease still present.
Dr Schiffrin: mIBG treatment.
Dr Perry: Would anyone consider chemotherapy at this stage?
Dr Perry: Would anyone watch and wait?
Heads shaking “No”
Since her surgery 20 months ago she has had 3 courses of 131I mIBG (10 000 MBq on each occasion) and has tolerated this well, allowing her to return to her studies. Her disease is stable in terms of biochemistry and disease bulk, with most recent 24-hour urinary norepinephrine being recorded at 987 nmol/24 hour and 24-hour free normetanephrine 4198 nmol/24 hour. Despite there being no clear family history of neuroendocrine tumors, genetic testing revealed a pathogenic mutation in the succinate dehydrogenase B (SDHB) gene, which is predicted to affect the normal splicing of exon 1. This was later found in other members of her paternal family.
Dr Schiffrin: I would like to hear a little bit more about genes and mutations and pheochromocytoma.
Dr Perry: I think it is important here to consider the approach to genetic testing. You may consider screening for most of the known genetic mutations, looking in particular for RET, SDHB, SDHD, von Hippel-Lindau (VHL); however in this patient I think you would predict that a mutation in the SDHB gene would be the most likely genetic predisposition to pheochromocytoma. This is based on her having abdominal disease with metastatic spread, rather than it being multicentric, and the biochemical phenotype was norepinephrine, rather than epinephrine, secreting. I think that takes you more toward an SDHB mutation than SDHD and away from RET; it is less likely to be a VHL mutation as there are no other associated features or relevant family history. As would be applicable to any other investigation, I think that there is value in identifying the most appropriate initial investigation, rather than a broad approach to screening for all the genetic abnormalities. And if it were not a SDHB or SDHD mutation, you can start to think of other possibilities,
Dr Schiffrin: The association with thyroid cancer and the RET gene mutations?
Dr Perry: There was no history in the family or the patient to suggest multiple endocrine neoplasia type 2, or features of medullary thyroid cancer.
Dr Schiffrin: Is there any reason for looking at the armpits of patients who have pheochromocytoma or possible pheochromocytoma?
Dr Perry: It is always worth considering the phenotype of neurofibromatosis type 1 (NF-1), looking for café au lait patches and axillary freckling. NF-1 is very interesting because I think if you have NF-1 and a pheochromocytoma, the chance, we are told, of malignancy is higher than were it to be a sporadic pheochromocytoma. Perhaps as many as 6% of NF-1 patients develop pheochromocytomas, depending on which series you look at. The interesting question is how best to identify disease early; many NF-1 patients are only screened by asking them whether they have high blood pressure. That may not be sufficient.
Prof Dominiczak: I have an additional question. She is now 22. You have done debulking. You have done the treatment. She is likely to come to your clinic in a year or 2 to ask you, “Doctor, should I become pregnant?” What are you going to say?
Dr Perry: I think there is a danger in a future pregnancy and we would be concerned were she to plan this. We have had at least 1 VHL patient whose disease accelerated in the context of pregnancy. There would have to be a careful discussion of the associated risks.
Prof. Dominiczak: Another related question. We had a patient with this mutation discovered during her first pregnancy and this was a new mutation. This must be very rare in this genetic presentation. In your looking through the literature, have you seen many new mutations in SDHB?
Dr Perry: We have several families with the same SDHB mutation and the reason I think we are accumulating considerable experience locally is that we seem to have an SDHB founder mutation in the West of Scotland.
Mr Marc de Buyzere: In older literature, we learn when you have syndromic paragangliomas there was a kind of association possible with hemangioblastomas. Are there still arguments today that there is still an association?
Dr. Perry: There is no doubt that carriers of the VHL mutation could develop both pheochromocytoma and hemangioblastoma. I have seen a similar presentation in a young man with VHL and bilateral pheochromocytoma and again a norepinephric secretory phenotype in association with hemangioblastomas and renal cell carcinoma. There are of course also ocular manifestations. So, I think a full history is undoubtedly appropriate and in someone like this you may be guided toward the test for the most likely mutation.
Pheochromocytomas are tumors arising from the chromaffin cells of the adrenal medulla. Paragangliomas also arise from chromaffin cells but in extra-adrenal tissue, mainly along the sympathetic and parasympathetic chains. Both tumors are extremely rare; their combined incidence is ≈8 per 100 000 patient years,1 whereas the prevalence of pheochromocytoma and paraganglioma in patients with hypertension in outpatient clinics varies between 0.2% and 0.6%.2–4 However, the incidence at postmortem is higher suggesting that these tumors are under diagnosed; undiagnosed tumors may be found in 0.05% to 0.1% of patients.5–7 A recent Endocrine Society Clinical Practice Guideline provided clear guidance on diagnosis and treatment of these rare tumors.8
The majority of pheochromocytoma and paraganglioma are sporadic; however, a significant proportion arise because of underlying germline mutations. For example, recent studies estimate that between 30% to 50% of paragangliomas and up to 20% of pheochromocytomas may be associated with an inherited syndrome.9 Hereditary pheochromocytomas are associated with multiple endocrine neoplasia type 2, VHL syndrome, and NF-1. The estimated frequency of pheochromocytomas in these disorders is 10% to 20% in VHL, 50% in multiple endocrine neoplasia type 2, and 0.1% to 6% in NF-1.10,11 Hereditary paragangliomas are most often associated with mutations in genes encoding or stabilizing the SDH enzyme complex (SDHB, SDHD, SDHC, and SDHA), which forms the mitochondrial complex 2 and links the Krebs cycle to electron transport,12 whereas mutations in other genes that have been identified as predisposing to pheochromocytoma and paraganglioma include SDHAF2, MAX, and TMEM127.13
Overall, the risk of malignancy, defined as the presence of metastases in nonchromaffin tissue, is relatively low, with prevalence between 10% and 17%.14,15 The incidence of malignancy in patients with mutations in the B subunit of SDH is reported as 17%, with disease presenting most often as abdominal norepinephrine-secreting paraganglioma; SDHD mutations are more frequently manifest as multifocal paraganglioma, often in the head and neck, and may be less frequently associated with malignancy.16
Management in such cases is challenging and there is limited clinical trial evidence to support the value of therapeutic interventions such as 131I mIBG. A recent meta-analysis of the efficacy of 131I mIBG in metastatic pheochromocytoma found values for complete response, partial response, and stable disease of 0.02, 0.27, and 0.41 for tumor volume and of 0.10, 0.43, and 0.12 for biochemical response.17 There are, however, no large randomized controlled trial data to support its efficacy. Chemotherapy may also be considered in the form of cyclophosphamide, vincristine, and dacarbazine, with a trial of 18 patients finding complete response in 11%18 and a more recent meta-analysis suggesting partial response in terms of tumor volume and catecholamine excess of ≈40%.19 There is now early experience of tyrosine kinase inhibitors such as sunitinib in the treatment of metastatic disease. The First International Randomized Study in Malignant Progressive Pheochromocytoma and Paraganglioma (FIRSTMAPP) is a randomized, double-blind, multicenter study, which aims to determine the efficacy of treatment with sunitinib in patients with malignant pheochromocytoma.
Prognosis in patients presenting with malignant disease is variable. The overall 5-year survival may be <50%; however, the rate of progression of disease is unpredictable; Hescot et al20 demonstrated a 50% progression-free survival at 1 year in asymptomatic patients presenting with metastatic pheochromocytoma who received no treatment.
Here, we describe a young woman who presented with metastatic paraganglioma in the context of an SDHB mutation, but who has responded well to a combination of debulking surgery and repeated doses of 131I mIBG. Future therapeutic options include further 131I mIBG therapy, combination chemotherapy, or experimental treatments (eg, Sunitinib); however, none will afford the possibility of cure and will require careful consideration of risks versus benefits.
We thank Dr Lorna Cooper (Department of Pathology, Southern General Hospital, Glasgow, UK) for provision of histology slides.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
- © 2014 American Heart Association, Inc.
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